Formulation and Evaluation of Controlled
Release Matrices of Selected Propionic Acid
Derivatives
A Thesis Submitted
To
Gomal University, D.I. Khan
In partial fulfillment of the requirements for the degree of
DOCTOR OF PHILOSOPHY
(Pharmaceutics)
By
Abdul Wahab
B. Pharm.
Department of Pharmaceutics, Faculty of Pharmacy
Gomal University, D.I. Khan, KPK, Pakistan
(2006-2010)
Formulation and Evaluation of Controlled
Release Matrices of Selected Propionic Acid
Derivatives
A Thesis Submitted
To
Gomal University, D.I. Khan
In partial fulfillment of the requirements for the degree of
DOCTOR OF PHILOSOPHY
(Pharmaceutics)
By
Abdul Wahab
B. Pharm.
Department of Pharmaceutics, Faculty of Pharmacy
Gomal University, D.I. Khan, KPK, Pakistan
(2006-2010)
In the name of Allah, the Most Merciful, the Most
Beneficent
“He who creates everything from nothing and
creates all things with the knowledge of what will
happen to them”
DECLARATION
I hereby declare that this Ph.D thesis entitled “Formulation and Evaluation of
Controlled Release Matrices of Selected Propionic Acid Derivatives” is my own
original piece of work and it has not been published anywhere else previously.
Abdul Wahab
Faculty of Pharmacy,
Gomal University,
D.I. Khan, Pakistan
CERTIFICATE OF APPROVAL FROM
SUPERVISOR
The thesis entitled “Formulation and Evaluation of Controlled Release Matrices
of Selected Propionic Acid Derivatives” prepared by Mr. Abdul Wahab under
my guidance in partial fulfillment of the requirements for the degree of Doctor of
Philosophy (Pharmaceutics) is hereby approved for the award of Degree of Doctor
of Philosophy in Pharmaceutics.
.
Prof. Dr. Gul Majid Khan
Research Supervisor
CERTIFICATE OF APPROVAL
This thesis entitled “Formulation and Evaluation of Controlled Release
Matrices of Selected Propionic Acid Derivatives” submitted by Abdul Wahab is
hereby approved & recommended as partial fulfillment for the award of Degree of
Doctor of Philosophy in Pharmaceutics.
1- ______________________
Prof. Dr. Gul Majid Khan
Research Supervisor
2- ______________________
Internal Examiner
3- ______________________
External Examiner
4- ______________________
Prof. Dr. Gul Majid Khan
Dean Faculty of Pharmacy
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pkaistan
To
MY PARENTS
Whose foresight, love, zeal to educate and moral support have brought me
to the position where I am today
CONTENTS
Acknowledgement i
Objectives ii
Hypothesis ii
Specific aims ii
Abstract iv
List of Abbreviations vi
List of Figures viii
List of Tables xiv CHAPTER 1
INTRODUCTION Part-1
INTRODUCTION 1
1.1 Drug Delivery 1
1.2 Drug Delivery systems 2
1.2.1 Traditional or conventional or immediate release drug delivery systems 2
1.2.2 Modified release drug delivery systems 2
1.2.2.1 Controlled release drug delivery Systems 2
1.2.2.1.1 Reservoir or membrane controlled systems 5
1.2.2.1.2 Osmotic pump systems 6
1.2.2.1.3 Ion-exchange resins systems 7
1.2.2.1.4 Matrix tablets systems 8
1.2.2.1.5 Oral controlled drug delivery 12
1.2.2.1.6 Concepts in oral controlled release 15
1.3 Preparation of Matrix tablets 16
1.3.1 Direct compression method 17
1.3.2 Wet granulation method 18
1.4 Release mechanism of drug from matrix tablets or systems 19
1.4.1 Diffusion 20
1.4.2 Swelling 23
1.4.3 Erosion 23
1.5 Factors affecting release of drug from matrix tablets or systems 24
1.5.1 Formulation variables 24
1.5.1.1 Particle size of drug 25
1.5.1.2 Effect of drug-polymer ratio 25
1.5.1.3 Type of polymer 26
1.5.1.4 Particle size of polymer 26
1.5.1.5 Effect of fillers 27
1.5.1.6 Impact of ion-exchange resins 27
1.5.1.7 Surfactants 27
1.5.2 Process variables 28
1.5.2.1 Compression force 28
1.5.2.2 Tablets size 28
1.5.2.3 Tablets shape 28
1.6 Polymers used in the formulation of matrix tablets 29
1.6.1 Polymer 29
1.6.1.1 Polymer Ethocel® 30
1.7 Excipients 32
1.7.1 Lactose 33
1.7.2 Magnesium stearate 34
1.7.3 Methocel® 34
1.7.4 Starch 35
1.7.5 Carboxymethylcellulose (CMC) 35
1.8 Solid dispersions 36
1.8.1 Carrier used in solid dispersions 37
1.8.2 Preparation of solid dispersions 38 INTRODUCTION
Part-2 1.9 Nanoparticles 38
1.9.1 Application of nanoparticles 40
1.9.2 Polymers used in nanoparticle preparation 41
1.9.2.1 Poly (glycerol adipate) PGA 42
1.9.3 Nanoparticle preparation methods 43
1.9.3.1 Solvent Evaporation method 43
1.9.3.2 Interfacial Polymer Deposition Method (IPD) 44
1.9.3.3 Spray Drying Method 45
1.9.3.4 Salting out Method 45
1.9.3.5 Supercritical fluid expansion method 45
1.9.3.6 Complex Coacervation Method 46
1.9. 4 Drug Release Mechanisms 46
1.9.5 Methods of determination of drug release 46
1.10 Model drugs 46
1.10.1 Ketoprofen 46
1.10.1.1 General description and properties 47
1.10.1.2 History and synthesis 48
1.10.1.3 Clinical and pharmacological aspects of Ketoprofen 51
1.10.1.4 Anti-inflammatory effects 52
1.10.1.5 Antipyretic and analgesic effect 52
1.10.1.6 Mechanism of action 52
1.10.1.7 Therapeutic uses 54
1.10.1.8 Contraindications 54
1.10.1.9 Adverse reactions of ketoprofen 54
1.10.1.10 Ketoprofen interaction with other drugs 55
1.10.1.11 Pharmacokinetic of ketoprofen 55
1.10.1.12 Pharmaceutics of ketoprofen 56
1.10.1.13 Dose of ketoprofen for different disease conditions 57
1.10.2.1 General properties and description of ibuprofen 58
1.10.2.2 History and synthesis of ibuprofen 59
1.10.2.3 Mechanism of action 59
1.10.2.4 Therapuetic uses of ibuprofen 60
1.10.2.5 Pharmacokinetic of Ibuprofen 61
1.10.2.6 Contraindications 61
1.10.2.7 Adverse reactions of ibuprofen 62
1.10.2.8 Interaction of ibuprofen 62 CHAPTER 2
REVIEW OF LITERATURE
REVIEW OF LITERATURE 63
2.1 MODIFIED RELEASE FORMULATION 63
2.1.1 Polymers for modified release formulations 63
2.1.2 Development of modified release formulation 65
2.1.3 Formulation development via direct compression method 67
2.1.4 Drug release mechanism and kinetics 68
2.1.5 Ibuprofen and Ketoprofen modified release formulations 69 CHAPTER 3
MATERIALS AND METHODS Part-1
MATERIALS AND METHODS 76
3.1 MATERIALS 76
3.1.1 Chemical and reagent 76
3.1.2 Instruments and equipments 76
3.1.3 Animals 77
3.2 METHODS 77
3.2.1 Pre-formulation Studies 77
3.2.1.1 Drugs identity conformation 77
3.2.1.2 Percentage purity determination of model drugs 78
3.2.1.3 Particles size analysis 78
3.2.1.4 Selection of suitable wave length of model drugs 78
3.2.1.5 Powder‟s flow properties 79
3.2.1.6 Angle of Repose 79
3.2.1.7 Compressibility index and Hausner Ratio 80
3.2.1.8 Differential scanning calorimetry (DSC) studies 81
3.2.1.9 Fourier transform Infrared (FT-IR) studies 81
3.2.1.10 Preparation of Phosphate Buffer solutions (pH 7.4) 81
3.2.1.11 Construction of standard curves 82
3.2.1.12 Calculation of concentration of Ibuprofen and Ketoprofen 82
3.2.1.13 Solubility study 82
3.2.1.14 Preparation of solid dispersions 83
3.2.1.15 Preparation of physical mixtures 83
3.2.1.16 Evaluation of solid dispersions and physical mixtures 84
3.2.1.16.1 Determination of drug content 84
3.2.1.16.2 Differential scanning calorimetry (DSC) studies 85
3.2.1.16.3 Fourier transform Infrared (FT-IR) studies 85
3.2.1.16.4 X-ray powder diffractometory studies 85
3.2.1.16.5 Scanning electron microscope (SEM) analysis 85
3.2.1.16.6 Solubility measurement 86
3.2.1.16.7 In –vitro dissolution studies 86
3.2.2 Formulation studies 86
3.2.2.1 Formulation of matrix tablets containing Ibuprofen and ketoprofen by
direct compression method
86
3.2.2.2 Physical evaluation of matrix tablets 88
3.2.2.2.1 Weight variation test 88
3.2.2.2.2 Thickness and diameter 89
3.2.2.2.3 Crushing strength or Hardness test 89
3.2.2.2.4 Friability test 89
3.2.2.2.5 Content Uniformity Assay 89
3.2.2.3 In vitro dissolution studies 90
3.2.2.4 Drug Release kinetics 91
3.2.2.4.1 Zero-order kinetics 91
3.2.2.4.2 First-order kinetics equation 92
3.2.2.4.3 Hixon Crowel‟s Equation (Erosion model) 92
3.2.2.4.4 Higuchi‟s Squre of Time Equation (Diffusion model) 93
3.2.2.4.5 Power law equation or Korsmeyer- Peppas equation for mechanism of
drug release
93
3.2.2.5 Testing dissolution equivalency 94
3.2.2.6 Accelerated stability and reproducibility studies 95
3.2.2.7 Preparation of matrix tablets containing solid dispersions of model
drugs
96
3.2.2.8 In-vivo evaluation 96
3.2.2.8.1 Study Protocol and Design 96
3.2.2.8.2 Animals used for in-vivo studies 97
3.2.2.8.3 Food, animal housing and maintenance for rabbits 97
3.2.2.8.4 Tablets administration to rabbits 97
3.2.2.8.5 Blood sample‟s withdrawal or collection from rabbits 97
3.2.2.9 Extraction of drugs from plasma 98
3.2.2.9.1 Extraction procedure for Ibuprofen and Ketoprofen from plasma 98
3.2.2.10 HPLC analysis of drugs in rabbit plasma 99
3.2.2.10.1 Analysis of plasma Ibuprofen concentration 99
3.2.2.10.2 Analysis of plasma Ketoprofen concentration 100
3.2.2.11 Pharmacokinetic analysis 100
3.2.2.11.1 In-vitro and In-vivo correlation 101
3.2.2.12 Statistical analysis 101 CHAPTER 4
RESULTS AND DISCUSSION Part-1
RESULTS AND DISCUSSION 102
4.1 Drugs identity conformation studies 102
4.2 Particle size analysis 104
4.3 Selection of suitable wavelength for model drugs (Ibuprofen and
Ketoprofen)
105
4.4 Powder‟s flow properties 106
4.5 Differential scanning calorietry (DSC) studies 110
4.6 Fourier transform infrared (FT-IR) studies 112
4.7 Construction of standard curves 114
4.8 Solubility study 116
4.9 Preparation of solid dispersions 117
4.9.1 Solubility study of solid dispersion 118
4.9.2 Differential scanning calorimetry (DSC) studies 118
4.9.3 Fourier transform Infrared (FT-IR) studies 120
4.9.4 X-ray diffractometry studies 122
4.9.5 Scanning electron microscope analysis 124
4.9.6 In –vitro dissolution studies 126
4.10 Physicochemical Assessment of Matrix Tablets 128
4.11 In-vitro dissolution study of directly compressed matrix tablets 133
4.11.1 Effect of Ethocel® viscosity grade (Molecular weight) on drug release 133
4.11.2 Effect of drug-to- polymer (D: P) ratio on release rate 135
4.11.3 Ethocel® standard premium vs. Ethocel® standard FP premium 138
4.11.4 Influence of co-excipietns on drug release rate 140
4.12 In-vitro release study of the matrix tablets containing solid dispersions 149
4.13 Analysis of drugs release kinetics 150
4.14 Selection of the optimized test tablets 168
4.15 Reproducibility and accelerated stability study 168
4.16 In-vivo evaluation 174
4.17 In-vitro and in-vivo correlation 186 CHAPTER 5
MATERIALS AND METHODS Part-2
MATERIALS AND METHODS 189
5.1 MATERIALS 189
5.1.1 Chemical and reagent 189
5.1.2 Instrumentation and equipments 189
5.2 METHODS 190
5.2.1. Nanoparticles formulation 190
5.2.1.1 Differential scanning calorimetry (DSC) studies 190
5.2.1.2 Fourier transform Infrared (FT-IR) studies 190
5.2.1.3 Preparation of Stock Solution 190
5.2.1.4 Preparation of Empty Nanoparticles 190
5.2.1.5 Preparation of drug-loaded particles 190
5.2.1.6 Separation of free drug from nanoparticles 191
5.2.1.7 Freeze-drying study 191
5.2.1.8 Drug Release study 192
5.2.1.9 HPLC analysis of the nanoparticles 192
5.2.1.10 Preparation of standard solutions and construction of calibration curves 193
5.2.1.11 Determination of drug loading 195 CHAPTER 6
RESULTS AND DISCUSSION Part-2
NANOPARTICLES RESULTS AND DISCUSSION 196
6.1 Drug-polymer interaction studies 196
6.1.1 Differential scanning calorimetry (DSC) 196
6.1.2 Fourier transforms infrared spectroscopy (FT-IR) 198
6.2 Preparation of empty and drug loaded nanoparticles 201
6.2.1 Physical evaluation of nanoparticles 202
6.3 Drug loading 205
6.4 In-vitro drug release study 206
OVER ALL CONCLUSION 209
REFERENCES 211
LIST OF PUBLICATIONS 249
ACKNOWLEDGEMENTS
For most I am humbly obliged to ALLAH ALMIGHTY, who helps me always in every step of
my life. Salam & respect for the HOLY PROPHET MUHAMMAD (SAW), who is the real
code of the ethics.
I do wish to express my real feelings, appreciations and thanks to my supervisor and mentor,
Prof Dr. Gul Majid Khan for his continuous academic, moral and emotional support and for his
valuable advices, nice attitude and encouragement throughout my research work. Special thanks
to him for giving me the opportunity to work in his research group and for giving me the
guidance to grow into an independent researcher. He has transferred me his courage and
determination through valuable discussion and friendly dealings, which I will try to maintain.
It is a delightful moment for me to put into words all my gratitude to Dr. Paraskevi Kallinteri,
who supervised me for “Nanoparticles part of my research work” at University of KENT, UK.
I highly acknowledge the Higher Education Commission of Pakistan for granting me PhD
Fellowship and financial assistance for my research work and for my visit to UK.
I am obliged to Dr. Nadeem Irfan Bukhari, Asstt. Professor, University College of Pharmacy,
Punjab University Lahore for extending his kind co-operation in calculation of
Pharmacokinetics Parameters, Prof Dr. Nisar-ur-Rehman, Comsats Abbotabad, and Mr.
Mubasher Ali Hussain Abid & Muhammad Amir of WELSHIRE Pharmaceutical, Laboratory,
Lahore for their assistance regarding HPLC analysis of plasma samples.
I am indebted to my teachers viz. Prof Dr. Muhammad Farid Khan (Former-Vice Chancellor),
Mr. Satar Bakhash Awan, Mr. Nusrat Ullah, Mr. Anayat Ullah Bhatti, Mr. Fayaz Ahmad and
Mr. Fazal Rehman for their valuable suggestions and continuous encouragement.
My warmest thanks go to all of my friends and research fellows at the Faculty of Pharmacy,
especially to Muhammad Akhlaq, Nauman Rahim, Abid Hussain, Hroon Khan, Saif Ullah
Mehsud, Tahir Saleem Faiz, Kamran Ahamad Khan, Asium-ur-Rehman, Kafayt Ullah Shah,
Sheik Abul Rahsid, Hashmat Ullah, Asif Nawaz, Nasim Ullah, Mukhtyar, Fakhar Uddin, and
Alm Zaib for all of their cheer-ups and many unforgettable moments with them.
My deepest thanks are also for the lab and office staff viz. Ihsan Ullah Khan (Engr), Mirzali
Wazir, Mushtaq Ahamad, Asif, etc.
Words can‟t express my heartfelt appreciation to my ever loving and affectionate Daddy (Dr.
Saleem Mar Jan), Mummy, my wife, brothers (Abul Rahim Khan Mehsud and Rahim Uddin
Khan Mehsud), father-in-law (Mr. Muhammad Alam Khan Mehsood, Additional Registrar,
Gomal University), mother-in-law, cousins (Mirdil Khan, Najeeb and Falak Naz Mehsud), Dr.
Shafiullah Khan, Samiullah Khan, Sajid Anwar and all other family members for their life time
support, everlasting love, encouragement and prayers, without which I would not have achieved
my goal and to stand where I am today.
Abdul Wahab
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page ii
OBJECTIVES, HYPOTHESIS AND SPECIFIC AIMS
Objectives
The objectives of this research work were:
To develop and evaluate controlled release matrix tablets of two commonly used
non-steroidal anti-inflammatory drugs, Ibuprofen and Ketoprofen, using
hydrophobic matrix system.
To develop solid dispersions of the model drugs (Ibuprofen and Ketoprofen).
To develop nanoparticle of Ibuprofen, Ibuprofen sodium salt and Ketoprofen.
Hypothesis
Ethylcellulose Ether Derivatives Polymers (Ethocel® standard premium and
Ethocel® standard FP premium) may produce 24 hours controlled release matrix
tablets of Ibuprofen and Ketoprofen.
Glucosamine HCl may be used for the preparation of solid dispersions to enhance
the dissolution rate and solubility of sparingly soluble drugs, Ibuprofen and
Ketoprofen.
Novel polymer poly (glycerol adipate) and its acylated derivatives may be used to
develop nanoparticles of Ibuprofen, Ibuprofen sodium salt and Ketoprofen.
Specific Aims
To perform pre-formulation studies of the model drugs (Ibuprofen and
Ketoprofen).
To prepare controlled-release matrix tablets of Ibuprofen and Ketoprofen.
To study the effect of the following variables on the release rate and release
mechanisms of the respective drugs from the test tablets.
Ethylcellulose Ether Derivatives Polymer of different viscosity grades
(Ethocel® standard premium and Ethocel
® standard FP premium).
Different Drug-to-Polymer
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page iii
Partial replacement of primary filler (lactose) with co-excipients such as
hydroxypropylmethylcellulose (HPMC), corboxymethylcellulose (CMC)
and starch.
To determine the quality of newly developed formulations by using different
pharmacopeial and non-pharmacopeial tests.
To compare the in-vitro release profiles of the optimized test tablets of the model
drugs.
To conduct the stability studies of the selected/optimized test tablets of Ibuprofen
and Ketoprofen in ambient and accelerated conditions.
To compare the in-vitro dissolution profiles of the optimized test tablets with the
available marketed brands.
To evaluate the in-vivo pharmacokinetic parameters of the optimized test tablets
of model drugs (Ibuprofen and Ketoprofen) and compare with reference SR
tablets available in market.
To develop in-vitro and in-vivo correlation between test formulations and their
reference formulations.
To develop solid dispersions of the respective drugs.
To develop nanoparticles of Ibuprofen, Ibuprofen sodium salt and Ketoprofen.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page iv
ABSTRACT
Ibuprofen and Ketoprofen are propionic acid derivatives and belong to the non-steroidal
anti-inflammatory group of drugs. These are also used as analgesics, antipyretics and as
adjuncts in steroid therapy, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis,
acute musculoskeletal injury and for systematic relief of dysmenorrhea.
Due to their short half-life, dosage frequency, patient non-compliance and side effects
such as gastrointestinal disturbance, peptic ulceration and gastrointestinal bleeding, they
are considered to be good candidates for formulation into controlled release dosage
forms.
Optimization of a drug substance through the determination and/or definition of some
physical and chemical properties are mandatory in the development of stable, effective,
safe and reproducible dosage form. Therefore, during our pre-formulation work, our
efforts encompassed the detailed study of parameters such as optical rotation, melting
point, percentage purity, particle size, size distribution, solubility at different
temperatures and pH, IR spectra for conformation, λ max determination, micromeritics
properties determination of model drugs, polymers and excipients used in this research
work and interaction conformation studies of drugs with polymers and co-excipients,
using DSC and FT-IR. During this studies attention was also focused on some
contributing approaches to improve the dissolution rates of Ibuprofen and Ketoprofen,
which are sparingly soluble drugs. For this purpose solid dispersions of Ibuprofen and
Ketoprofen were prepared by solvent evaporation technique, using Glucosamine HCl as
dispersion carrier. The drug-carrier interactions were investigated through SEM, DSC,
FT-IR and X-ray diffraction analysis. The influence of proportional amount of the
carrier on the dissolution rate of Ibuprofen and Ketoprofen were also investigated. The
results obtained did not show any chemical decomposition or well defined interaction
between drugs and carrier, indicating a good compatibility among them. The solid
dispersions with Glucosamine HCl demonstrated a marked increase in the dissolution
rate and solubility of Ibuprofen and Ketoprofen. The enhancement in the dissolution
rate and solubility of Ibuprofen and Ketoprofen could be attributed to several factors
such as improved wettability, local solubilization, conversion from crystalline form to
amorphous form and drugs particle size reduction.
In Part-1 of my research work conducted at Drug Delivery Research Centre, Faculty of
Pharmacy, Gomal University, D. I. Khan, Pakistan, directly compressed controlled
release matrix tablets, using granular Ethocel® standard premium and Ethocel
® standard
FP premium were designed, prepared and evaluated in-vitro, in the first instance,
followed by in vivo evaluation of the best products. Physicochemical assessment of the
formulated tablets was performed, using different physicochemical, dimensional and
quality control tests such as weight variation, thickness and diameter, hardness test,
friability test, content uniformity, disintegration and dissolution testing. Results for all
these tests were found within acceptable range and tablets meet the pharmacotechnical
requirments. The effect of different viscosity grades of Ethocel® on the tablets
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page v
characteristics, drug release rates, release patterns and release kinetics were
investigated. Ethocel® with lower viscosity grades showed good compressibility,
resulting in harder tablets. Particle size and amount of polymer used were found to be
the determining factors in controlling the release rates of Ibuprofen and Ketoprofen
from the tablets. The mechanism of drug release from the tablets seemed to be
changeable from formulation to formulation, depending on the amount of Ethocel® and/
particle size of the polymer used.
Our research also focused on the effect of partial replacement of primary excipient
(lactose) by various co-excipients such as hydroxypropylmethylcellulose (HPMC),
starch and corboxymethylcellulose (CMC) on the release rate and mechanism of drugs
release from the matrix tablets. All of the co-excipients used enhanced the release rates
to different extent.
In-vitro studies revealed that tablet formulations containing polymer Ehocel® standard 7
FP premium, at D: P ratio 10: 3 were the best amongst the formulations for both drugs
(Ibuprofen and Ketoprofen) because they provided better release patterns with optimum
amount of the drugs released in 24 hours; and due to their prolonged release rates with
either zero or near to zero-order release kinetics.
The optimized Ibuprofen and Ketoprofen matrix tablets formulations were further used
for in-vitro and in-vivo bioavailability-bioequivalence and stabilities studies as
compared to the comparative studies with SR Ibuprofen and Ketoprofen available in
market and stability studies. Stability studies were performed for the optimized
formulation for one year in ambient and accelerated condition and the tablets were re-
evaluated physicochemicaly at different interval of time. The results obtained showed
maximum stability for one year.
The comparative in-vitro dissolution studies showed prolonged release rate of test
formulations as 87.66% and 95.4% of Ibuprofen and Ketoprofen were release after 24
hours, respectively, while all of the drugs were released from the market SR
formulations well before 24 hours.
In-vivo studies of the optimized tablets were conducted; using HPLC based modified
methods for analysis of Ibuprofen and Ketoprofen in rabbit‟s plasma. Measured plasma
concentrations of the drugs were used in calculation of pharmacokinetic parameters
including Tmax, Cmax, AUC0-t, MRT0-t, t1/2, Vd, Vdss, Kel and Cltotal for the CR test
tablets and reference SR tables of Ibuprofen and Ketoprofen, using PK WinNolin
software. Significantly prolonged Tmax, t1/2 and MRT0-t of the test CR matrix tablets of
model drugs indicate smooth and extended absorption phase of the drugs under
investigation. As compared to reference SR tablet formulations the test CR tablets
showed better and linear in-vitro and in-vivo correlation.
In Part 2nd
of my research work conducted at the at University of KENT, UK,
Nanoparticles were also developed of the model drugs (Ibuprofen, Ibuprofen sodium
salt and Ketoprofen), which were evaluated for their capability prolonging the drug
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page vi
realse, using a novel functionalized biodegradable polymers PGA (poly glycerol
adipate) and its acylated derivatives, such as 40% C-18 PGA and 100% C-18 PGA by
interfacial deposition method. Before development of nanoparticles, different
techniques such as DSC and FT-IR were used for determination of drug-polymer
interactions. After development of nanoparticles different physicochemical
characteristics were determined, such as zeta potential, particle size, polydispersity
index and in-vitro drug release study was conducted for 17 days. These polymers are
able to self-assemble into well-defined particles of relatively small size and high
homogeneity with an ability to entrap Ibuprofen, Ibuprofen sodium salt and Ketoprofen
with high efficiency.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page vii
LIST OF ABREVIATIONS
CR Controlled release
IR Immediate release
SR Sustained release
ER Extended release
API Active pharmaceutical ingredient
IBF Ibuprofen
KTP Ketoprofen
SDs Solid Dispersions
DC Direct compression
IDP Interfacial deposition
MR Modified release
NSAIDs Non-steroidal anti-inflammatory drugs
USP United states pharmacopeia
BP British pharmacopeia
RH Relative humidity
GLP Good laboratory practice
IVIVC In-vitro and in-vivo correlation
HPMC Hydroxypropylmethylcellulose
CMC Corboxymethylcellulose
HCL Hydrochloric acid
HPLC High performance liquid chromatography
MDT Mean dissolution time
MEC Minimum effective concentration
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page viii
ICH International Commission on Harmonization
MTC Minimum effective concentration
PKa Ionization constant
UV Ultra violet
AUC Area under curve
Cltotal Total clearance
Cmax Maximum plasma concentration
Tmax Time to maximum plasma concentration
MRT Mean residence time
Kel Elimination rate constant
t1/2 Half-life
Vd Volume of distribution
H Hour
G Gram
µg Microgram
µL Microliter
Kg Kilogram
L Liter
Mg Milligram
Ml Milliliter
µm Micrometer
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page ix
LIST OF FIGURES
Figure # Title Page #
Figure 1.1. Schematic representation of reservoir controlled system, matrix
system and osmotic system
5
Figure 1.2. Schematic presentation of drug release from reservoir or
membrane controlled drug delivery system.
6
Figure 1.3. Osmotic pump system 7
Figure 1.4. Schematic presentation of Ion-exchange resigns system 8
Figure 1.5. Schematic presentation of non-erodible matrix tablets 11
Figure 1.6. Schematic presentation of erodible matrix tablets 11
Figure 1.7. Plasma drug concentration profile Immediate Release (IR) and
Controlled Release (CR) Formulations, MEC= Minimum
Effective Concentration and MSC= Maximum Safe Concentration
13
Figure 1.8. Schematic presentation of the powder compression process using
a single punch press.
17
Figure 1.9. Presentation of release mechanisms of drug from matrix tablets 20
Figure 1.10. Idealized schematic presentation of leaching-based released
mechanism
22
Figure 1.11. Structure of ethylcellulose 31
Figure 1.12. Structure of lactose 33
Figure 1.13. Structure of Methocele (HPMC) 34
Figure 1.14. Structure of CMC 36
Figure 1.15. (A) Matrix type nanoparticles where the drug molecules are
homogenously dispersed in the matrix, (B) Core shape
nanoparticles, (C) Matrix type nanoparticles in which drug
molecules(crystals) are Imbedded in a polymer matrix.
40
Figure 1.16. Structure of PGA and acylated PGA. 43
Figure 1.17. Schematic presentation of IDP (Interfacial Polymer Deposition
method)
45
Figure 1.18. Structure of ketoprofen 47
Figure 1.19. Ketoprofen Enantiomers 48
Figure 1.20. Ketoprofen synthesized by starting from (3-carboxyl-phenyl)-2-
propionitrile
49
Figure 1.21. Ketoprofen synthesized by starting from 2-(4-amenophenyl)-
propionic acid
50
Figure 1.22. Ketoprofen synthesized by starting from (3-benzoylphenyl)-
acetonitrile
51
Figure 1.23. Prostaglandin (PGs) formation pathaway 53
Figure 1.24. Ketoprofen metabolism pathway 56
Figure 1.25. Structure of Ibuprofen 58
Figure 1.26. Ibuprofen enantionmer 59
Figure 1.27. Synthesis of ibuprofen by Boot process and Hoechst process 60
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page x
Figure 3.1. Schematic representation of angle of repose 79
Figure 3.2. Pharma-test dissolution apparatus 91
Figure 3.3. Marginal ear vein of rabbit 98
Figure 4.1. FT-IR spectra of (a) BP Standard (b) Pure Ibuprofen sample 103
Figure 4.2. FT-IR spectra of (a) BP Standard (b) Pure Ketoprofen sample 103
Figure 4.3. Particle size distribution of Ibuprofen 104
Figure 4.4. Particle size distribution of Ketoprofen 105
Figure 4.5 UV/Visible spectra of Ibuprofen with different wave lengths in
phosphate buffer solution pH 7.4
105
Figure 4.6. UV/Visible spectra of Ketoprofen with different wave lengths in
phosphate buffer solution pH 7.4
106
Figure 4.7. DSC thermogram of pure Ibuprofen (a) and physical mixtures of
Ibuprofen with polymer ethylcellulosel, magnesium stearate,
lactose, using co-excipients; HPMC (b); starch (c); and CMC (d).
110
Figure 4.8. DSC thermogram of pure Ketoprofen (a) and physical mixtures of
Ketoprofen with polymer ethylcellulosel, magnesium stearate,
lactose, using co-excipients; HPMC (b); starch (c); and CMC (d).
111
Figure 4.9. FT-IR spectra of of pure Ibuprofen (a) and physical mixtures of
Ibuprofen with polymer ethylcellulosel, magnesium stearate,
lactose, using co-excipients; HPMC (b); starch (c); and CMC (d).
112
Figure 4.10. FT-IR spectra of pure Ketoprofen (a) and physical mixtures of
Ketoprofen with polymer ethylcellulosel, magnesium stearate,
lactose, using co-excipients; HPMC (b); starch (c); and CMC (d).
113
Figure 4.11. Standard curve for Ibuprofen in phosphate buffer 7.4 114
Figure 4.12. Standard curve for Ketoprofen in phosphate buffer 7.4 115
Figure 4.13. DSC Thermograms of (a) Glucosamine; (b) Pure ibuprofen; (c)
Physical mixture; and (d) Solid dispersions of ibuprofen with
glucosamine.
119
Figure 4.14. DSC Thermograms of (a) Glucosamine; (b) Pure ketoprofen; (c)
Physical mixture; and (d) Solid dispersions of ketoprofen with
glucosamine.
119
Figure 4.15. FT-IR spectra of (a) Glucosamine; (b) Pure ibuprofen; (c)
Physical mixture; and (d) Solid dispersions of ibuprofen with
glucosamine
121
Figure 4.16. FT-IR spectra of (a) Glucosamine; (b) Pure ketoprofen; (c)
Physical mixture; and (d) Solid dispersions of ketoprofen with
glucosamine.
121
Figure 4.17. X-ray diffractograms of (a) Pure Ibuprofen; (b) Physical mixture;
and (c) Solid dispersions of Ibuprofen and glucosamine
122
Figure 4.18 X-ray diffractograms of (a) Pure ketoprofen; (b) Physical mixture;
and (c) Solid dispersions of ketoprofen and glucosamine.
122
Figure 4.19. Scanning electron photomicrographs of (a) Carrier (Glucosamine
HCL); (b) Pure Ibuprofen; (c) Physical mixture of Ibuprofen-
124
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xi
Glucosamine HCL; (d) Solid dispersion of Ibuprofen-
Glucosamine HCL.
Figure 4.20. Scanning electron photomicrographs of (a) Carrier (Glucosamine
HCL); (b) Pure Ketoprofen; (c) Physical mixture of Ketoprofen-
Glucosamine HCL; (d) Solid dispersion of Ketoprofen-
Glucosamine HCL.
125
Figure 4.21. In-vitro dissolution profiles of pure Ibuprofen and physical
mixture with different drug-carrier (Glucosamine HCL) ratio.
126
Figure 4.22. In-vitro dissolution profiles of pure Ibuprofen and solid
dispersions with different drug-carrier (Glucosamine HCL) ratio
127
Figure 4.23. In-vitro dissolution profiles of pure Ketoprofen and physical
mixture with different drug-carrier (Glucosamine HCL) ratio.
128
Figure 4.24. In-vitro dissolution profiles of pure Ketoprofen and solid
dispersion with different drug-carrier (Glucosamine HCL) ratio.
128
Figure 4.25. Release profile of Ibuprofen from Ethocel®
matrices with
different viscosity grades and D: P ratio of 10:3.
134
Figure 4.26. Release profile of Ketoprofen from Ethocel®
matrices with
different viscosity grades and D: P ratio of 10:3.
134
Figure 4.27. Release profiles of Ibuprofen from Ethocel® standard 7 premium
and Ethocel® standard 7 FP premium matrices with different D: P
ratios.
135
Figure 4.28. Release profile of Ibuprofen from Ethocel® standard 10 premium
and Ethocel® standard 10 FP premium matrices with different D:P
ratios.
136
Figure 4.29. Release profiles of Ibuprofen from Ethocel®
standard 100
premium and Ethocel®
standard 100 FP premium matrices with
different D: P ratios.
136
Figure 4.30. Release profiles of Ketoprofen from Ethocel® standard 7 premium
and Ethocel® standard 7 FP premium matrices with different D: P
ratios.
137
Figure 4.31 Release profiles of Ketoprofen from Ethocel®
standard 10
premium and Ethocel®
standard 10 FP premium matrices with
different D:P ratios.
137
Figure 4.32. Release profiles of Ketoprofen from Ethocel®
standard 100
premium and Ethocel®
standard 100 FP premium matrices with
different D: P ratios.
138
Figure 4.33. Release profiles of Ibuprofen from Ethocel® standard 7, 10 and
100 premium and Ethocel® standard 7, 10 and 100 FP premium
matrices with D: P ratio 10:3.
139
Figure 4.34. Release profiles of Ketoprofen from Ethocel® standard 7, 10 and
100 premium and Ethocel® standard 7, 10 and 100 FP premium
matrices with D: P ratio 10:3.
140
Figure 4.35. Influence of partial replacement (30%) of lactose with various co- 143
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xii
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ibuprofen from tablets containing Ethocel® standard 7 premium
with D: P ratio, 10:3.
Figure 4.36. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ibuprofen from tablets containing Ethocel®
standard 7 FP
premium with D: P ratio, 10:3.
143
Figure 4.37. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ibuprofen from tablets containing Ethocel®
standard 10
premium with D: P ratio, 10:3.
144
Figure 4.38. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ibuprofen from tablets containing Ethocel®
standard 10 FP
premium with D: P ratio, 10:3.
144
Figure 4.39. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ibuprofen from tablets containing Ethocel®
standard 100
premium with D: P ratio, 10:3.
145
Figure 4.40. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ibuprofen from tablets containing Ethocel® standard 100 FP
premium with D: P ratio, 10:3.
145
Figure 4.41. Figure 4.41 Influence of partial replacement (30%) of lactose with
various co-excipients (HPMC K100M, CMC and Starch) on
release profiles of Ketoprofen from tablets containing Ethocel®
standard 7 premium with D: P ratio, 10:3.
146
Figure 4.42. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ketoprofen from tablets containing Ethocel®
standard 7 FP
premium with D: P ratio, 10:3.
146
Figure 4.43. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ketoprofen from tablets containing Ethocel®
standard 10
premium with D: P ratio, 10:3.
147
Figure 4.44. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles
of Ketoprofen from tablets containing Ethocel® standard 10 FP
premium with D: P ratio, 10:3.
147
Figure 4.45. Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profile
of Ketoprofen from tablets containing Ethocel®
standard 100
premium with D: P ratio, 10:3.
148
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xiii
Figure 4.46. Figure 4.46 Influence of partial replacement (30%) of lactose with
various co-excipients (HPMC K100M, CMC and Starch) on
release profile of Ketoprofen from tablets containing Ethocel®
standard 100 FP premium with D: P ratio, 10:3.
148
Figure 4.47. Comparative dissolution release profile of Ibuprofen and
Ibuprofen solid desperisons from matrix tablets containing
Ethocel® standard 7 FP premium polymer.
149
Figure 4.48. Comparative dissolution release profile of Ketoprofen and
Ketoprofen solid desperisons from matrix tablets containing
Ethocel® standard 7 FP premium polymer.
150
Figure 4.49. Drug-release profiles for Ibuprofen from test and reference tablets
up to 24 hours.
173
Figure 4.50. Drug-release profiles for Ketoprofen from test and reference
tablets up to 24 hours.
173
Figure 4.51. A representative chromatogram of standard solution consisting of
5µg/mL of Ibuprofen
175
Figure 4.52. A representative chromatogram of Ibuprofen extracted from a
sample of rabbit plasma spiked with 10µg/mL of Ibuprofen
176
Figure 4.53. A representative chromatogram of Ibuprofen extracted from a
sample of rabbit plasma with drawn 4 hours after administration
of Ibuprofen Test tablet.
177
Figure 4.54. A representative chromatogram of standard solution consisting of
5µg/mL of Ketoprofen
178
Figure 4.55. A representative chromatogram of Ketoprofen extracted from a
sample of rabbit plasma spiked with 10µg/mL of Ketoprofen
179
Figure 4.56. A representative chromatogram of Ketoprofen extracted from a
sample of rabbit plasma with drawn 4 hours after administration
of Ketoprofen Test tablet
180
Figure 4.57. Standard curve for Ibuprofen in plasma. 181
Figure 4.58. Standard curve for Ketoprofen in plasma. 181
Figure 4.59. Mean plasma concentration of Ibuprofen from test tablets and
reference tablets (n=12).
182
Figure 4.60. Mean plasma concentration of Ketoprofen from test tablets and
reference tablets (n=12).
183
Figure 4.61. Percent of drug absorbed (Fa, Y-axis) plotted against percent of
drug released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,
12, 18 and 24 hours to show the In-vitro and In-vivo correlation of
Ibuprofen Test tablets
187
Figure 4.62. Percent of drug absorbed (Fa, Y-axis) plotted against percent of
drug released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,
12, 18 and 24 hours to show the In-vitro and In-vivo correlation of
Ketoprfofen Test tablets
187
Figure 4.63. Percent of drug absorbed (Fa, Y-axis) plotted against percent of 188
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xiv
drug released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,
12, 18 and 24 hours to show the In-vitro and In-vivo correlation of
Ibuprofen Reference tablets
Figure 4.64. Percent of drug absorbed (Fa, Y-axis) plotted against percent of
drug released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,
12, 18 and 24 hours to show the In-vitro and In-vivo correlation of
Ketoprofen Reference tablets
188
Figure 5.1 Size Exclusion Chromatography column packed with Sepharose
4B-CL. Column length ~24 cm, diameter 16 mm
191
Figure 5.2 Viva spine Concentrator tubes 192
Figure 5.3 Standard curve for Ibuprofen 193
Figure 5.4 Standard curve for Ketoprofen 194
Figure 5.5 Standard curve for Ibuprofen sodium salt 194
Figure 6.1 DSC thermograms of (a) PGA polymer, (b) Ibuprofen-polymer
(PGA), (C) pure Ibuprofen.
196
Figure 6.2 DSC thermograms of (PGA polymer), (b) Ketoprofen-polymer
(PGA) mixture, (c) pure Ketoprofen.
197
Figure 6.3 DSC thermograms of (a) Ibuprofen sodium salt-Polymer (100%
PGA C-18) mixture, (b) Ibuprofen sodium salt-Polymer
(40%PGA C-18) mixture, (c) Ibuprofen sodium salt-Polymer
(PGA C-18) mixture, (d) Ibuprofen sodium salt pure.
198
Figure 6.4 FT-IR spectra of (a) PGA polymer, (b) Ibuprofen-polymer (PGA)
mixture, (c) pure Ibuprofen.
199
Figure 6.5 FT-IR spectra of (PGA polymer), (b) ketoprofen-polymer( PGA)
mixture, (c) pure Ketoprofen
200
Figure 6.6 FT-IR spectra of (a) Ibuprofen sodium salt-Polymer (PGA C-18)
mixture, (b) Ibuprofen sodium salt-Polymer (40%PGA C-18)
mixture, (c) Ibuprofen sodium salt-Polymer (100%PGA C-18)
mixture, (d) pure Ibuprofen sodium salt.
201
Figure. 6.7 Average drug contents on each plolymer 206
Figure. 6.8 The release behavior of various formulations (the results are the
mean and standard deviation of three determinations).
207
Figure. 6.9 The release behavior of various formulations (the results are the
mean and standard deviation of three determinations).
208
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xv
LIST OF TABLES
Table # Title Page # Table 1.1. Advantages and disadvantages of direct compression method 18 Table 1.2. Advantages and disadvantages of wet granulation method 19 Table 1.3 Application of matrix for drug delivery systems 25 Table 1.4. Polymer used in the matrix tablets 30 Table 1.5. General properties of Ethocel
® Standard polymers 31
Table 1.6 Different grades of Ethocel® and their physical properties 32
Table 1.7. Ketoprofen dosage forms, route and strength 57 Table 1.8. Dose of ibuprofen 62 Table 3.1. Angle of repose and flow properties according to B.P 2007 80 Table 3.2. Compressibility Index and Hausner Ratio limits according to B.P
2007. 81
Table 3.3. Composition of solid dispersions and physical mixtures Ibuprofen 84 Table 3.4. Composition of solid dispersions and physical mixtures of
Ketoprofen 84
Table 3.5. Different matrix tablets composition of Ibuprofen 87 Table 3.6. Different matrix tablets composition of Ketoprofen 88 Table 3.7. Interpretation of release exponent “n” in power law for release
mechanism of different geometries 94
Table 3.8. Dosing Schedule design of test tablets and reference tablets for
pharmacokinetics study 96
Table 4.1. Results of identity conformation tests 102 Table 4.2. Percentage purity of Ibuprofen and Ketoprofen 103 Table 4.3. Micromeritics or flow properties of pure Ibuprofen and
formulation blends 108
Table 4.4. Micromeritics or flow properties of pure Ketoprofen and
formulation blends 109
Table 4.5 Absorbance and concentration of Ibuprofen for different dilutions 114 Table 4.6. Absorbance and concentration of Ketoprofen for different
dilutions 115
Table 4.7. Solubility of Ibuprofen in different solvents at different
temperatures 116
Table 4.8. Solubility of Ketoprofen in different solvents at different
temperatures 117
Table 4.9. Solubility data of different Ibuprofen and Ketoprofen
formulations 118
Table 4.10. Physicochemical characteristics of Ibuprofen controlled release
matrices 131
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xvi
Table 4.11. Physicochemical characteristics of Ketoprofen controlled release
matrices 132
Table 4.12. Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Sandard
Premium polymer of different viscosity grade, (meanSD of three
determinations)
152
Table 4.13. Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard FP
Premium polymer of different viscosity grades, (meanSD of three
determinations)
153
Table 4.14. Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard
Premium polymer of different grades and co-excipient HPMC
K100M, (meanSD of three determinations)
154
Table 4.15. Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard FP
polymer of different grades and HPMC K100M, (meanSD of
three determinations)
155
Table 4.16. Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard
Premium polymer of different grades and co-excipient Starch,
(meanSD of three determinations)
156
Table 4.17. Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
standard FP
polymer of different grades and co-excipient Starch, (meanSD of
three determinations).
157
Table 4.18. Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard
simple Premium polymer of different grades and co-excipient
CMC, (meanSD of three determinations)
158
Table 4.19. Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
standard FP
polymer of different grades and co-excipient CMC, (meanSD of
three determinations).
159
Table 4.20. Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
simple
Premium polymer of different grades , (meanSD of three
determinations
160
Table 4.21. Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
FP polymer
of different grades, (meanSD of three determinations)
161
Table 4.22. Different kinetic models applied to determine the release profile of 162
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xvii
controlled release matrices of KTF consisting Ethocel
simple
Premium polymer of different grades and co-excipient HPMC
K100M, (meanSD of three determinations)
Table 4.23. Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
stand FP
polymer of different grades and co-excipient HPMC K100M,
(meanSD of three determinations)
163
Table 4.24 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
Standar
simple Premium polymer of different y grades and co-excipient
Starch, (meanSD of three determinations)
164
Table 4.25. Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
Standard
FP 7, 10, 100 polymers of different grades and co-excipient Starch,
(meanSD of three determinations)
165
Table 4.26. Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
standar
Simple Premium polymer of different grades and co-excipient
CMC, (meanSD of three determinations)
166
Table 4.27. Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
FP polymer
of different grades and co-excipient CMC, (meanSD of three
determinations)
167
Table 4.28. Stability indicating parameters (drug content, weight variation,
friability, hardness, % release after 24 hours and appearance) for
Ibuprofen matrices in ambient conditions (25oC and RH 65%)
170
Table 4.29. Stability indicating parameters (drug content, weight variation,
friability, hardness, % release after 24 hours and appearance) for
Ibuprofen matrices in accelerated conditions (40oC and RH 75%)
171
Table 4.30. Stability indicating parameters (drug content, weight variation,
friability, hardness, % release after 24 hours and appearance) for
Ketoprofen matrices in ambient conditions (25oC and RH 65%)
171
Table 4.31. Stability indicating parameters (drug content, weight variation,
friability, hardness, % release after 24 hours and appearance) for
Ketoprofen matrices in accelerated conditions (40oC and RH 75%)
171
Table 4.32. Difference factor ƒ1 and Similarity factor ƒ2 calculated for
Ibuprofen controlled release matrix tablets, while comparing their
dissolution profile at different time intervals with dissolution
profile at zero time (pre-storage) during stability study
172
Table 4.33. Difference factor ƒ1 and Similarity factor ƒ2 calculated for
Ketoprofen controlled release matrix tablets, while comparing their
dissolution profile at different time intervals with dissolution
profile at zero time (pre-storage) during stability study
172
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page xviii
Table 4.34. Pharmacokinetic parameters for Ibuprofen, following oral
administration of 300mg Reference and 300mg Test tablets of
Ibuprofen to two separate groups of rabbits (Mean±SD, n=12)
184
Table 4.35. Pharmacokinetic parameters for Ketoprofen, following oral
administration of 200mg Reference and 200mg Test tablets of
Ketoprofen to two separate groups of rabbits (Mean±SD, n=12)
185
Table. 6.1 Physical characteristics (size, polydispersity index and zeta
potential) of empty and drug loaded nanoparticles prepared from
various polymers by interfacial deposition method.
204
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 1
Part-1
CHAPTER 1
INTRODUCTION
Efforts and Struggles of humankind to eradicate disease date back to early civilization.
To treat abnormalities of physiological life processes, pain and discomfort, natural
substances have been used. With the advancement of science, active ingredients of these
materials (the drug) were isolated and identified. Later on their mechanism of action was
determined. Now-a-days new drug candidates are used to treat diseases as effective tools.
Drug activity is the result of molecular interaction(s) in certain cells. It is necessary for
drug molecules to reach somehow the site of action after administration (oral, parenteral,
transdermal, etc.) at a sufficient concentration to show proper action. The scientific field
dealing with this issue is known as drug delivery.
1.1 Drug Delivery
“It is the process or method of administering active pharmaceutical ingredients (APIs) to
achieve a therapeutic or pharmacological effect in humans or animals” (Drug delivery,
2010; Ravi, 2008). Drug delivery today is at leading age of product development and
pharmaceutical science. Historically, the drug delivery field concentrated on introducing
and creating new forms of already established drugs. Now-a-days, drug delivery is being
used as a method or process of product life cycle management to prolong the product life
in market by providing improved version of drugs, as patents are getting ready to expire
(Definition, 2010). Drug delivery techniques or technologies are patent protected
formulation technologies which are used for the modification of drug release pattern,
absorption, distribution and elimination. Due to these technologies product safety,
efficacy and patient compliance are improved (Drug delivery, 2010; Ravi, 2008).
Basically the aim of the drug delivery is, to deliver the drug at right place, at the right
concentration for the right period of time. To achieve a safe and effective drug
concentration in body tissues, different drug delivery systems are developed.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 2
1.2 Drug Delivery Systems
The drug delivery systems can be defined as “Systems for the delivery of drugs to target
the sites of pharmacological actions” (Drug delivery systems, 2010). The systems in their
own are not pharmaceutically active, but improve the safety and efficacy of the active
pharmaceutical ingredients that they carry.
The goal of the drug delivery systems is to deliver the specific amount of APIs to site of
action for attaining proper therapeutic response in the body (Gibaldi, 1997; Chiao et al.,
1995; Shargel et al., 2005; Aulton, 2002).
1.2.1 Traditional or conventional or immediate release drug delivery systems: These are
the systems which are characterized by rapid and unresrictracted drug release rates and
kinetics, usually leading to abrupt increase of drug concentration in body tissues followed
by a similar decrease, that may causes a dangerous approach to the toxic threshold or fall
down below therapeutic level (Grassi and Grassi, 2005).
1.2.2. Modified release drug delivery systems: These are the drug delivery systems in
which modification of the rate, site or kinetic behavior of release of active pharmaceutical
ingredients takes place for the achievement of specific therapeutic objectives. It cannot be
achieved with conventional dosage form similarly administered. These systems include
targeted drug delivery systems, delay or repeated drug delivery systems, prolonged or
extended drug delivery systems (e.g. controlled release, sustained release and long acting
dosage forms (Khan, 2007).
1.2.2.1. Controlled release drug delivery Systems: For many decades, treatment of
chronic diseases and acute illness has been accomplished by delivering drug to patient via
different types of pharmaceutical dosage forms, like tablets, capsules, injectable,
suppositories, syrups, creams, gels, etc. To achieve and maintain the drug concentration
within the effective therapeutic range, it is often necessary to take these dosage forms
(drug delivery systems) several times a day which may result fluctuations and saw-tooth
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 3
effects in drug blood levels and consequently undesirable toxicity and poor efficacy. Due
to these and other factors, like unpredictable absorption lead to the development of
controlled drug delivery systems (Tripathi, 2003; Chien, 1992).
Recently for controlling the rate of drug delivery, extending the duration of therapeutic
activity and/or targeting the delivery of drug to the tissue several technical advancements
have been made. For these systems various terminologies are used such as controlled
release, sustained release, prolonged release, time release etc. The term controlled release
implies to the reproducibility and predictability in drug release kinetics. This means that
the release of drugs from drug delivery systems proceeds at a rate profile that is not only
predictable kinetically but also reproducible from one unit to another (Tripathi, 2003;
Chien, 1992).
Two important aspects are included in the objectives of controlled release drug delivery
systems, namely spatial placement and temporal delivery of a drug. Spatial placement
deals with the targeting of a drug to a specific organ or tissue, while temporal delivery
relates to controlling the rate of the drug to the targeted tissues.
Controlled release drug delivery systems include any drug delivery system that “achieves
slow release of a drug over extended period of time” if the system can provide some
control wether of spatial or temporal in nature. In general controlled release drug delivery
attempts to:
1. Prolong drug action at a predetermined rate by maintaining a relatively constant
and effective drug levels in the boy with concomitant minimization of undesirable
side effects with a valley and peak kinetic profile.
2. Provide local drug action due to spatial placement of controlled release drug
delivery system adjacent to or in the diseased organ or tissue.
3. Targeting drug by using carriers or chemicals (Lee and Robinson, 1987).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 4
The basic rationale for controlled drug delivery systems is to change the
pharmacokinetics and pharmacodynamics of APIs by modifying the molecular structure
and/or by using novel drug delivery systems.
Controlled release formulation can be classified as follow (Chiao et al., 1995; Shargel et
al., 2005; Aulton et al., 2002; Ansel et al., 2005; De Haan and Lerk, 1984; Caramella,
1995; Chien, 1985; Sala et al., 1997).
Reservoir systems or membrane controlled systems including:
enteric coated tablets,
coated granules,
capsules, and
microcapsules
Osmotic systems
Ion-exchange resins
Matrix tablets systems
Matrix system can be further classified as:
1. Inert monolithic matrix tablets system
2. Solvent activated matrix tablets system
The solvent system can be further sub-divided into the following two types
Gel- forming hydrophilic matrix tablets.
Erodible hydrophobic matrix system tablets.
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These systems are shown in the following figure (Fig.1.1).
Figure 1.1 Schematic Representation of Reservoir Controlled System, Matrix
System and Osmotic system
1.2.2.1.1. Reservoir or membrane controlled systems: these systems are prepared with a
drug reservoir in which the API is either dispersed as solid particles, or as solution that
has been encapsulated by an outer rate controlling polymeric membrane that is usually
semipermeable membrane (Chiao et al., 1995; Aulton, 2002; Chien, 1985; Katz et al.,
1995; Imandis et al., 1998).
The reservoir systems are different from matrix systems because in these systems the
membrane does not erode and swell on hydration with passage of time (Chiao et al.,
1995; Aulton, 2002; Chien, 1985; Katz et al., 1995; Imandis et al., 1998). The rate of
drug release from these systems is first controlled by interfacial partitioning of the drug
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 6
from the reservoir into the membrane or by matrix controlled process (Chiao et al., 1995;
Aulton, 2002; Chien, 1985; Katz et al., 1995; Imandis et al., 1998).
The schematic presentation of drug release from reservoir systems is shown in the Fig.
1.2 (Reservoir, 2010; Rumiana and Assen, 2006).
Figure 1.2 Schematic presentation of drug release from reservoir or membrane
controlled drug delivery system.
The reservoir containing drug is encapsulated with a polymeric membrane through which
drug is released by means of diffusion. Constant or zero order release is mostly occurred
as shown in the Fig. 1.2.
1.2.2.1.2. Osmotic pump systems: These systems can be used as an alternative to
reservoir or membrane controlled systems. However, the energy source in these systems
which pushes the drug out of the systems is either, due to the drug properties or other
osmotic pressure generating substance included in the systems (Chiao et al., 1995;
Aulton, 2002; Chien, 1985; Katz et al., 1995; Imandis et al., 1998; Thombre et al., 2004;
Makhiji and Vavia, 2003).
In these systems the drug or active pharmaceutical ingredients are incorporated into water
soluble tablet core and then it is coated with semipermeable membrane (Chiao et al.,
1995; Aulton, 2002; Chien, 1985; Katz et al., 1995; Thombre et al., 2004).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 7
The membrane used in these systems has the properties that only water can penetrate to
the tablet core, which dissolves the drug or active pharmaceutical ingredients or energy
producing source. It creates hydrostatic or osmotic pressure with in the delivery device,
which is used for the release of drug from the dosage form (Chiao et al., 1995; Aulton,
2002; Chien, 1985; Katz et al., 1995; Thombre et al., 2004).
Due to the diffusion of water into the device the release of drug from the system occurs
on the basis of an osmotic potential difference between the interior and exterior of the
device. In this case a constant drug release will occur until the concentration of drug or
energy producing source falls below saturation levels (Chiao et al., 1995; Aulton, 2002;
Chien, 1985; Katz et al., 1995; Thombre et al., 2004). The schematic presentation of drug
release from these systems is shown in Fig. 1.3, which shows the release of drug through
an opening in the coating following permeation of solvent into the device.
Figure 1.3 Osmotic pump system
1.2.2.1.3. Ion-exchange resins systems: These are the systems in which active
pharmaceutical ingredient or drug is bound to ion-exchange resins and forms a drug-
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 8
resin complex (Chiao et al., 1995; Aulton, 2002; Chien, 1985; Amsel et al., 1984; Anand
et al., 2001).
The resins which are used to form the backbone of drug delivery systems are cross-linked
water insoluble polymer containing the salt forming functional groups of anionic and
cationic nature which are repeated across the polymeric chain (Chiao et al., 1995; Aulton,
2002; Chien, 1985; Amsel et al., 1984; Sriwongjanya and Bodmeir, 1998). The release of
drug molecules from these systems take place by ion exchange in the gastrointestinal
tract and the drug molecules are allowed from drug-resins complex for dissolution
(Chien, 1985; Amsel et al., 1984; Anand et al., 2001).
The cross sectional diffusional area of these systems play a vital role to controlled the
rate and extant of drug release (Chiao et al.,1995; Aulton, 2002; Chien, 1985; Amsel et
al.,1984; Anand et al.,2001). A Schematic presentation of these systems is shown in Fig.
1.4 (Amsel et al., 1984).
Figure 1.4 Schematic presentation of Ion-exchange resigns system.
1.2.2.1.4. Matrix tablets systems: The term “matrix” indicates a three dimensional
network, more often polymeric, design and prepared for specific and particular
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application containing APIs and other substances such as solvent and excipients
(Rumiana and Assen, 2006). These systems, due to low production costs and robustness
are the most commonly used type of controlled drug delivery systems, as controlled
release technology evolved with matrix technology and several articles in the 1950s and
1960s reported simple matrix tablets or monolithic granules (Nandita and Sudip, 2003;
Controlled-release, 2010). In 1952, Smith Kline and French introduced the first time
released formulation with the name of “Spansule” that launched a wide spread search for
other applications in the designs and of dosage forms or drug delivery systems (Helfand
and Cowen, 1983).
A matrix system is simply a homogenous mixture of drug particles within a polymer
matrix, often manufactured by simple direct compression method. Among the oral
controlled release technologies, matrix systems have often prominent popularity because
of low costs, simplicity, ease in manufacturing, high level of reproducibility, stability of
raw materials and dosage form, easy to scale-up and process validation. Controlled
release product development has made much easier then before because of the
technological advancements in the area of matrix formulation. It is reflected by large
number of patents filed each year and commercial success of different novel drug
delivery systems based on matrix technologies. The different types of matrix tablet
systems are further explained and reviewed.
Inert monolithic matrix tablets system: It is the simplest method to obtain an oral
sustained or controlled release dosage form, in which the drug is incorporated in
an inert matrix (Rowe, 1975). As the name indicates inert means non-interacting
with the biological fluids. The application of inert polymer tablets matrix dates
back to the mid 1950s, when the first matrix tablets containing soluble powder of
drug and the non-toxic , strong and coherent structure of resin was introduced
(Tablet and Method, 1959). Since the introduction of plastic matrix tablets these
preparations have gain considerable use.
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 10
During its passage through GIT these matrix tablets do not undergo disintegration
process like conventional tablets but remain intact and the skeleton can be
recovered in the faeces. The materials used in the preparation of these matrices
are mostly insoluble inert polymers and lipophilic materials. The first polymers to
be used for the preparation of matrix tablets were semi-synthetic polymers such as
polyethylene, polyvinylchloride, polymethyl methacrylate, polystyrene, polyvinyl
acetate, cellulose acetate, and ethylcellulose. The fat compound used such as,
carnauba wax, hydrogenated castor oil, and tristearin (Caramella, 1995). Now-a-
days research in this area focuses on natural biopolymers such as cellulose and
starch derivates, some of which can be consider semi-inert (ethycellulose).
Solvent activated matrix tablets: It is a collective term which is used for the
systems in which the interaction between polymer and water is responsible for
achieving controlled release. The interaction of polymer with water may include
plasticization, swelling, erosion or degradation of the polymer. The solvent matrix
tablets are used as a method to achieve a zero- order release, which was first
proposed by Hopfenberg (Hopfenberg and Hsu, 1996).
Depending on the nature of retarding or polymeric materials, the matrix system can be
also be divided into the following two types.
Gel-forming hydrophilic matrix tablets: These are gel-forming hydrophilic or
swellable heterogamous or homogenous systems in which the APIs are dispersed
in swellable hydrophilic polymer. Hydrophilic polymer forms a gel layer when
contacts with a liquid, which is essential for sustaining and controlling of drug
release from the matrices.
Gel-forming hydrophilic matrix tablets are plasticized by gastric fluid after
ingestion and then volume expansion and macromolecular chain relaxation take
place. Release of drug is governed by diffusion of the dissolved drug through the
swollen gel layer and generally shows a burst effect and leaching of drug
molecules present at the surface prior to formation of release-controlling gel.
Erodible hydrophobic matrix tablets: In erodible hydrophobic matrix tablets the
drugs are incorporated or dispersed in erodible hydrophobic materials. Release of
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drug molecules from these systems is governed by erosion of the polymeric
materials
The schematic presentation of the drug release from erodible and non erodible matrix
tablets is shown in Figs.1.5 and 1.6 (Reservoir, 2010; Rumiana and Assen, 2006).
Figure 1.5 Schematic presentation of non-erodible matrix tablets
Figure 1.6 Schematic presentation of erodible matrix tablets
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Fig.1.5 shows drug release from non-eroding matrix tablets. The drug is initially
dispersed in the matrix system, at time t=0 has 100% in the dosage form, and after
administration at time t=t some of the drug has been released and erosion of system has
accorded.
In contrast of drug release from non-eroding systems, the release from erodible systems
or tablets depends on the erosion or degradation of the polymeric materials, in which the
drug is dispersed or incorporated to achieve constant release rate as shown in the Fig. 1.6.
1.2.2.1.5. Oral controlled drug delivery: The majority of drug substances exist as
crystalline or amorphous powders. A delivery system is required to deliver the drug to the
action of site, effectively, safely and reliably. For the delivery of these substances
different routes are used like oral route, parental, rectal transdermal etc.
The oral route is the most frequently route for administration of drugs. Tablets form by
far the majority oral dosage form (Van der, 1997). Important reasons for their popularity
are the ease of their preparation on industrial scale and their convenience of application
(patient compliance). The majority of oral tablets formulations are presented in
conventional or immediate release (IR) dosage forms. Drugs administered with an IR
dosage forms exhibit fluctuations in plasma concentration of a drug, peaks and then
declines due to multiple dosing of the said dosage forms.
The use of multiple dosing with immediate release (IR) dosage forms has several
limitation, including the requirement that the patient follows a strict dosing regimen in
order for optimum therapeutic benefits to be achieved (Chiao et al., 1995; Shargel et al.,
2005; Aulton, 2002; Ansel et al., 2005).However, the need to adhere rigidly to a dosing
regimen often lead to non compliance and some time doses are missed. Thus the desired
therapeutic effects or outcomes are affected (Chiao et al., 1995; Shargel et al., 2005;
Ansel et al., 2005).
Doses frequency may lead to maximum toxic concentration and result in unwanted side
effect whereas, due to infrequent dosing sub-therpeutic level of drug in blood is achieved
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(Chiao et al., 1995; Shargel et al., 2005; Aulton, 2002; Ansel et al., 2005). As low patient
adherence, more side effect and fluctuations in drug concentration following
administration of IR dosage forms lead to the development of controlled release
formulations. A hypothetical blood-level-time curve obtain after administering immediate
release dosage form and controlled release dosage form depicted in Fig. 1.7 (Nandita and
Sudip, 2003).
Figure 1.7 Plasma drug concentration profile Immediate Release (IR) and
Controlled Release (CR) Formulations, MEC= Minimum Effective Concentration
and MSC= Maximum Safe Concentration.
Oral controlled release dosage forms overcome the drawbacks of traditional or IR
formulations. As compare to IR formulations or dosage forms controlled release (CR)
tablets are not associated with alternating periods of toxic levels and sub-therapeutic
concentrations, and thereby improving the therapeutic efficacy and avoid side effects
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(Saks and Gardner, 1998). This makes the controlled drug delivery systems suitable
especially for drugs which have plasma peaks levels associated with unwanted side
effects and for those which have short elimination half life. The reduce side effects and
lower dosage frequency of controlled release (CR) tablets shows more comfort, improved
patient compliance and more reliable tablets intake which is of special important for
those patients who are instructed to follow chronic medication regimen (Saks and
Gardner, 1998; Richter, 2004). The controlled drug delivery has the following advantages
over convention dosage forms.
Improved patient convenience and compliance due to low dosage frequency.
Reduction in fluctuation in steady-state and therefore better control of disease
condition and reduce intensity of systemic side effects.
Safety margin of high potent drug increased due to better control of plasma levels.
Maximum amount of drug is utilized because of reduction in total amount of dose
administered (Brahmankar and Sunil, 2001).
Furthermore, controlled release dosage forms have the capability to reduce
hospitalization cost because self administration is relatively easy.
Using controlled drug delivery, many pharmaceutical products available in market and
new molecular entities can be delivered in such a ways that not only improve its efficacy
and safety, but in some cases may improve its therapeutic procedures. As it is believed
that for improvement of therapeutic responses modification in release profile of a drug is
an effective method.
When feeling the need for novel oral controlled release technologies of delivery systems,
the time and cost associated with the process of drug development should be considered
and kept in mind. To introduce a new chemical entity (NCE) drug into market, mostly
takes more then 10 years and development costs more than 600-800 million dollars
(Malick, 1998). Due to huge costs and more time consumption on the development of
NCE drugs, the pharmaceutical industries believe in line extensions or modification of
existing products. The development costs and risks associated with line extensions are
lower as compare to NCE drugs. Line extensions based on advanced controlled release
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systems or technologies may provide patent protection, which is an important point from
a product life cycle management point of view. For the generic pharmaceutical industries
controlled drug delivery or technology because of cheap excipient and low manufacturing
costs may provide to develop bioequivalent generic product at low costs as compared to
high priced originators.
Because of the above mentioned market drivers, the demand of safe, reliable and novel
controlled release drug delivery systems is continuously increasing.
1.2.2.1.6. Concepts in oral controlled release technologies: The driving force and idea
behind oral controlled release technologies is that with help of this technology plasma
levels of the drug can be optimized by controlling the delivery of drug from controlled
release dosage forms into gastro-intestinal tract (GIT). Control can be achieved by
developing simple sustained release formulations which release the drug at a specific rate
over a predetermined period of time. For those drugs which are inherently short acting, a
useful and reliable prolongation of pharmacological effect is sufficient and on the basis of
this idea many controlled drug delivery systems were developed in the 1980s.
As controlled release drug delivery systems provide a specifically designed dissolution
profile of the drug from the dosage forms, therefore for displaying the desire profile and
control over the drugs‟ absorption into the systemic circulation, different physicals and
chemicals approaches are applied to develop and produce such delivery systems (Qiu and
Zhang, 2000).
Some of the systems include: Insoluble, slowly eroding or swelling matrices; polymer
coated tablets, pellets, or granules; osmotically driven systems; systems controlled by ion
exchange mechanisms and various combinations of these approaches (Saikh et al., 1987a;
Saikh et al., 1987b; Tahar et al., 1995; Charman and Charman, 2002; Jeong and Park,
2008). Oral modified release (controlled release) formulations can be classified into
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different ways. One is to differentiate between single unite dosage forms such as tablets
and capsules and the other one is multi-particulate dosage forms, like pellets or beads.
Among the oral controlled release technologies, matrix systems have often prominent
popularity because of low costs, simplicity, ease in manufacturing, high level of
reproducibility, stability of raw materials and dosage form, easy to scale-up and process
validation. Controlled release product development has made much easier then before
because of the technological advancements in the area of matrix formulation. It is
reflected by large number of patents filed each year and commercial success of different
novel drug delivery systems based on matrix technologies.
1.3. Preparation of Matrix tablets
A tablet can be described as an aggregate of smaller particles, which are strongly adhere
to each other. A large number of developments in the field of pharmaceutical ingredients,
the tablet machines have made tablet manufacturing a science and the tablets a most
favorite dosage form (Rasenak and Muller, 2002). Tablets are versatile drug delivery
systems, which are easy to manufacture and convenient to use (Chiao et al., 1995; Ansel
et al., 2005; Armstrong et al., 2002). The tablets possess relatively good stability
properties as compared to other pharmaceutical dosage forms such as suspension,
solutions (Jivraj et al., 2000).
There are three methods which are used for the preparation of tablets such as direct
compression (DC), and compression following wet granulation or dry granulation.
Generally there are three basic steps, which are involved in the preparation of tablets, viz.,
die filling, compression and the ejection and all these steps are shown in the Fig. 1.8
(Aulton et al., 2002; Banker and Rhodes, 1990).
The successful manufacture of tablets depends on appropriate balance between a brittle
fracture and plastic behavior within a formulation mix. These are dependent on the
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compression characteristics of excipients and the APIs that are blended together to
achieve a particular uniform and acceptable dosage form (Armstrong et al., 2002; Jivraj
et al., 2000; Hiestrand et al.,1977; Imbert et al.,1997; Venkatesh et al.,1998).
Figure 1.8 Schematic presentation of the powder compression process using a single
punch press.
1.3.1. Direct compression method: The term direct compression refers the manufacturing
process, in which the tablets are compressed or compacted directly from powder blends
of drug and excipients without further manipulation (Aulton et al., 2002; Ansel et al.,
2005; Augsburger, et al., 2002; Gohel, 2005). In wet granulation method there is
granulation before compression, while in DC no granulation is required. It is easier than
wet granulation as fewer unit operations are used (Aulton et al., 2002; Ansel et al., 2005;
Augsburger, et al., 2002; Gohel, 2005). However, to avoid the formulation failure of this
method due to its simplicity some critical aspects, such as compressibility and flowability
the materials are seriously considered. As this method has some advantages and
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 18
disadvantages which are listed in the table 1.1 (Aulton et al., 2002; Ansel et al., 2005;
Augsburger, et al., 2002; Gohel, 2005).
Table 1.1 Advantages and disadvantages of direct compression method
Advantages Disadvantages
1. Fewer unit operations
2. Anhydrous process
3. No drying procedures
4. Faster dissolution rates achieved
5. Fewer excipients may be required
6. Economical
1. Particles segregations
2. APIs contents may be limited
3. Unsuitable for poor flowing APIs
4. Static charges on drug may lead to
5. Not applicable to low bulk density
materials
1.3.2. Wet granulation method: Wet granulation is a method of tablets preparation, in
which APIs are mixed with excipients and appropriate binding solution to form
agglomerate. From this agglomerate larger, multi-particulate entities called granules are
formed (Aulton et al.,2002; Augsburger et al.,2002; Wauters et al.,2002; Lister et
al.,2001; Iverson et al.,2001; Badway et al.,2000). In manufacturing of tablets by wet
granulation method, granulation is often an important step as segregation of the
components of the powder may be prevented or minimized by the formation of granules.
These granules also provide better flow properties to poweder blend (Aulton et al., 2002;
Augsburger et al., 2002; Wauters et al.,2002; Lister et al.,2001; Iverson et al.,2001;
Badway et al.,2000). As compared to the individual powder constituents of a blend
granules posses better compressibility and flow properties (Aulton et al., 2002;
Augsburger et al., 2002; Faure et al., 2001). The process of granules formation or
preparation can be divided in to three broad categories, such as wetting, nucleation and
consolidation and growth followed by attrition and breakage (Lister et al., 2001; Iverson
et al.,2001; Faure et al., 2001). During granules formation the wetting or nucleation stage
of granules starts when a binding solution or agent is brought into contact with the
powder materials to be granulated to form a nuclei (Lister et al., 2001; Iverson et al.,
2001; Faure et al., 2001). Then consolidation or granules growth starts after collision
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between granules. The final stage attrition occurs as a result of wet or dried granular
materials fracturing or crumbling due to impact of wear or compaction and subsequent
powder handling throughout the manufacturing process (Lister et al., 2001; Iverson et al.,
2001; Faure et al., 2001). Like direct compression method this method also has some
advantages and disadvantages which are listed in table 2 (Aulton et al., 2002; Augsburger
et al., 2002).
Table 1.2 Advantages and disadvantages of wet granulation method
Advantages Disadvantages
1. Reduces air entrapment
2. Enhances fluidity and compatibility
3. Suitable for high does drugs
4. Reduces cross contamination and dust
5. Permits handling of powder without
loss of blend quality
6. Enhances wettability of an API
7. Drug stability and distribution during
drying
1. Each unit process adds complications
2. Large numbers of unit processes
3. Increases the problems and possible
operator errors
4. Difficult to control and validate
5. Potential adverse effects of
temperature
6. More costly than DC
1.4. Release mechanism of drug from matrix tablets or systems: The knowledge of drug
release mechanism is an important part of drug development process, because factors
affecting the drug release may vary and depending on the drug release mechanism of
drug delivery systems.The release mechanism of drug from different matrix systems is
different. The most important drug release mechanisms are diffusion, swelling,
dissolution, erosion and combination of dissolution and erosion. As shown in the Fig. 1.9
(Polymer for oral, 2010).
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Figure 1.9 Presentation of release mechanisms of drug from matrix tablets
1.4.1 Diffusion: The release of drug from a porous monolithic matrix system or matrix
tablets is via leaching or diffusion mechanism (Fig. 1.10). The dispersed particles of drug
in the hydrophobic polymer matrix dissolve in the gastro-intestinal fluids and then release
of these particles take place from the matrix tablets by diffusion through already existing
porous network of pores and those pores which are formed by the dissolution of drug
particles(Qiu and Zhang, 2000; Crowley et al.,2004; Pohja et al.,2004). If drug loading is
increasing approximately 10-15%, a continuous structure forms and connecting all
particles (percolating drug network). If drug loading is lower then a proper fraction of the
drug may be surrounded by the polymer matrix (trapped fraction). In this case incomplete
release of drug would take place.
Higuchi and his co-workers developed a model for release mechanism of drugs from a
homogenous ointment base (Higuchi, 1961). However, modification in higuchi model
enabled the predication of drug release from a porous matrix tablets or systems with
connecting capillaries (Higuchi, 1963).
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M = [Ds Ca (2C0 - Ca) t]1/2
(1.1)
where:
M is the amount of drug released per unit surface area
P is the porosity of the matrix
t tortuosity
Ca solubility of drug in release medium
C0 total amount of drug in a unit volume of matrix
DS diffusion co-efficient in release medium
The porosity factor (p) was introduced to correct for the volume fraction of the matrix
that is filled with water. The tortuosity factor (t) was required for further correction for
increase of the diffusional pathway of the drug in the porous structure.
Similarly, for pseudo- steady state (C0>>CS), where Cs, is the saturated concentration of
drug with in the matrix.
M = [2Ds Ca C0 t]1/2
(1.2)
As porosity is the matrix fraction existing in the form of channels or pores, through which
the surrounding liquid can penetrates.
For the purpose of the data treatment the equation (1.1) above can be reduced to:
M= k t1/2
(1.3)
Where k is a constant, if the release of drug from matrix system is diffusion controlled,
then the amount of drug release versus square root of time will be linear.
Tremendous studies have been performed to analyze the release mechanism of drug using
the Higuchi model of drug release (Desai et al., 1965; Fessi, 1978; Gurny et al., 1982;
Hernandez, 1994; Dabbagh, 1996).
The Higuchi model was actually developed for planar diffusion, but later on Korsmeyer
and Peppas introduced a simple exponential equation for describing the release
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 22
mechanism from other geometries, such as slabs, spheres and cylinders (Korsmeyer et al.,
1983).
Q = ktn (1.4)
Where Q (Mt/M∞) is fractional release, k constant n is the diffusional exponent. For
characterization of different release mechanisms, n value can be used (Costa and Sousa,
2001).
In the case of cylindrical, the exponent n has value of 0.45 for Fickian diffusion ( leading
to square root of time release kinetics), if n has value from 0.45 to 0.89 than it shows
non-Fickian anomalous transport (leading to first order release kinetics), if n value 0.89
shows non-Fickian case-II transport (leading to zero-order kinetics)
Figure 1.10 Idealized schematic presentation of leaching-based released mechanism (Bakker, 1987).
Water soluble drugs are released mainly by diffusion with a partial in put from erosion
while the anomalous diffusion results from the relaxation of the macromolecular polymer
chains (Melia, 1990).
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1.4.2. Swelling: Drug release mechanism controlled by swelling is not easy process
because of macromolecular changes, such as chain relaxation and volume expansion take
place in polymer during release. Mostly, this release mechanism takes for those
controlled release systems in which water soluble drugs are dispersed in glassy polymer
matrices, such as HPMC (Colombo, 1993; Narasimhan, 2000).
When the polymeric matrix contacts with water or liquid, then swelling of polymer
occurs and the polymer changes from glassy state to rubbery state, forming a gel layer.
This process is also termed as the glassy-to-rubbery state transition of the polymer (Ju et
al., 1995; Karali et al., 1990). At this stage the core of the tablets remains essentially dry.
After formation of a gel layer, the dissolved drug can be transported because of increase
mobility of the polymeric chains. In case of a highly soluble and large dose drugs, burst
release takes place because of the presence of drugs on the surface of the matrix tablets.
The gel layer plays a rule to control additional water penetration and matrix
disintegration. The gel layer formation and drug dissolution is controlled by various
factors, such as water penetration, swelling, drug dissolution and diffusion, and matrix
erosion (Colombo et al., 1996; Colombo et al., 2000). The gel layer thickness and rate at
which forms can modify the release kinetics of the drug (Kanjicckal and Lopina, 2004).
As with the increase of the proportion of the polymer in the tablet matrix, gel formed
reduces the diffusion of the drug and prolong the erosion of the matrix (Ford et al., 1985).
1.4.3. Erosion: Mostly this release mechanism takes place in those systems in which the
drug disperses in hydrophilic polymeric matrix. Matrices swell and followed by polymer
and drug dissolution when contact with water or gastro-intestinal fluid. However, erosion
of the gel or polymer dissolution rate is faster than the diffusion of the drug in the gel
layer (Ford et al., 1987; Lee, 1985).
The erodible hydrophilic matrix, containing poorly water-soluble drugs, the release rate
can be controlled either by erosion or diffusion of the drug through the gel layer, but in
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 24
case of water-soluble drugs it can be controlled by erosion of the gel (Ford et al., 1985a;
Ford et al., 1985b; Lee, 1985).
Moreover, the strength of the gel layer impacts drug release. The matrices containing low
viscosity grade polymers lead to erosion release mechanism and zero-order kinetics
(Zuleger and Lippold, 2001), while those matrices containing high viscosity grade
polymers or high amounts of polymers are stable. In this case polymer dissolution is
negligible and drug release is primarily by Fickian diffusion following square root of
time kinetics (Zuleger and Lippod, 2001; Katzhendler et al., 1997; Pharm and Lee, 1994).
More often the release of drug occurs by both diffusion and erosion, leading to
anomalous transport (Zulger and Lippold, 2001).
Erosion is the major release mechanism for insoluble drugs, apart from their dose
(Rajabi-Siahboomi and Jordan, 2000; Li et al., 2005). There are two types of matrix
erosion mechanism, surface erosion and bulk erosion (Kanjickal and Lopina, 2004).
Those polymers which contain highly reactive functional groups (e.g. polyanhydrides)
undergo faster degradation than diffusion of water in the matrix, leading to surface
erosion. However, polymers with less reactive functional group, such as PLGA, undergo
bulk erosion.
1.5. Factors affecting release of drug from matrix tablets or systems
Factor affecting the release of drugs from matrix tablets are categorized in to two groups,
viz., formulation variables and process variables.
1.5.1. Formulation variables: In the preparation or formulation of the matrix systems,
the physicochemical characteristics of a drug, especially its solubility in water should be
considered before processing. Some recommendations are given in the table (Qiu and
Zhang, 2000). Apart of these other properties of drug affecting matrix systems include
drug stability in the system and at the site of its absorption, particles size, specific area
and pH dependent solubility of drug.
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Table 1.3 Application of matrix for drug delivery systems.
Matrix systems Drug Release mechanism Drugs not recommended
Hydrophilic
Swellable / erodible
Erodible
Diffusion/Erosion
Erosion
Very soluble
Freely soluble
Hydrophobic
Monolithic
Multi-particulate
Erodible / Degradable
Diffusion
Diffusion
Erosion/Enzymatic
degradation
Practically insoluble
Freely soluble
1.5.1.1. Particle size of drug: In the case of moderately soluble drugs the effect of
particle size on the release mechanism of drugs from matrix systems or tablets is
important, because particle size greatly influences the release of drugs from matrices. As
diclofenac sodium particle size showed great effects on the release mechanism and rate
from HPMC tablets (Velasco et al., 1999). Depending on the penetration of dissolution
medium through the matrix tablets the particle of smallest size dissolve easily and
diffuses quickly through the matrix, while the larger particles are dissolved slowly and
are more prone to erosion at the matrix surface. Similar observations were shown in case
of less soluble drug, indomethacin (Ford et al., 1985).
1.5.1.2. Effect of drug-polymer ratio: Drug-polymer ratio has great effect on the release
of drugs from matrix tablets, as increase of drug-polymer quantity reduces the release rate
of drug from a system. Hydroxypropylmethylcellulose containing diclofenac sodium
showed a decreased release rate when the polymer and drug ratio was increased (Velasco
et al., 1999). This decrease in release rate was because of an increase in polymer
concentration and subsequently increases in viscosity of the gel and formation of the gel
layer with a longer diffusion path. Similar findings were observed by other researchers;
as in case of water soluble drug metoprolol decreased diffusional rate was observed with
increasing amount of HPMC (Rekhi et al., 1999).
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By varying the polymer level, different drug release profile is observed. As different
metoprolol release profiles were observed by varying the Methocel K4M value (Nellore
et al., 1998). Similar observations were observed by Sung et al., as a wide range of drug
adinazolam mesylate release rate was observed when HPMC and lactose ratio was
changing (Sung et al., 1996).
1.5.1.3. Type of polymer: Polymer type is another factor which has an influence on the
release of drug from matrices. As different types of polymers are used for preparation and
formulation of extended release matrices, such Hydroypropyl methylcellulose (HPMC),
ethyl cellulose, eudragit etc. Each polymer is available in different grades, such as
different grades of HPMC are available, with different proportion of the hydroxypropyl
and methoxyl substitutions. Faster hydration takes place with increasing the amount of
hydrophilic hydroxypropyl groups as, Methocel®
K > Methocel®
E > Methocel® F. For
highly soluble drugs more hydrating grade of HPMC, methocel® K is preferred, because
for highly water soluble drug rapid hydration rate is necessary, as inadequate hydration of
polymer may lead to dose dumping because of fast penetration of gastric fluid into the
tablets core (Dow Pharmaceutical, 1996) The viscosity of the different grades of a
polymer also has an influence on the diffusion and mechanical properties of matrix
tablets. Higher viscosity gel layers showed a more tortuous and resistant barrier to
diffusion which resulted in slower release of a drug (metoprolol HCl) (Nellore et al.,
1998).
As ethyl cellulose is used for the preparation of extended release matrices. The low
viscosity grades of ethyl cellulose are more compressible than the higher viscosity
grades. The matrices formulated with low viscosity grades resulting in harder and slower
release matrix tablets (Katikaneni et al., 1995; Shileout and Zessin, 1996; Upadrashta et
al., 1993).
1.5.1.4. Particle size of polymer: Polymer particles size has the impact on the release of
drugs from matrices. According to a study conducted on the release rate of diclofenac
sodium from HPMC, decreased release rate of diclofenac sodium was observed as there
was an increase in the particle size of HPMC (Velasco et al., 1999). According to one
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another study, that in the case of polymer ethyl celloluse, that the characterization of
tablets prepared of polymer with different particle sizes revealed different release
profiles, using different particle sizes showed that the porosity of the tablets increased
with increase of particle size of polymer and resulted in faster drug release due to
increase porosity (Katikaneni et al., 1995).
1.5.1.5. Effect of fillers: Different fillers are used for increasing the volume of tablets.
These are having influence on the release of drugs from matrix tablets. Neullore et al
studied the influence of filler on the release rate of metoprolol matrix tablets containing
polymer methocel® K4M. They observed that filler solubility has an effect on the release
rate. A decreased release profiles of about 5-6 % after 6 hours was observed when the
filler was changed from lactose-microcrystalline cellulose to dicalcium phosphate
dehydrate (Nellore et al., 1998). According to another study, replacing the filler 100%
dicalcium phosphate dehydrate with 100% lactose showed an increase in metoprolol
release from matrix tablets containing methocel® K100LV(Sung et al.,1996).
1.5.1.6. Impact of ion-exchange resins: Ion-exchange resins can be used in the
formulation of matrix tablets as release modifiers. According to the study conducted by
Sriwongjanya and Bodmeier (Sriwongjanya and Bodmeier, 1998).They studied the
release of cationic drug propranolol from matrix tablets of HPMC containing drug
without resin, drug-resin complex and drug-resin physical mixture. They concluded
fastest release from a formulation free of resin.
1.5.1.7. Surfactants: The use of surfactants in the formulation of matrix tablets has the
influence on the release of drug. To study the effect of surfactants on the release rate of
drug from HPMC tablets Feely and Davis conducted a study, and they characterized the
ability of charged ionic surfactants to delay the release of oppositely charge bearing
drugs, such as chlormpheniramine maleate, sodium alkylsulphates, sodium salicylate and
cetylpiridinium bromide from HPMC containing tablets (Feely and Davis, 1988).
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1.5.2. Process variables
The process variables, such compression force, tablet shape, table size have also effect on
the release of drug from matrix tablets.
1.5.2.1. Compression force: The compression force has a minimum effect on the release
profile of tablets but it has a significant effect on the hardness of matrix tablets. As
according to velasco and his colleagues that compression had a significant effect on the
hardness and minimal effect on the release of drug from HPMC tablets (Velasco et al.,
1999). According to their assumption that this change is due to relationship between
porosity of tablets and compression force. The less influence of compression force on the
release of drug from matrix tablets is due to that there is no dependency between the
porosity hydrated matrix tablets and initial porosity. The same observation were observed
by Rekhi and his colleagues that change in compression force or crushing strength
showed to have a low effect on the release of drug from matrix tablets of HPMC (Rekhi
et al.,1999).
1.5.2.2. Tablets size: Size of matrix tablets has also an influence on the release of drug, as
Siepman and his colleagues observed that tablets size has an impact on the release rate of
drug from matrix tablets. According to them the release of drug from matrix tablets of
different size, such as small, medium and large after 24 hours was, 99.8%, 83.1% and
50.9%, respectively. As according to them the maximum release from small tablets was
due to higher surface area and diffusion pathway. The diffusion pathways for small
tablets were smaller as compared to larger tablets (Siepmann et al., 1999).
1.5.2.3. Tablets shape: Like other process variables tablets shape has also impact on the
release of drug. According to Rekhi and his colleagues that the drug dissolution rate of
those matrix tablets which are undergoing diffusion and erosion mechanism is affected by
the size and shape (Rekhi et al., 1999). As according to their observations, 20-30%
increase in the dissolution rate of metoprolol tartrate tablets formulated with methocel®
K100LV was observed at each time point after the modification in the surface area from
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concave shape to caplet shape. On the basis of these observations they suggested that for
possible lowest release the shape of the matrix tablet should be near to spherical.
Karasulu and his colleagues also studied the effect of shape on the release of drug
(Karasulu et al., 2000). According to another study conducted by Siepman and his
colleagues that the release rate of drug from flat shape was higher than regular shaped
cylinders with same volume. According to them, the difference in the release was due to
the difference in the surface area of the tablets (Siepmann et al., 1999).
1.6. Polymers used in the formulation of matrix tablets
1.6.1. Polymer: As the name indicates it is the combination of two Greek words “poly”
means many and “meros” means units/parts, so polymer is a compound or large molecule
which is formed by the combination of large number of simple small units or molecules
(monomers) (Polymer, 2010). The chemical reactivity and polymer properties depend on
the chemistry of the monomers and on the assembly of the monomers which are put
together (Jain, 2006). For the last few years, Polymer science has been the back bone for
the development and preparation of new dosage forms. Moreover, due to its
advancement, it has several applications in pharmaceutical sciences and used as coating
agent, adhesive, adjuvant, emulsifying agent and suspending agent, encapsulating agent,
drug carrier, thickness or viscosity enhancers, stabilizers, disintegrates, solubilizers,
gelling agents and bioadhesives (Udeala and Aly, 1998; Guo et al.,1989). For temporal or
spatial control of drug delivery polymeric systems are mostly intended to achieve (Jain,
2006). The different polymers which are used for the formulation of matrix tablets are
shown in table (1.4).
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Table 1.4 Polymer used in the matrix tablets (Caramella, 1995; Ford et al., 1985a;
Korsmeyer and Peppas, 1981; Venkatraman et al., 2000).
Polymers Characteristics
Ethylcellulose, Polyethylene, Polyvinyl chloride,
Mehtyl-acrylate-methacrylate co-polymer, etc. Hydrophobic, inert
Carnauba wax: Stearyl alcohol, stearic acid,
polyethylene glycol.
Castor wax: Polyethylene glycol monostearate
Triglycerides, polyanhydrides,etc.
Hydrophobic, erodible
Methyl cellulose, Hydroxy propylmethyl cellulose,
Sodium carboxy methyl cellulose, Carboxy
polymethylene, Sodium alginate, carbopols, etc.
Hydrophilic
In line with scope of the present study, the Ethylcellulose derivative, Ethocel® will be
discussed in detail.
1.6.1.1. Polymer Ethocel®: Polymer ethocel
® is ethylcellulose derivative and
ethylcellulose is an ethyl ether of cellulose. It is commercially available, inert polymer
used widely for the preparation of matrix tablets of water soluble and poorly water
soluble drugs (Saikh et al., 1987a; Saikh et al., 1987b; Rekhi and Jambhekar, 1995). It is
also used in tablets technology as binder and hydrophobic coating agent for tablets and
graules (Desai et al., 2001; Chowhan, 1980; Sadeghi et al., 2001). It is also used in the
preparation of microcapsules and microspheres (Desai et al., 2001). It is also used for the
preparation of modified release matrix formulation (Pollock and Sheskey, 1996). Ethyl
cellulose derivatives, such as Ethocel® polymers are colorless, odorless, tasteless and
noncaloric. They have outstanding chemical and physical properties as shown in table
1.5.
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Table 1.5 General properties of Ethocel® Standard polymers (Majewicz et al., 2002;
Ethocel, 2010).
Chemical names: Cellulose ethyl ether, ethyl ether of cellulose.
Chemical formula: C12H23O6 (C12H22O5) n C12H23O5
R= H or C2H5
Figure 1.11 Structure of ethylcellulose
Where “n” can be vary to provide a wide variety of molecular weights. Ethylcellulose is
available with different particle sizes, in different qualities. It is insoluble in water but
soluble in organic solvents, such as ethanol, ispropanol, metylene chloride, acetone etc.
Ethocel® standard premium and Ethocel
® standard FP premium are the two derivatives of
the Ethylcellulose which are used in the present study. Bothe these derivatives have have
different grades, used in the prepration of controlled release formulations.
Appearance White powder
Odor Odorless
Taste Tasteless
Density (bulk), g/cm3, Ethocel 0.3-0.4
Specific gravity, g/cm3 1.12-1.15
Melting point, 0C 165-173
0C
Refractive index 1.47
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Table 1.6 Different grades of Ethocel® and their physical properties (Ethocel
premium, 2010).
Name of polymer Average particle
size (µm)
Viscosity
(cp)
Ehylcellulose
(%w/w)
Ethocel® standard premium 7 310 7 48.0-49.5
Ethocel® standard FP premium 7 6.1 7 48.0-49.5
Ethocel® standard premium 10 375 10 48.0-49.5
Ethocel® standard FP premium 10 9.7 10 48.0-49.5
Ethocel® standard premium 20 ---- 20 48.0-49.5
Ethocel® standard premium 45 ---- 45 48.0-49.5
Ethocel® standard premium 100 465 100 48.0-49.5
Ethocel® standard FP premium 100 41 100 48.0-49.5
As according to Khan and Zhu JB, that Ethocel® standard premium is the conventional
granular and Ethocel® standard FP premium is the newel finally milled form of
ethylcellulose and due to this property it is allowing the use of direct compression to
incorporate into the controlled release dosage forms (Khan and Zhu, 2001). Fine particle
ethylcellulose has shown a better efficiency as a release retarding matrix former (Agrawal
et al., 2003).
1.7. Excipients
According to International Pharmaceutical Excipients council, excipients can be defined
as “any substance other than the active pharmaceutical ingredient or prodrug that is
incorporated in the manufacturing process or is contained in a finished pharmaceutical
dosage form (Excipient, 2010). As excipients have been traditionally included or used in
different dosage forms as inert substances mainly to make up volume and help in the
manufacturing process. Mostly they are used in different dosage forms to fulfill the
specialized functions for improving drug delivery (Carien et al., 2009). According to
USP Pharmacopeia, the excipients are categorized, as binder, disintegrants, diluents,
lubricants, glidants, emulsifying agents, solubilizing agent, sweeting agent, coating agent,
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and so forth. Moreover, the excipients should be stable, chemically inert, non-reactive
with drug and other excipients in the formulation. Different excipients, with different
names are available in the market, but in line with the scope of the present work, the
lactose, Magnesium stearate, Methocel®
(Hydorxyporpymethycellulose), starch,
Corboxymethycellulose, which are used as filler, lubricant and co-excipient, respectively,
will be discussed in detail.
1.7.1. Lactose: It is the most commonly used excipient which is used in tablets
technology as filler. It is a natural disaccharide found in milk, formed from galactose and
glucose. The name lactose is the combination of two Latin workds “lac” means milk and
“ose” means sugar, so it is also called milk sugar. Lactose was first dicoverd by Fabricci
Bartoletti in 1619 in milk and later on in 1980 Carl Wilhelm Scheele idintified it as sugar
(Linko, 1982). The gernal properties (Lactose, 2010) are given as follow:
Chemical formula: C12H22O11 (MW= 342.30)
Chemical name: 4-O-β-D-galactopyranosyl-D-glucose
Melting point: 222.8 0C
Figure 1.12 Structure of lactose
Mostly it is available in two isomeric forms alpha and beta, either in crystalline or
amorphous form (Tablets ingredients, 2010).
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1.7.2. Magnesium stearate: It is a fine, impalpable white powder with a characteristic
metallic test and faint odour of stearic acid. It is widely used in, tablets and capsules
formation as lubricant at a varying concentration ranging from 0.25% to 5.0% w/w. It is
listed as non-toxic compound, but taking orally in large quantity may lead to laxative
effect because of mucosal irritation. It is stable compound and is non-reactive and
compatible with strong acids, alkalis and iron salts, but with product containing aspirin
and alkaloidal salts magnesium stearate can not be used (Rowe, 2003).
1.7.3. Methocel®: It is the propriety name for the methylcellulose derivative that is also
known as hydroxypropylmehtylcellulose (HPMC) or hypromellose. It is a mixed alkyl
hydroxyalkyl cellulos etiher containing methoxy or hydroxy group. Its hydration rate
depends on hydroxypropyl content. As with the increase in the hydroxypropyl content the
hydration rate also increases. Its solubility is pH independent (Deppa et al., 2008). It is
stable with in a wide pH range and resistant to enzymatic degradation (Hardy et al.,
2006). It has the chemical name cellulose, 2-hydroxypropy methyl ether. It is widely
accepted pharmaceutical excipient because of its availability in different molecular
weights and the effective control of gel viscosity is easily possible (Alderman, 1984).
Figure 1.13 Structure of Methocele (HPMC)
General structure of HPMC containing methoxyl (CH3-O-) and hydroxypropoxyl
(CH3CHOHCH2-O-) substituents. Where the R-group can be single or combination of
substituent. HPMC is white or creamy white, tasteless and odorless fibrous or granular
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powder. It is non-toxic and non-irritating but ingestion in large quantity may lead to
laxative effect (Rowe, 2003). It is mostly used in the preparation of tablets and capsules
as coating agent, binder and modifier to control or extend the release of drug (Saha et al.,
2001). It is available in different viscosity grades, but higher viscosity grades are being
used in different concentration to retard or extend the release of a drug from tablets or
capsules. The viscosity of the polymer depends on the number of constituents on the
polymeric backbone and the length of the cellulose chain. Three viscosity grades of
HPMC (Methocel®
K100M, K15M and K4M) are used in the formulation of extended
release matrix (Ford, 1999). Due to its gelling property because it form diffusion and
erosion-resistant gel layer on hydration which is able to control drug release (Vasques et
al.,1992; Sung et al.,1996; Siepmann et al.,1999). This gel layer acts as a barrier
especially for high water soluble drugs. As on exposure to water it forms a gel layer and
retard the release of drug and the release of drug from these systems is due to Fickian
diffusion and matrix relaxation and erosion (Saha et al., 2001).
1.7.4. Starch: It is white stable powder. It is also known with different names such as,
soluble starch, corn starch, tapioca starch, amyldextrin, amylopectin, amylum, arrowroot
starch and etc. It is slightly water soluble, its melting point is around 250 0
C, but it
decomposed before its melting point is reached. It is represented with chemical formula
(C6H10O5)n. It is incompatible with strong oxidizing agent (Starch, 2010). Mostly two
types of starch viz., partially pre-gelatinized and fully pre-gelatinized starch is used as
binder, disintegrant and filler. The partially pre-gelatinized starch used as binder and
disintegrant while the fully pre-gelatinized starch loses its disintegrating properties and
only acts as binder (Tablet ingredients, 2010).
1.7.5. Carboxymethylcellulose (CMC): It is free flowing white to off white powder,
stable under ordinary condition and soluble in water. It has a melting point of 274 0C. It is
also called carboxymethyl ether (CMC, 2010; Corboxy methyl cellulose, 2010).
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Figure 1.14 Structure of CMC
At low concentration CMC structure is rod-like, but at higher concentrations it entangles
to become a thermoreversible gel like structure because of overlapping and coiling up of
its molecules. It is more soluble in cold water and mostly used for controlling viscosity
without gel formation, due to this property it is used as thickener, emulsion stabilizer and
suspending agent (Corboxy methyl cellulose, 2010).
1.8. Solid dispersions
Solid dispersions (SDs) are defined as a range of pharmaceutical products with one or
more active ingredients homogenously dispersed in an inert carrier or matrix in a solid
state, prepared by the melting, solvent or melting-solvent methods (Damian et al., 2000;
Ford, 1986; Craig, 2002; Sethia and Squillante, 2003; Kauahal et al., 2004).
SDs are divided according to their physicochemical characteristics into three different
types. A broad distinction can be made based on the physical state of the drug within the
system, i.e. is it crystalline or amorphous. In eutectic and monotectic systems, both drug
and carrier are present in the crystalline state. In eutectic systems, the drug and carrier are
completely miscible in the liquid state, and when cooling their mixture with the eutectic
composition they form a microfine physical mixture with a lower melting point than the
drug or the carrier alone (Leuner and Dressman, 2000; Carig, 2002; Vippagunta et al.,
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2007). In monotectic systems, the melting point of the carrier does not change with
incorporation of the active ingredients (Vippagunta, 2007). In eutectic drug/hydrophilic
carrier systems, the highly water soluble carrier dissolves quickly in an aqueous medium,
releasing very fine drug crystals and this drug size reduction has been noted to be
responsible for improved dissolution rate e.g. as observed for fenofibrate and loperamide
in solid dispersions with poly(ethylene glycols) (Law et al.,2003; Weuts et al.,2005a).
In the second type of SDs, the active ingredient may be dispersed as a separate
amorphous or crystalline phase or some combination of the two in glassy matrix (Carig,
2002; Vasconcelos et al., 2007). These types of SDs are mostly formed with amorphous
polymers, such as polyvinyl pyrolidone (PVP) (Van den Moorter et al., 1998; Sethia and
Squillante, 2004), or with semicrystlline materials, such as Poly ethylene glycol (PEG)
(Nair et al., 2002; Verheyen et al., 2002; Van den Moorter et al., 1998). Moreover,
complex formation might be possible with some carriers, such as PVP (Garekani et al.,
2003)
The third type of SDs is a solid solution in which the drug and carrier are totally miscible
with one another, and a result of specific molecular interactions, the drug is present as a
molecular dispersion within the carrier (Leuner and Dressman, 2000; Carig, 2002; Sethia
and Squillante, 2003, Kaushal et al.,2004; Vasconcelos et al.,2007).
1.8.1. Carrier used in solid dispersions: Different carriers which are used in the
preparation of SDs are mostly hydrophilic materials with varying physicochemical
characteristics, ranging from low molecular weight sugars to high molecular weight
polymers. The carriers materials which are commonly used for SDs are different grades
of PVP and PEG, either alone or in combination of surface active ingredients (Leuner and
Dressman, 2000; Sethia and Squillante, 2003; Kaushal et al., 2004). Other polymeric
materials which are used as carrier are, poly (acrylic acid) (PAA), poly (
vinylpyrrolidone-co-vinylacetate) (PVP/VA), povidone, Poloxamer and Pluronic F68 etc
(Broman et al., 2001; Weuts et al.,2005b; Matsumoto and Zogrfi, 1999; Vippagunta et
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al.,2002; Ahuja et al., 2007; Nair et al., 2002); organic acids such as, citric acid and urea
(Ahuja et al., 2007); sugar such as chitosan, inulin, mannitol, sorbitol and glucosamine
(Asada et al., 2004; Ahuja et al., 2007) have been used as carriers in SDs. In the present
work Glucosamine HCl was used as carrier. As it is hydrophilic carrier, used as
dissoulution rate and solubility enhancer. The mechanism by which the solubility and
dissolution rate of the drug are increased using solid dispersion has several contributing
factors.
Firstly, the particle size of a drug is reduced to submicron size or molecular size where a
solid solution is obtained, this particles size reduction increase the solubility and
dissolution rate. Secondly, in some sample the drug is converted from crystalline to
amorphous form, which has high energetic state with increased solubility. Moreover, the
wettability of the drug particle can be improved by the dissolved hydrophilic carriers
(Ford, 1986).
1.8.2. Preparation of solid dispersions: Two methods are mostly used for the preparation
of solid dispersions such as melt (fusion) methods and solvent evaporation methods. Melt
(fusion) methods include traditional hot melting, melt extrusion, direct capsule filling,
compression moulding and hot spin melting (Leuner and Dressman, 2001). The solvent
methods include traditional solvent evaporation by spray or freeze-drying, supercritical
fluid technology, co-precipitation and spin-coating.
Part-2
1.9. Nanoparticles
In recent years tremendous efforts have been made to introduce nanotechnology for the
delivery of small molecular weight drugs and macromolecules such as proteins, peptides
and genes by either localized or targeted delivery to the site of interest (Moghimi et al.,
2001; Liu, 2007). Nanotechnology is referred to systems such as nanoparticles,
nanocapsules, micelles and conjugates of therapeutic agents. These systems are often
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polymeric and submicron in size and they have multidimensional advantages in drug
delivery. These systems can be used for targeted drug delivery to improve the oral
bioavailability, to persist the drug/gene effect in site of action, to improve the solubility
of drug for intravenous administration, to prevent the instability of drugs against
enzymatic action with in the body (Moghimi et al., 2001).The nanometre size range of
these delivery systems provides prominent advantages for drug delivery. Due to sub-
cellular and submicron size, these particles can penetrate into deep tissues through
capillaries, cross the fenestration present in the liver epithelial lining and these
nanoparticles can be taken up by the cells (Vinagradov et al., 2002). They could show
controlled release properties due to the biocompatibility, pH, ion and temperature
sensibility and they can prove the utility of drugs and reduce drug side effects (Zonghua,
2008). Nanoparticles are spherical particles having smaller size less than 1um (Singh and
Lillard, 2009) as these are submicron-sized, colloidal vehicles that carry and release
drugs in a controlled way to the target site of action. Nanoparticles are different both, in
shape and in composition. Nanopaticles are different from their macroscopic/bulk
analogues due to increased surface area and quantum effects. a. Due to these quantum
effect and surface effects the optical, electrical, chemical and magnetic properties of
particles also change which ultimately affect the in vivo behaviour.
Nanoparticles are dispersed after preparation in a liquid and then these can be
administered for example via the parenteral route, oral route and/or transdermally.
Nanoparticles can be dried to a powder which can be used for pulmonary delivery.
Drug nanoparticles are the particles containing drug molecules and biocompatible
polymer (Kreuter, 1994; Couvreur et al., 1995; Kreuter, 1983). The drug can be
dissolved, entrapped, adsorbed, attached or encapsulated onto or into the nanoparticles.
Nanoparticles are classified into two groups on the basis of their structure. Nanocapsules
and Nanospheres (Allémann et al., 1993; Kreuter, 1994; Couvreur et al., 1995; Legrand
et al., 1999; Fresta et al., 1996). Nanocapsules consist of an oily core and polymeric
shell. The hydrophobic drug is contained in the oily core. Nanosphere has a matrix
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structure in which polymer and drug are homogenously distributed. Some drug
containing nanoparticles are shown in the Fig 1.15.
Figure 1.15 (A) Matrix type nanoparticles where the drug molecules are homogenously
dispersed in the matrix, (B) Core shape nanoparticles, (C) Matrix type nanoparticles in
which drug molecules(crystals) are Imbedded in a polymer matrix.
1.9.1. Application of nanoparticles: For systemic drug delivery and for drug dissolution
modification both biodegradable and non-biodegradable nanoparticles have been studied
(Soppimath et al., 2001; Couvreur et al., 1995; Brannon-Peppas, 1995; Schmidt and
Bodmeier, 1999). Nanopaticles can be used for drug targeting and delivery (Chawla and
Amiji, 2002; Vauthier et al., 2003).
The nanoparticles prepared from natural and synthetic polymers have got great attention
due to its more stability and further opportunities for surface nanoengineering (Vanrell et
al., 2005; Vauthier et al., 2003). Moreover, nanoparticles can be used for controlled drug
delivery and site specific delivery by changing the polymer characteristics and surface
chemistry (Panyam et al., 2003; Kreuter, 1994). Nanoparticles have been very
significantly used in cancer therapy because they can extravasate from the leaky vessels
of tumours (Kallinteri et al., 2005). Nanoparticles are currently being studied as that they
can pass through the smallest capillaries because of its smaller size and its prolonged
duration in systemic circulation. To avoid rapid clearance by phagocytes, they can
penetrate tissue gap to reach the targeted site such as liver, spleen, lung, spinal cord and
lymph.They can improve the utility of drugs and reduce side effects (Zonghua, 2008).
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Many studies have shown that nanoparticles have advantages over microparticles as drug
delivery systems (Linhardt, 1989). Micoparticles injected into tissue tend to stay where
they are placed and these can cause toxicity if used for chronic treatment. This was
observed in an experiment where 60um polymeric particles composed of a slowly
degrading polymer were injected at the sciatic nerve which was still found at the site after
eight weeks (Daniel, 2006). Microparticles 5, 25, 60 and 250um in diameter were
injected into the peritoneum of mice remained there for two weeks and an equal amount
of material but nanopaticles were injected and showed complete clearance from the
peritoneum in the same time frame (Daniel, 2006). Micropaticles mostly cause infarction
while the nanopaticles size is too small and don‟t cause emobolism and circulated in the
vasculature (Daniel, 2006).
The uses of biodegradable materials for the preparation of nanoparticles allow the
sustained and prolonged release of active entity at the site of action. Nanoparticles
formed from biodegradable polymers such as Poly DL-lactide co-glycolide (PLGA) and
Polylactide (PLA) have been developed for intracellular sustained drug delivery (Panyam
and Labhasetwar, 2003; Barrera et al., 1993; Davda and Labhasetwar, 2002)
1.9.2. Polymers used in nanoparticle preparation: Polymers are large molecules, which
are made up of simple repeating units. The name polymer is derived from Greek poly,
meaning „„many‟‟ and mer, meaning „‟part‟ (Stevens, 1999). Polymers are synthesised
from simple molecules called monomers by a process called polymerization (Stevens,
1999). A wide range of polymers are used for the formulation of nanoparticles, like
synthetic, natural, biodegradable and non-biodegradable (Chowdary and Srinivasa, 1997).
Biodegradable polymers are used for short term treatment and for long term therapy non-
biodegradable polymers are used for the preparation of nanoparticles such as for the
administration of vaccines and hormones (Roland, 1999). Biodegradable nanoparticles
are prepared from a variety of synthetic and natural polymers. Synthetic polymers such as
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polyacrylates, polycaprolactones, polylactides and its copolymers with polyglycolides are
mostly used (Soppimath et al., 2001; Hans and Lowman, 2002). Natural polymers such
as albumin, gelatine, collagen, chitosan are used, too (Moghimi et al., 2001). Polymers
such as poly (D, L-lactide-co-glycolide) (PLGA) and polylactides (PLA) have been used
mostly for drug delivery (Jain, 2000; Langer, 1997). Poly-lactic acid (PLA), Poly glycolic
acid (PGA) and the copolymer as mentioned above PLGA are the biodegradable
polymers and no surgical removal is needed from the body (Indu et al., 2004). PLGA and
PLA have been approved by FDA but their disadvantages are their low drug
encapsulation and burst release phenomenon (Leo et al., 2004; Govender et al., 1999;
Govender et al., 2000). Also, the degradation products responsible for acidic conditions
at the surrounding tissues might affect drug bioavailability or cause tissue irritation or
inflammation. Another drawback is the need for surfactant during nanoparticle formation.
However, poly (glycerol adipate) consists of glycerol and adipic acid which is both
naturally metabolised in cells. Therefore the polymer is biodegradable and biocompatible
without any side effects (Kallinteri et al., 2005). The synthesis is achieved using a lipase
so the synthetic procedure has no harmful side products. The polymer can self-assemble
into nanoparticles in the absence of surfactants (Kallinteri et al., 2005). The main
advantage of PGA over PLGA and PLA is the ability of modification of the pendant
hydroxyl group on the polymer back bone. Thus, its physicochemical properties are
altered by introducing different functional groups (Puri et al., 2008).
1.9.2.1. Poly (glycerol adipate) PGA: It is novel co-polymer and is being synthesised by
the combination of glycerol and adipic acid which are both natural components.
For successful polycondensation reaction of PGA polymer lipase enzyme is used (Puri et
al., 2008). As mentioned above, this polymer is preferred than other polymers because of
its acylation properties.This polymer produces various acylated derivatives depending on
the percentage of the acylation of the pendant hydroxyl group (for example 0% PGA,
40%, 100%). This polymer and its derivatives are biodegradable and biocompatible; its
metabolites are used by the cell in Kerb‟s cycle. As discussed above the main advantage
as compare to other polymers is the absence of burst release phenomenon.
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Figure 1.16 Structure of PGA and acylated PGA.
1.9.3. Nanoparticle preparation methods: For the preparation of nanoparticles several
methods are used such as emulsification solvent evaporation, interfacial polymer
deposition, spray drying, salting out, supercritical fluid expansion, complex coacervation.
Emulsification/solvent diffusion, emulsification/solvent evaporation, nanoprecipitation
and salting out methods are widely used methods (Pinto et al., 2006; Hans and Lowman,
2002; Soppimath et al., 2001; Qintanar et al., 1998).
1.9.3.1. Solvent Evaporation method: It is the most common method which is used for
the preparation of solid, polymeric nanoparticles. In this method the polymer dissolved in
water, immiscible volatile organic solvent is emulsified in presence of an aqueous phase.
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Then, the organic solvent evaporates and polymeric nanoparticles are formed. This
method was described by Niwa et al and since it has been widely used for the preparation
of nanoparticles from different polymers. This method is used for the preparation of
nanoparticles containing polymers such as PLA and PLGA (Niwan et al., 1995). This
method has been successfully used for hydrophobic drugs. The drawback is the use of
surfactants which are difficult to remove. Polyvinyl alcohol (PVA) is mostly used as
emulsifier. As PVA remains on the surface of nanoparticles, its removal is very difficult
and due to the presence of PVA on the surface of nanoparticles, the biodegradability,
biodistribution, particle cellular uptake and drug release behaviours are affected (Scholes
et al., 1999).
1.9.3.2. Interfacial Polymer Deposition Method (IPD) or Nanoprecipitation Method:
Interfacial polymer deposition method is also called Nanoprecipitaton method because
the particle formation is based on precipitation and subsequent solidification of polymer
at the interface of solvent and non-solvent. Therefore, it is also called solvent
displacement method. This method was first introduced by Fessi and his co-workers
(Fessi et al., 1995). According to this, the polymer is dissolved in water miscible solvent
such as acetone, methanol and then it is added into an aqueous non-solvent under stirring.
The interfacial tension between the two phases is decreased because of the rapid diffusion
of solvent into the aqueous phase. Increase interfacial surface area is produced by the
turbulence and due to these small droplets of organic solvent is formed; the solvent
further diffuses into the aqueous phase. Then, polymer particles are formed from the
droplets. Thus, the polymer deposited at the interface plays a role for the particle
stability. Finally the solvent is evaporated.
The particle size prepared by this process varies from 100-500 nm. Drug encapsulation
occurs by dissolving a hydrophilic drug in the aqueous phase or a hydrophobic drug in
the organic phase. The advantages of the method are the lack of residual solvents and the
particles formed are in the nanometer range.
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Figure 1.17 Schematic presentation of IDP (Interfacial Polymer Deposition method
1.9.3.3. Spray Drying Method: In this method fine nozzles are used while polymer and
drug are sprayed through the fine nozzles after being dissolved in organic solvent. Then,
after solvent evaporation, solid particles are formed. In this high temperature is used.
The particles prepared by using this process are mostly in micrometre size, due to high
temperature it creates problem during encapsulation of peptides and proteins. This
method is mostly used for the production and formulation of nanocrystals in industries.
1.9.3.4. Salting out Method: In this method, polymer precipitation is achieved via phase
separation by the addition of a salting out agent, e.g. electrolytes in case of acetone as a
solvent for polymer. This technique was introduced by Bindschaedler et al. in 1988
(Bindschaedler et al., 1988).
1.9.3.5. Supercritical fluid expansion method: This is a new approach for the
preparation of micron and nano sized particles (Dong and Feng, 2004). In this method
particles are formed free of organic solvent, and mild temperature is mostly used for
biological materials and the encapsulation of drugs for controlled release of therapeutic
agents is easier (Chattopadhyay and Gupta, 2002). Supercritical CO2 is used in this
technique under high pressure, it is termed rapid expension of supercrical solution.
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1.9.3.6. Complex Coacervation Method: In this method spontaneous phase separation
occurs when two oppositely charged polyelectrolytes are mixed in an aqeous solution.
The process takes place at low temperature and in aqueous phase only. Particles of
nanometre or micrometer size are produced depending on the substrate and processing
parameters such as pH, ionic strength and polyelectrolyte concentration (Li and Zhang,
2002).
1.9. 4. Drug Release Mechanisms: The drug release may occur by desorption of surface
bound drug, diffusion through the nanoparticle matrix, but in case of nanocapsules,
(diffusion occurs through the polymer wall), nanoparticle matrix erosion, a combined
erosion diffusion process.
1.9.5. Methods of determination of drug release: Different method are used for In-Vitro
drug release determination from nanoparticles and some methods which have been
mostly used for release study are, Ultra filtration technique (Centrifugal), reverse
dialysais sac technique, dialysais bag technique, ultracentrifugation technique, side by
side diffusion cells with artificial or biological membrane. Dialysis technique is mostly
used and it is used for release study of drug from nanoparticles and colloidal suspensions
1.10. Model drugs
1.10. 1. Ketoprofen: Ketoprofen is anionic non-steroidal anti-inflammatory drug. Like
ibuprofen it is propionic acid derivative, which is used for the treatment and management
of rheumatoid disease (Dollery, 1991). It is one of the most useful NSAID drugs, has
received much attention in the last two decades. Its anti-inflammatory effect is
approximately 160 times that of aspirin (Guoa et al., 2006).
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Figure 1.18 Structure of ketoprofen (C16H14O3, Molecular Mass 254.3 g/mol)
On the basis of its chemical structure different chemicals name are used for its
description such as, 2-(3-benzoylphenyl) propionic acid, (2RS)-2-(3-benzoylphenyl)
propionic acid, 2-(benzoyl-3-phenoyl) propionic acid, m-benzoylhydratropic acid, 3-
benzoly-α-methylbenzeneacetic acid, α-(benzoylphenyl) propionic acid, α-(3-
benzolyphenyl) propionic acid, (+)-(RS)-2-(3-benzoylphenyl) propionic acid (Dollery,
1991; BP, 2007; Moffat, 1986; Lund, 1994; Liversidge, 1981; Kantor, 1986; Vavra,
1987; Winholz, 1983; Delgado and Remers, 1998; Sweetman, 2002)
1.10.1.1. General description and properties: Ketoprofen is odourless, white crystalline
powder having sharp bitter teste (Dollery, 1991; Moffta, 1986; BP, 2007; Lund, 1994;
Sweetman, 2002). It has a melting point from 94 to 970C (BP, 2007; Lund, 1994;
Sweetman, 2002). It is practically insoluble or sparingly soluble in water, but freely
soluble in organic solvents, such as acetone, ethanol, methylene chloride, chloroform,
ether, benzene and etc (BP, 2007; Sweetman, 2002). As it is a weak monocarboxylic acid
(Sridevi and Diwan, 2002; Legen and Kristl, 2003), having dissociation constant, pKa, of
4.23 to 4.60 in water (Dollery, 1991; Lund, 1994; Legen and Kristl, 2003; Betge et al.,
2000; Hadgraft and Gossen, 2002; Corrigan et al., 2007). And 5.02 in aqueous solution of
pH 1.5 (de Jalon et al., 2000). Ketoprofen has two enantiomers, (S)-enantiomer and (R)-
enantiomer, which are both active and possess different biological activites (Sweetman,
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2002; Liu et al., 2004). The (S)-enantiomer is used to relieve pain and inflammation,
while (R) - enantiomer is also used in toothpaste to treat peritoneal disease.
(R) - enantiomer (S) – enantiomer
Figure 1.19 Ketoprofen Enantiomers
1.10.1.2. History and synthesis: In the middle of the twentieth century dangerous
corticosteroids were used for the treatment of rheumatoid arthritis, then a safe anti-
inflammatory drug ibuprofen with simple molecular structure was synthesized by Dr.
Stewart Adams, after the discovery of ibuprofen in 1967 another safe drug ketoprofen of
the same group was synthesised by a French chemical company Rhône-Poulenc and later
on it was first approved in 1973 for clinical use in France and United Kingdom(Kantor,
1986; Vavra, 1987)
Different methods are used for the synthesis of ketoprofen, as shown in figs. 1.20, 1.21
and 1.22 the synthesis of ketoprofen starting from (3-carboxyl-phenyl)-2-propionitrile, 2-
(4-amenophenyl)- propionic acid and (3-benzoylphenyl)-acetonitrile, respectively.
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Figure 1.20 Ketoprofen synthesized by starting from (3-carboxyl-phenyl)-2-propionitrile
(Liversidge, 1981).
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Figure 1.21 Ketoprofen synthesized by starting from 2-(4-amenophenyl)- propionic
acid (Liversidge, 1981).
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Figure 1.22 Ketoprofen synthesized by starting from (3-benzoylphenyl)-acetonitrile
(Liversidge, 1981).
1.10.1.3. Clinical and pharmacological aspects of Ketoprofen: In clinical practice
ketoprofen acts as anti-inflammatory and analgesic drug and it is also used widely for the
treatment of rheumatoid arthritis and osteoarthritis (Fossgreen et al., 1976). It is effective
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like other NSAIDs and has anti-inflammatory, analgesic and anti-pyritic properties
(Dollery, 1991; Green, 2001).
1.10.1.4. Anti-inflammatory effects: Ketoprofen has shown anti-inflammatory activity
against acute inflammation, sub acute inflammation and chronic inflammation in several
animal models, such as rats, mice, rabbits, guinea pigs and pigeons (Kantor, 1986). Its
anti-inflammatory property is 20 time more potent than ibuprofen, 80 time more than
phenylbutazone and 160 times more than asprine (Dollery, 1991; Kantor, 1986).
1.10.1.5. Antipyretic and analgesic effect: It was shown that it is peripherally acting
analgesic drug in different animal models. It was also shown that in pain management it
is equivalent to indomethacin, slightly more potent than naproxen and 30 time more
potent analgesic than asprin (Kantor, 1986).
1.10.1.6. Mechanism of action: The pharmacodynamic activity of Ketoprofen, like other
NSAIDs, is presumed to be interference with the metabolism of arachidonic acid (Kantor,
1986). Arachidonic acid is the most important and abundant precursor of the eicosanoids.
It is a 20 carbon fatty acid containing four double bonds (Katzung, 2001). Free release of
arachidonic from memarane phospholipid is catalyzed by the enzymatic activation of
phospholipid A2. Then various forms of prostagalandin, such as prostaglandin D2 (PGD2),
prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), prostaglandin I2 (PGI2) and
thromboxane A2 (TXA2) are catalysed by cyclooxygenase (COX). Cyclooxygenase
(COX) is the main enzyme which plays a role in the formation of prostaglandin from
arachidonic acid (Howard and Delfontaine, 2004).
Ketoprofen also inhibits the lipoxygenase pathway of arachidonic acid cascade. The
lipoxygenase pathway is responsible for the production of leukotriens and non-cyclized
monohydroxy acids, which are promoting inflammation. The inhibition of lipoxygenase
pathway may attenuate cell mediated inflammation and thus retard the progression of
inflammation in inflamed joints. Ketoprofen also inhibits the production of bradykinin,
which is the chemical mediator of pain and inflammation. Ketoprofen also acts on the
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lysosomal membranes and stabilizes the membranes and prevents the release of
lysosomal enzymes which are playing role in tissue destruction and damage during
inflammatory reactions (Hardman and Limbird, 2001; Vavra, 1987).
Figure 1.23 Prostaglandin (PGs) formation pathaway (Joan, 2003)
So ketoprofen acts on the cyclooxygenase (COX) and inhibits its synthesis because
ketoprofen is the powerful inhibitor of cyclooxygenase at concentrations well with in
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therapeutic plasma concentration range (Kantor, 1986). This inhibition results in the
reduction of prostaglandins (PGE2 and PGF2α) production which is produced in the
different tissues (Dollery, 1991; Chan, 1983; Chan et al., 1982).
1.10.1.7. Therapeutic uses: Ketoprofen is used for the treatment of osteoarthritis,
rheumatoid arthritis, ankylosing spodylitis, bursitis, and tendinitis. It is also used for
painful and anti-inflammatory conditons, such as acute gout, soft tissue disorder, and to
reduce fever (Dollery, 1991; Delgado and Remers, 1998; de Jalon et al., 2000; Green,
2001).
It can be used in gynaecological conditions, such as dysmenorrhoea, pain related
relexation of utrine and post-partum pain in non-nursing women (Dollery, 1991). It is
used for the treatment and prophylaxis of migraine headaches. It is also used in the
traumatic and surgical situations where pain management is required, such as sports
injuries, dental extraction, and orthopaedic manipulation. It can be used as anti-
inflammatory, analgesic and antipyratic agent in infectious diseases
1.10.1.8. Contraindications: Ketoprofen is contraindicated in bronchospasmal condition
such as, rhinitis, asthma, nasal polyps (Dollery, 1991; Green, 2001). It is also
contraindicated in peptic ulceration and sever renal insufficiency (Dollery, 1991; Green,
2001).
1.10.1.9. Adverse reactions of ketoprofen: As ketoprofen inhibits cylcooxygenase
enzymes (COX1 and COX2), so the therapeutic effecs of ketoprofen are due to the
inhibition of COX2 enzymes and the unwanted side effects or adverse reactions are due to
the inhibition of COX1 enzymes (Villegas et al., 2004; Sweetman, 2002).
Ketoprofen has mild upper GI complaints such as, epigastric discomfort, nausea, and
dyspepsia and some times lower GI complaints are also involved such as diarrhea,
constipation and fluctuation (Dollery, 1991; Kantor, 1986; Vavra, 1987). Ketoprofen also
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has some central nerve system (CNS) related side effects which are headache, vertigo,
dizziness, nervousness, tinnitus, depression, drowsiness, and insomnia. Some times
hypersensitivity reactions may occur such as angio oedema, fever, rashes, bronchospasm
and visual disturbances in some patients (Sweetman, 2002; Grahame, 1995).
Hematological adverse reactions of ketoprofen are anaemias, neutropenia,
thrombocytopenia, eosinophilia and agranulocytosis. It also causes nephritis and nephritic
syndrome and heart failure in elder patients may accrue (Evans and MacDonald, 1996;
Halpern, 1994; Grahame, 1995).
It has other adverse effects such increase blood urea nitrogen, photosensitivity,
pulmonary eosinophilia, pancreatitis, Stevens Johnson syndrome, colitis, and toxic
epidermal necrolysis, dermatitis (Dollery, 1991; Hardman and Limbird, 2001; Sweetman,
2002).
1.10.1.10. Ketoprofen interaction with other drugs: Ketoprofen has interaction with
other drugs such as aspire, warfarin, sulphonylurease, hydantoins, methotrexate, lithium,
cardiac glycosides, β-blockers, furosemide, angiotensin converting enzyme inhibitors,
probenecide, zidovudin (Dollery, 1991; Kantor, 1986; Vavra, 1987; Sweetman, 2002).
The concomitant use of ketoprofen with some drugs may cause sever adverse reactions
and gastrointestinal bleening and the risk of GI bleeding and ulceration may increase
when used corticosteroids, alcohol (Sweetman, 2002; Turner, 2001)
1.10.1.11. Pharmacokinetic of ketoprofen: Oral ketoprofen absorption is 94% ± 4
(Ketoprofen, 2010). Plasma protien binding of ketoprofen is 95% and volume of
distribution is about 0.1-0.2 l/kg (Ketoprofen, 2010). Plasma half life is about 1-3hours
(Ketoprofen, 2010). It is metablized in the liver. The main path way of its metabolism is
glucuronide conjugation along with minor hydroxylation pathway (Dollery, 1991;
Liversidge, 1981; Sweetman, 2002). Acyl-glucuronides formation is involved in the
metabolism of ketoprofen, which are excreted in the urine (Ishizaki et al., 1980). Acyl-
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glucoronides are physiologically unstable and they are hydrolyzed back to parent
compound and accumulation of these metabolitis in the plasma can prolonged the
ketoprofen elimination (Verbeeck, 1990). The renal excrition of unmetabolized
ketoprofen is less than 10% (Ishizaki et al., 1980).
Figure 1.24 Ketoprofen metabolism pathways (Ishizaki et al., 1980).
1.10.1.12. Pharmaceutics of ketoprofen: It is available in different dosage forms such as,
tablets, capsules, injectable solutions, gels and suppositorie (Kantor, 1986).
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Table 1.7 Ketoprofen dosage forms, route and strength
Dosage form Route Strength
Tablets Oral 50mg
Capsules Oral
50mg
75mg
100mg
Extended release ( tablets and capsules) Oral 100mg
200mg
Parenteral Intramuscular 100mg/2ml
Rectal Suppository 100mg
Topical Gel 2.5g/100g
1.10.1.13. Dose of ketoprofen for different disease conditions: The usual daily oral dose
of ketoprofen for rheumatic disorder is 100 to 200mg in 2 to 4 divided doses, but its
modified dosage form may be used once in a day. It may be used in suppository form at
night time in a dose of 100mg. For local pain relief a 2.5% gel may be applied on the
affected area 2 to 3 times a day for 10 days (Sweetman, 2002).
It may be given by deep intramuscular injection for soft tissue disorder, management of
pain after orthopedic surgery, and joint pain. The dose may be given in divided doses
after every 4 hours, up to a maximum dose of 200 mg in 24 hours, for up to three days.
1.10.2. Ibuprofen
Ibuprofen is propionic acid derivative of non-steroidal anti-inflammatory group of drugs,
which is used as analgesic and antipyretic agent (Baum et al., 1985; Herzfeldt and
Kümmel, 1983).
On the basis of chemical structure different names are given to describe ibuprofen, such
as, α- Methyl-4-(2-methylpropyl) benzeneacetic acid, [(±)-2-(4- isobulphenyl) propionic
acid] (Laura and Evangelos, 2007), (2-(4-isobulphenyl) propionic acid) (Philip et
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al.,1999), (iso-butyl-propionic-phenolic acid) (A thesis, 2000), (2RS)-1[4-(2-methyl
propyl) phenyl] propionic acid (Rabia and Nousheen, 2010).
Figure 1.25 Structure of Ibuprofen (C13H18O2, Molecular Mass 206.3 g/mol)
1.10.2.1. General properties and description: Ibuprofen is white crystalline powder. It
has melting point from 74 to77 0
C (Ibuprofen, 2010). Slightly soluble in water but soluble
in organic solvents, such as methanol, ethanol, acetone etc (Ibuprofen, 2010). It has a half
life 1.8 to 2 hours (Gennaro, 1990). It has dissociation rate constant pKa, 5.3 (Herzfeldt
and Kummel, 1983). Like ketoprofen it has chiral carbon atom on the propionic side
chain and therfore, it also has two enantionmers, such as R (-)-ibuprofen and S (+)-
ibuprofen. S (+) – ibuprofen is pharmacologically 160 times more active than R (-) –
ibuprofen (Adams et al., 1976).
Basically, almost all of the pharmacological activity of ibuprofen comes from S (-) –
ibuprofen (Neupert et al., 1997).
The R (-) – ibuprofen is converted or inverted to S (+) – ibuprofen in vivo to the extent of
57-69% (Hutt and Caldwell, 1983; Cheng et al.,1994; Lee et al.,1985)
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R (-)-ibuprofen S (+)-ibuprofen
Figure 1.26 Ibuprofen enantionmer
1.10.2.2. History and synthesis of ibuprofen: Ibuprofen was first derived in 1960s by
the research arm of Boot Group from propionic acid (Adams, 1992). And it was
discovered by Stewart Adams and his colleagues and they were patented in 1961s. It was
first launched in the United Kindom market in 1969s and in the United States in 1974s
for the treatment of rheumatoid artheritis. Boots was awarded for the this achievement
with Queen‟s Award Tehnical Achievement in 1987s (Ibuprofen, 2010). The two most
popular methods are used for the synthesis of ibuprofen, such as Boots Process and
Hoechst Process. The Boots process is the older one, it was developed by the Boots Pure
Drug company. And the other method which is called Hoechst process developed by
Hoechst company, in both process the synthesis of ibuprofen begins with isobutybenzene
as shown in the fig. 1.27.
1.10.2.3. Mechanism of action: Ibuprofen inhibits the synthesis of cyclooxygenase
(COX) enzymes (COX1 and COX2) (Vane and Botting, 1996; Neupert et al., 1997;
Oleson, 2009). As shown in the fig. 1.23 the ezymes COX1 and COX2 act as catalyste in
the production of prostaglandin and thromaxanes, which are involved in different
physiologic processes (Vane and Botting, 1996; Neupert et al., 1997). As prostaglandin is
responsible for the sensitization of pain receptors, and also plays a role in production of
inflammation and fever (Wahabi et al., 2005), and thus ibuprofen acts as indirect
analgesic by blocking the continues production of prostaglandin, the supression of
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prostaglandin is also responsible for ibuprofen antipyratic activity (Vane and Botting,
1996).
Other possible mechanisms of action are the influence on lipoxygenase enzymes,
peroxisome proliferator-activated receptors and inhibiting cell signaling molecules such
as nuclear factor kappa B (Kukar and Golde, 2008).
Figure 1.27 Synthesis of ibuprofen by Boot process and Hoechst process (Synthesis
of Ibuprofen, 2010).
1.10.2.4. Therapuetic uses of ibuprofen: As it is widely used as analgesic, antipyretic and
anti-inflammatory agent (Wood et al., 2006; Nuzu, 1978; Adams et al., 1969).
It is mostly used in the treatment of mild to moderate pain related to headach,
dysmenorrhea, migrain, post-operative dental pain, mangement of sponylitis,
osteoartheritis, rehumatoid artheritis, and soft tissue disorders (Pottas et al., 2005).
Ibuprofen can be used in the management of Patent Duct Arterosus (PDA) (Kravs and
Pharm, 2005). It is used in the treatment of sever orthostatic hypotension as with other
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NSAIDs (Zawada, 1982). It is also used in high dose for the reduction of inflammation in
Cystic Fibrosis (CF) (Mackey and Anbar, 2004; Rifai et al., 1996). It is also used for
prophylaxis of Alzheimers disease (Townsend and Pratic, 2005). It is used to lower the
risk of Parkinson‟s disease (PD) (Chen et al., 2005; Carrasco et al., 2005). It is also used
as chemo preventive agent in Breast Cancer (BC) (Harris et al., 1999).
1.10.2.4. Pharmacokinetic of Ibuprofen: Ibuprofen has oral bioavalability of 97% ± 2
(Pharmacokinetic of Ibuprofen, 2010). Its half life is 1.8-2hours and volum of distribution
0.1 l/kg and (Davies, 1998; Aarons et al., 1983; Paliwa et al., 1993). As there are two
enantiomers of ibuprofen, R(-) ibuprofen and S (+) – ibuprofen, both are metabolized to
in active hydroxy and corboxy metabolitis, two major metabolitis are 2-
hydroxyibuprofen and corboxyibuprofen (Mills et al.,1973; Tan et al.,2002; Burke et
al.,2006). All Phase I metabolitis of ibuprofen and intact enantiomer can be conjugated
with glucoronic acid and covert to phase II metabolitis (Kepp et al., 1997). Mostly two
enzymes are involved in the metabolism of ibuprofen enantiomers, such as CYP2C9 and
CYP2C8, S (+) – ibuprofen is metabolized by the enzyme CYP2C9 and R(-) ibuprofen is
metabolized by enzyme CYP2C8 (Leemann et al.,1993; Hamman et al.,1997).
1.10.2.5. Contraindications: Ibuprofen is contraindicated in individuals who are
hypersensitive to NSAIDs. It is also contraindicated in branchospasmal conditions, such
rhinitis, asthama and nasal polyps (Ibuprofen Drug monongraph, 2010; Oleson, 2009).
Ibuprofen should be used in caution in patients with hepatic diseases. It is also
contraindicated in patients with GI diseases such as ulcerative colitis, and peptic ulcer
disease (Green, 2001). It is also cotraindicated in patients having sever renal problems
(Green, 2001). It is also contraindicated in the pre-operativ pain related to coronary artery
bypass graft sugery. According to FDA it is pregnancy B category drug in first trimester
and D category in the third trimester dru because of potential constriction of the fetal
ductus arteriosus (Oleson, 2009).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
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1.10.2.6. Adverse reactions of ibuprofen: Like other NSAIDs, ibuprofen also has some
adverse reactions. The most common and major adverse reactions of ibuprofen are,
affects on the GI tract, the coagulation system and the kidney (Sweetman, 2002). It may
cause GIT bleeding, increase the risk of gastric ulcers and damage, renal failure, heart
failure, hyperkalaemia, confusion, bronchospasm, apoptosis, and epistaxis (Wolfe et al.,
1999; Oermarn et al., 1999; Gambero et al., 2005; Fulcher et al., 2003; Kennedy, 2001;
Kovesi et al., 1998; Durkin et al., 2006; Vale and Meredith, 1986). Ibuprofen has some
other adverse reactions but these are not most common, such as thrombocytopenia,
rashes, headache, blurred vision, dizziness, toxic amblyopia, edema and fluid retention,
nephritis, nephritic syndrome (Burke et al., 2006).
1.10.2.7. Interaction of ibuprofen: Ibuprofen has serious interactions like other NSAIDs
with drugs, such as aspirin, warfarin, lithium, oral hypoglycemic drugs, high does
methotrexate, antihypertensive drugs, β-blockers, angiotensin converting inhibitors, and
diuretics when used concomitantly (Hansen and Elliot, 2005). It has also interaction with
Desmopressin and thiopurines (Oselin and Anier, 2007; Garcia et al., 2003). Ibuprofen
interaction was observed with caffeine, naproxen, gemfibrozil, vericonazole and
fluconazole (Lόpez et al., 2006; Dooley et al., 2007; Tornio et al., 2007; Haynninen et
al., 2006; Rahman et al., 2005; Guindon et al., 2006).
Table 1.8 Dose of ibuprofen (Burke et al., 2006).
Patients Ibuprofen Doses
Adults
Analgesia n 200-400mg, every 4-6 hours
Anti-inflammatory 300mg, every 6-8 hours or
800mg, 3-4 times daily
Children Antipyretic 5-10mg/kg, every six hours or
(Max. 40 mg/kg per day)
Anti-inflammatory 20-40mg/ kg/day in 3-4 divided
doses
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 63
CHAPTER 2
REVIEW OF LITERATURE
2.1. MODIFIED RELEASE FORMULATION
2.1.1 Polymers for modified release formulations
Shah et al. (2011) developed controlled release matrix tablets of Ofloxacin, using
different grades of Ethocel® polymer.
Mesnukul et al. (2009) formulated the polyethylene glycol matrix tablets of
Indomethacin by mold technique, using hydroxypropylmethylcellulose (HPMC) polymer.
Chandira et al. (2009) developed a single tablet in which combination of Atorvastatin
and Gliclazide were used by wet granulation method, using HPMC 4000cps and HPMC
100cps as retardant polymers.
Tamizharasi et al. (2008) formulated and evaluated cephalexin microspheres, using
Eudragit. The in-vitro release profile indicated that cephalexine loaded Eudragit
microspheres provide sustained release over a period of 12 hours.
Gohel et al. (2008) fabricated the modified release press coated tablets of venlafaxine
hydrochloride, using hydroxypropylmethylcellulose (HPMC K4M) and (HPMC K100M)
polymers as release modifier in core and coat, respectively.
Shivkumar et al. (2008) formulated controlled release solid dispersion of dilclofenac
sodium in Eudragit SR and RL.
Suresh et al. (2007) developed ion-exchange resonates of propranolol hydrochloride,
using amberlite IR 120 by solvent evaporation method coated with polymer ethyl
cellulose.
Ribeiro et al. (2007) prepared Vinpocetine–cyclodextrin-tartaric acid multicomponent
complexes in HPMC matrix tablets. The drug release was evaluated for 12 hours.
Andrade-Vivero et al. (2007) increase the potential of poly (hydroxyethyl methacrylate),
pHEMA hydrogels as non-steroidal anti-inflammatory drugs delivery systems by using
the 4-vinyl-pyridine and N-(3-aminopropyl) methacrylamide.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 64
Mayo-Pedrosa et al. (2007) prepared sustained release matrix plellets, using poly (N-
isopropyl acrylamide.
Diez-Sales et al. (2007) developed and formulated the matrix system of acyclovir, using
chitosan
Sotthivirat et al. (2007) formulated prednisolone controlled porosity osmotic pump
pellet formulation consisting of microcrystalline cellulose and sulfobutylether-β-
cyclodextrine. The influence of formulation and processing variables on the physical
characteristics of predinisolone was studied.
Tatavarti et al. (2006) developed a prototype matrix system consisting of trimethoprim,
hydroxypropylmethylcellulose and polymeric and nonopolymeric modulator.
Rigo et al. (2006) formulated swellable drug-polyelectrolyte matrices, using alginic acid.
Different parameters were studied such as solvent up-take, release kinetic, erosion and
dynamics of swelling.
Dashevsky et al. (2005) formulated and physicochemicaly evaluated extended release
pellets coated with Kollicoat SR 30 D, novel aqueous polyvinyl acetate dispersion for
extended release.
Santos et al. (2005) evaluated the compaction and compression of xanthan gum pellets of
Ibuprofen. Physical properties of pellets were evaluated.
Ribeiro et al. (2005) studied the impact of multicompartment complexation of
Vinpocetine with β-cyclodexrin, sulfobutylether β-cyclodextrin, tartaric acid,
polyvinylpyrrolidone and HPMC, on the design of controlled release hydrophilic HPMC
tablets.
Ceballos et al. (2005) developed the extended release theophylline matrix tablets, using
different pH-dependent (Eudragit L100, S100 and L100-55) and pH-independent
(Eudragit RLPO and RSPO) polymers combination by direct compression method.
Kim (2005) formulated extended release triple layer, donut-shaped tablets (TLDSTs).
The core tablets consisted of enteric polymers such as hydroxypropylmethylcellulose
acetate succinate, and the bottom and top layers made of hydrophobic polymer, ethyl
cellulose.
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 65
Miyazaki et al. (2004) studied jelly fig extract for sustained release tablets as a matrix
base.
Parojcic et al. (2004) developed hydrophilic matrix tablets, using Carbopol 971P and
71G. The influence of polymer level on drug release kinetics was evaluated.
Crowley et al. (2004) developed matrix tablets of water soluble drug guaifenesin by
either direct compression or hot melt extrusion, using ethy cellulose polymer. Different
physicochemical characteristics, drug dissolution and release kinetic were investigated.
Comolu et al. (2003) formulated the Ketoprofen microsponges, using Eduragit RS 100.
The impact of drug-polymer ratio on the physical properties as in vitro release rate of the
drug was studied.
Alock et al. (2002) evaluated a range of oligosaccharide ester derivatives as drug
matrices for controlled release
Mehta et al. (2001) fabricated and evaluated the multi-unit controlled release system of
poorly soluble thiazole bsed leukotriene D4 antagonist, using Eudragit L 100 55 and
Eudragit S100. In-vitro drug release from the pellets was evaluated.
Montouses et al. (1999) formulated theophylline extended-release spheres by extrusion-
spheronization of matrix granultions, using Gelucire 50/02 or 55/18. The release
mechanism of theophylline was Fickian diffusion.
Pather et al. (1998) developed sustained release theophylline tablets, using ethyl
cellulose polymer.
Codd and Deasy (1998) prepared two-layered novel bioadhesive antifungal lozenges
with an upper modified-release drug containing layer and a lower bioadhesive layer
composed of drum-dried waxy maize starch and Carbopol 980.
2.1.2. Development of modified release formulation
Shah et al. (2011) developed controlled release matrix tablets of Ofloxacin using
different grades of Ethocel® polymer
Conti et al. (2008) formulated swellable matrices of Diltiazem HCl, using a mixture of
HPMC and NaCMC. A matix containing a 1:1 mixture of NaCMC and HMPC exhibited
a significantly slower drug release rate than either polymer shows alone.
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 66
Lin et al. (2007) prepared sustained release tablets of asprin, using
polymethylmethacrylate. The drug release followed Fickian diffusion model.
Philip and Pathak (2006) formulated a nondisintegrating, controlled release, asymmetric
membrane capsular system of flurbiprofen. The influence of different formulation
varaibles was evaluated.
Savaşer et al. (2005) formulated diclofenac sodium tablets by wet granulation and direct
compression methods, using different ratio of HPMC and Chitosan.
Royce et al. (2004) prepared controlled release 6-N-Cyclohexyl-2-O-methyladenosine
formulations.
Uner and Altinkurt (2004) developed theophylline tablets using honey locust gum as a
hydrophilic matrix material.
Talan et al. (2004) formulated a once-daily extended release formulation of ciprofloxacin
Qui et al. (2003) prepared a once-daily controlled release matrix system of divalproex
sodium, using different rate controlling hydrophilic polymers.
Qui et al. (1998) formulated layered matrix system of pseudoephedrine hydrochloride for
zero-order sustained release.
Eddington et al. (1998) formulated hydrophilic matrix extended release metoprolol
tablets and dissolution data was analysized.
Ughini et al. (2004) prepared diclofenac sodium tablets and capsules, using a highly
substituted galactomannan from Mimosa scabrella Bentham, extracted from the seeds of
a Brazilian leguminous tree and xanthan.
Huang et al. (2004) developed and optimized the propranolol once-daily extended
release formulations containing HPMC, CMC and lactose.
Emami et al. (2004) developed sustained release matrix tablets of lithium carbonate,
using different types of polymer, including Carbopol, NaCMC and HPMC by either
direct compression or wet granulation.
Reddy et al. (2003) formulated once-daily sustained release matrix tablets of nicorandil,
using wet granulation method. HPMC, NaCMC and sodium alginate were used as matrix
materials, while ethanolic solutions of ethyl cellulose, Eudragit RL-100, Eudragit RS-100
and polyvinylpyrrolidone were incorporated as granulating agents.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 67
Samani et al. (2003) prepared controlled release matrices of diclofenac sodium, using
different proportion of HPMC, Carbopol 940 and lactose.
Hasan et al. (2003) formulated and evaluated controlled release hydrophilic matrix
formulation of metoclopramide HCl, using chitosan and sodium alginate.
Makhija and Vavia (2002) prepared the once-daily sustained release matrix tablets of
Venlafaxine, using HPMC, cellulose acetate, Eudragit RSPO, ethyl cellulose polymers.
The effect of polymer ratio on in-vitro drug release and different physicochemical
parameters such as appearance, weight variation, and drug content were evaluated.
Espinoza et al. (2000) formulated a prolonged release formulation of Pelanserin, using
HPMC and citric acid.
Nellore et al. (1998) prepared extended release matrix tablets of metoprolol tartrate,
using several grades and levels of HPMC, filler and binder.
2.1.3. Formulation development via direct compression method
Shah et al. (2011) developed controlled release matrix tablets of Ofloxacin using
different grades of Ethocel® polymer
Yun-Tyng et al. (2007) formulated sustained-release tablets by direct compression
method.
Varshosaz et al. (2006) prepared matrix sustained-release tabltes of tramadol HCl by
direct compression method, using natural gums (xanthan and guar gums). Tablets were
evaluated physicochemically.
Miyazaki et al. (2006) formulated two kinds of theophylline dextran tablets by direct
compression method.
Vendruscolo et al. (2005) formulated extended release matrix tablets of theophylline,
using commercial xanthan (Keltrol®) and highly hydrophilic glatomannan from the seeds
of Mimosa scarbella by direct compression method.
Pose-Vilarnovo et al. (2004) formulated matrix tablets of diclofenac sodium and
sulphamethizole by direct compression method, using HPMC K4M.
Miyazaki et al. (2003) formulated three kinds of controlled release theophylline tablets,
using carboxymethyldextran, a mixture of carboxymethyldextrane and [2-(diethyl amino)
ethyl] dextran (EA) and mixture of dextran sulfate and EA by direct compression method.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 68
Reza et al. (2003) prepared matrix tablets of theophylline, diclofenac sodium and
diltiazem HCl, using Kollidon SR, Carnauba was and HPMC-15cps by direct
compression method.
Siepmann et al. (2002) formulated tablets of chlorpheniramine maleate, propranolol
HCl, acetaminophen, and theophylline and diclofenac sodium by direct compression
method, using different grades of HPMC as matrix forming agent.
Capella and Landing (2002) developed a stable nitroglycerin tablets by direct
compression method.
2.1.4. Drug release mechanism and kinetics
Jeong et al. (2007) evaluated the release kinetics of polymer-coated/ion-exchange resin
complexes for sustained drug delivery.
Wu et al. (2005) mathematical models were developed to describe the transport
mechanism of water soluble drug (caffeine) from highly swellable and dissoluble
polyethylene oxide cylindrical tablets.
Fu et al. (2004) derived a working equation to calculate drug release from matrices
containing HPMC.
Koester et al. (2004) investigated the release kinetics of carbamazepine from HPMC
matrix tablets, using different mathematical models.
Ferrero et al. (2003) studied drug release kinetics and front moment from matrix tablets
of methacrylate copolymer. Data was analyzed mathematically, using Higuchi,
Korsmeyer and Peppas models.
Siepmann and Peppas (2001) studied different kinetic models to describe drug release
from pharmaceutical devices containing HPMC.
Bettini et al. (2001) studied the release mechanisms of different soluble drugs matrix
tablets contusing HPMPC. Diffusion, erosion and swelling mechanisms were studied.
Abrhamsson et al. (1998) investigated the erosion of two different compositions of
hydrophilic matrix tablets containing HPMC.
Khan and Zhu (1998a) studied Ibuprofen release from controlled-release tablets
containing ethylcellulose polymer, using different kinetics models.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 69
2.1.5. Ibuprofen and Ketoprofen modified release formulations and nanoparticles
Gohel and Nagori (2009) prepared a novel colonic drug delivery system of Ibuprofen.
Capsules containing HPMC, adsorbate of eutectic mixture of Ibuprofen, methanol and
pregelatinized starch were coated with ethyl cellulose. The ethyl cellulose coated
capsules were incorporated into other capsules and the capsules were coated with
Eudragit S100. The in-vitro dissolution study was conducted.
Valot et al. (2009) prepared biocompatible Ibuprofen loaded-micrcapsules in the size
range from 20-60µm, using Eudragit RSPO or ethylcellulose, by the water in oil
emulsion-solvent evaporation method. The influence of different process parameters,
such as the volatile organic solvent, the oily core, the stirring rate on the properties of
microcapsules was investigated.
Chandran et al. (2008) designed and formulated controlled release matrix tablets of
Ibuprofen, using ethyl cellulose and cellulose acetate phthalate as the rate controlling
agents. The Ibuprofen release was extended for 14-16 hours.
Xiang et al. (2008) four different formulation of Ibuprofen nanostructured lipid carrier
were formulated using, Gelucire 44/14 by melted ultrasonic method. Investigated their in-
vitro and in-vivo properties.
Brabander et al. (2008) bioavailability of Ibuprofen from matrix mini-tablets containing
microcrystalline wax and starch derivative was investigated. Healthy human volunteers
were used for in-vivo evaluation.
Abbaspour et al. (2008) designed sustained-release Ibuprofen tablets which upon oral
ingestion rapidly disintegrated into sustained release pellets in which the integrity of the
pellets coat and core was preserved.
Adamo et al. (2008) prepared eight formulation containing model drug Ibuprofen in the
form of orally disintegrating tablets. By suitable combination of excipients it was thus
possible to obtain a delayed release of Ibuprofen using simple and conventional
techniques.
Golam and Reza (2008) prepared Ketoprofen pellets, using ammonio methacrylate
copolymer type A (Eudragit® RL 30 D) and ammonio methacrylate copolymer type B
(Eudragit® RS 30 D) as release rate retarding agents. The pellets were prepared by
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 70
extrusion spheronization techniques. The influence of physicochemical properties of the
polymers on the release profile of Ketoprofen from the pellets dosage form was also
investigated. The result obtained in this study revealed that proper selection of polymeric
materials based on their physicochemical properties was important in developing
sustained release pellets dosage form with suitable dissolution profile.
Norihiro et al. (2008) Assessed percutaneous penetration and pharmacological effect of
Ketoprofen after transdermal administration, compared to oral route of administration.
Microdialysis technique was used for skin and knee penetration of Ketoprofen, while for
in-vivo study retrodialysis technique was used. The results obtained, indicated that
transdermal patch formulation of Ketoprofen were useful.
Laura and Evangelos (2007) prepared loaded microspheres of Ibuprofen and in-vitro
drug release study was conducted.
Thompson et al. (2007) prepared Ibuprofen-loaded microspheres, using copolyesters.
Effect of various manufacturing parameters such as temperature, disperse phase volume
and polymer: drug ratio on morphology of microspheres was investigated.
Adi and Moawia (2007) encapsulated Ketoprofen particles with polyions and gelatin to
control the release of Ketoprofen in aqueous solutions. Ketoprofen release from the
coated microparticles in aqueous solution of different pH such as 1.4, 4.1 and 7.4 was
studied.
Burcu and Kandemir (2006) microspheres of Ibuprofen were prepared by modified
quasi-emulsion solvent diffusion method. The effect of different formulation factors such
as drug: polymer ratio, volume of solvents, polyvinyl alcohol concentration and type of
polymer on morphology, particle size distribution, drug loading capacity, micromeritical
characteristics and in-vitro drug lease profile were studied.
Nerurkar et al. (2005) developed Ibuprofen controlled-release matrix tablets, using
polymer blend of carrageenanas or cellulose ethers by direct compression method. The
influence of polymer on the drug release rate was studied. Linear release profile was
observed (r2 ≥ 0.96-0.99). The release of the Ibuprofen was sustained over 12-16 hours.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 71
Kim et al. (2005) prepared a swelling-conrolled release delivery system of Ibuprofen,
using monoacrylate-poly (ethylene glycol)-grafted poly (3-hydroxyoctanoate) (PEGMA-
gPHO) copolymers.
Abbaspour et al. (2005) prepared Ibuprofen pellets, using Eudragit RL PO and RS PO
by extrusion-spheronization.
Maurizio et al. (2005) designed composite microcapsules of alginate/poly-L-
ornithine/alginate filled with biodegradable microspheres of Ketoprofen. Polyester
microspheres were developed by solvent evaporation technique. Different characteristics
such as encapsulation efficiency, particle size and in-vitro release were evaluated.
Helton et al. (2005) prepared two types of pellets of Diclofenac sodium and Ibuprofen,
using xanthan gum as sustained releasing agent by extrusion-spheronization technique.
Physical properties of pellets were evaluated
Tamer et al. (2004) developed sustained release suppositories containing Ibuprofen
microspheres, using hydrophilic polyethylene glycol 600 and whitepsol bases by solvent
evaporation method.
Al-Saidan (2004) prepared saturated solution of Ibuprofen, of different concetrations and
investigated their effect on permeation of Ibuprofen across rat epidermis. The
permeability study was also performed, using human epidermis and silastic membrane.
Fernández-Carballido et al. (2004) developed and optimized biodegradable PLGA
microspheres loaded with Ibuprofen for intraarticular administration. The formulation
was developed to provide in-vitro therapeutic concentration of Ibuprofen (8µg/ml) long
period of time.
Caroline et al. (2004) prepared hot melt extruded mini-matrices of Ibuprofen, using ethyl
cellulose and a hydrophilic excipient. Bioavailability study was performed using human
volunteers.
Costa et al. (2004) Ibuprofen pellets were developed and examined the effects of citric
acid and two common fillers (lactose and tricalcium phosphate) on the release profile
from pellets.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 72
Luana et al. (2004) formulated new mucoadhesive patches of Ibuprofen for buccal
administration, using film-forming polymer, polyvinylpyrrolidone (PVP) and
mucoadhesive polymer, NaCMC.
Vueba et al. (2004) formulated and evaluated the hydrophilic matrix tablets of
Ketoprofen, using cellulose methyl cellulose, hydroxypropyl methylcellulose and
hydroxypropylcellulose as polymers, while lactose monohydrate and β-cyclodextrin as
diluents or fillers. The influence of cellulose ether polymer on the drug release was
evaluated. Different physicochemical characteristics, such as drug content, hardness,
weight variation, thickness, tensile strength, friability, swelling and release ratio were
determined. Polymers HPC and MC25 were found, not suitable candidates for the
preparation of modified release Ketoprofen matrix tablets, while HPMC K100M and
K15M were found good for modified release formulation of Ketoprofen. Different
Kinetic models such as zero-order, first-order, Higuchi and Korsmeyer-Peppas were used
for analysis of drug release profile, indicated that polymer type did not show any effect
on the rerlease mechanism of the drug. The formulations containing HPMC also showed
the higher MDT value.
Vostalova et al. (2003) formulated HPMC based hydrophilic matrix tablets of two drugs
with different solubility, well soluble diltiazem HCl and sparingly soluble Ibuprofen.
Barbara et al. (2003) prepared pH-sensitive physical mixture of Ibuprofen for site
specific delivery, using polymethacrylic acid-co-methylmethacrylate substituted with
different degree and types of fatty acids. In-vitro dissolution study was performed at
different pH levels.
Costa et al. (2003) prepared uncoated pellets of Ibuprofen. Both dependent an
independent models were used to assess the difference in dissolution profiles.
Brabander et al. (2003) formulated sustained release mini-matrices of Ibuprofen, using
ethyl cellulose as sustained release agent by hot-melt extrusion technique. The Ibuprofen
release from ethyl cellulose matrices was slow and other excipient such as HPMC and
xanthan gum were used to increase the release of Ibuprofen.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 73
Manish et al. (2003) developed Ibuprofen beads with lower amount of excipient by a
single step novel melt solidification technique. Influence of different variables such as
speed of agitation and amount of cetyl alcohol was studied, using 32 factorial design.
Nadia et al. (2002) formulated Ibuprofen containing granules, using meltable hydrophilic
binder, poloxamer 188 and diluent, lactose by melt granulation.
Rosario et al. (2002) prepared polymeric nanoparticle suspension loaded with Ibuprofen,
using Eudragit RS 100. These suspensions were prepared for improving the availability
of Ibuprofen at the intraocular level. These nanosuspensions were made by modification
quasi-emulsion solvent diffusion technique.
Solinís et al. (2002) prepared sustained release matrix tablets of different enantiomers of
Ketoprofen, HPMC K100M as sustained release agent. Difference in the release profile
was observed due to chiral interaction of HPMC and Ketoprofen. HPMC showed more
interaction to S-enantiomer of Ketoprofen. Influence of formulation pH on the in-vitro
release profile of Ketoprofen was also studied. Diffusion study was also performed.
Roda et al. (2002) developed a new sustained release formulation of Ketoprofen
(Ibifen®) that gradually release Ketoprofen within 24 hours. For comparative in-vivo
study Ibifen® 200mg was administered to 12 human volunteer. Plasma profile was
compared with 200 mg Orudis retard® and two prompt release 100 mg Ibifen
®.
Vergote et al. (2002) in-vivo study of nanocrystalline Ketoprofen after oral
administration to drug was performed. No significant difference in AUC values was
noted between pellets formulation containing nanocrystalline or microcrystalline
Ketoprofen and commercially available prolonged release Ketoprofen formulation.
Perumal (2001) developed modified release microsphers of Ibuprofen by the emulsion
solvent diffusion technique. The in-vitro drug release and micromeritics propreties were
investigated.
Vergote et al. (2001) formulated controlled release pellets of Ketoprofen, using
NanoCyrstal colloidal dispersion. The in-vitro dissolution release pattern of wax based
pellets loaded with nanocrystalline Ketoprofen were compared with dissolution pattern of
wax based pellets loaded with microcrystalline Ketoprofen and commercially available
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 74
Ketoprofen sustained release formulation. Complete release of nanocrystalline
Ketoprofen was observed as compared to other formulations.
Sipahigil and Dortunҫ (2001) prepared and evaluated Verapamil and Ibuprofen
controlled release beads, using carrageenan by ionotropic gelation method. The effect of
different formulation factors such as drug content, polymer concentration, counterion
type and concentration and outer phase volume on particle size, encapsulation efficiency
in-vitro characteristics of beads were evaluated
Giunchedi et al. (2000) developed the hydrophilic matrix tablets of Ketoprofen, using
calcium gluconate, sodium alginate and HPMC in different ratios and combinations by
direct compression method. In-vitro release profile and erosion of the tablets were
investigated. The matrix tablets containing highest quantity of HPMC maintained their
capacity to release the drug for a longer period of time.
Claudia et al. (2000) prepared soy-lecithin aggregates for dermal use containing model
drug, Ketoprofen by compressed gas technique. After evaluation, it was concluded that
soy-lecithin aggregates were best candidates for new drug delivery in dermatology and
cosmetology.
Khan and Zhu (1999) formulated controlled-release matrix tablets of Ibuprofen, using
Carbopol 9334 P and blended mixture of Carbopol 934P and 971P, at different drug to
polymer ratio, by direct compression method. The effect of the proportion of the matrix
material and several co-excipients such as lactose, microcrystalline cellulose and starch
on the release mechanism was investigated.
Philip et al. (1999) prepared the S (+)-Ibuprofen mini-matrix tablets, using wet
granulation method. In-vitro drug release profile and mechanisms were studied.
Khan and Zhu (1998) developed Ibuprofen tablets, using surelease as granulating agent.
Wet granulation technique was used for the preparation of tablets. The influence of
several parameters such as levels of granulating agent, pH of dissolution media and
agitation speed on the release mechanism and release profile was investigated
Paul et al. (1998) formulated eutectic system of Ibuprofen and seven terpene skin
penetration enhancers were used to study.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 75
Khan and Jiabi (1998) developed controlled-release matrix tablets of Ibuprofen, using
Carbopol 974P-NF, at different drug to polymer ratios by direct compression technology.
Nurten and Jülide (1997) designed controlled release osmotic pump system of
Ibuprofen, using polyethylene glycol 600 and sodium chloride as osmoting agents. In this
study, the influence of the delivery orifices and concentration of osmotic agents on the
release rate of Ibuprofen was evaluated.
Ntawukulilyayo et al. (1996) formulated two sustained release Ibuprofen formulation,
using xanthan gum and combination of xanthan gum and n-octenylsuccinate starch
(CL490) by direct compression method. In-vitro and in-vivo studies were conducted.
Blasi et al. (2007) formulated nanoparticles of Ketoprofen, using poly (lactide-co-
glycolide) polymer and physical interaction with drug was determined.
Eerikäinen et al. (2004) prepared Ketoprofen nanoparticles, using Acrylic Polymers
Prepared by an Aerosol Flow Reactor Method.
Thompson et al. (2004), prepared Ibuprofen-loaded microsphers, using novel
copolyesters.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 76
CHAPTER 3
MATERIALS AND METHODS
3.1. MATERIALS
3.1.1. Chemical and reagent
The chemicals and reagents used in pre-formulation and formulation studies of
controlled release matrix tablets and solid dispersions are:
Model drugs Ibuprofen and Ketoprofen (Gratis sample by drug testing laboratory,
Peshawar, Abbott Laboratory, Pakistan, Sanofi-Aventis Pharmaceutical company,
Pakistan and Sigma, UK), Profenid SR® Ketoprofen 200mg tablets by Aventis
Pharmaceutical Company, Islamabad, Pakisstan and Ibuprofen Taiji SR® Ibuprofen 0.3g
(300mg) by China Pharmaceutical Company, Chongqing (Mainland), China (Purchased
from local market), Monobasic Potassium Phosphate (KH2PO4) (Merck, Germany),
Sodium Hydroxide (NaOH) (Merck, Germany), Magnesium Stearate (Solmom
Enterprise, Karachi, Pakistan), Lactose (BDH Chemical Ltd, UK), Different grades of
Ethyl Cellulose Polymer (Dow Chemical Co., Midland, USA), Hydroxypropyl methyl
cellulose (HPMC K100M) (Dow chemical Co., Midland, USA), Corboxy methyl
cellulose (CMC) (Merck, Germany), Starch (Merck, Germany), HPLC grade water
(Fisher, UK), Acetonitrile HPLC grade (Fisher, UK), Diethyl ether (Norway),
Orthophosphoric acid HPLC grade (Merck, Germany), Methanol, HPLC grade (Merck,
Germany), Ethanol (Fisher Scientific, UK), Double distilled water.
3.1.2 Instruments and equipment
Following instruments and equipment were used in this reaserch work.
UV/Visible Spectrophotometer (Shimadzu 1601, Japan), HPLC (Perkin Elmer, 200
series, USA; Millipore water, France), Dissolution apparatus (Pharma Test, PTWS-11/P,
Hunburg, Germany), Magnetic stirrer (VelpScientica, Germany), pH meter (Inolab,
Germany; Denver, USA), Analytical balance (Shimadzu, AX 200, Japan), Oven
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 77
(Mammert, Germany), Single punch tablets compression machine (Erweka, AR 400,
Germany), Fraibilator (Roche, Germany), Hardness tester (Erweka, Germany), Beaker,
test tubes, flasks (Pyrex, Japan; Fisherbrand, UK), Verniar caliper (Germany), Vacuum
filter assembly (Sartorius, Goettingen, Germany), Water distillation apparatus (IRMECO
GmbH, IM-100, Germany), Whatman filter paper (Whatman, Germany), Vacuum pump
(ILMVAC, Germany), Vortex mixer (Gyromixer, Pakland scientific, Pakistan),
Centrifuge machine (Helttich, Germany; Kubota, Janpan), Disposable Syringes (BD,
Pakistan), React vials (Greiner lavortechnik, Germany), Sonicator (Elma D78224,
Germany), Particle scanning distribution size analyzer (Horiba, LA-300, Japan), Shaking
water bath (Shel Lab, 1217-2E, USA), DSC instrument (Mettler Toledo DSC 822e,
Greifensee, Switzerland), FT-IR SpectrumOne spectrophotmer (Perkin Elmer, UK),
Stability Chamber (Ti-Sc-THH-07-0400, Faisalabad, Pakistan), Micropipette (20µl-
1000µl) (TreffLab, France; Gilson, France), Membrane filter paper (Sartorius AG,
Germany), Cannula (BD, Pakistan), Glass vials (Fisherbrand, UK), Glass pipettes
(Fisherbrand, UK), Pipette tips (Gilson, France), Microcentrifuge (Hettich, Micro 120,
Germany), Water bath (Grant, OLS 200, UK).
3.1.3 Animals:
Local breed rabbits of either sex (male and female) (Purchased from local market,
Lahore, Pakistan)
3.2 METHODS
3.2.1 Pre-formulation Studies
Pre-formulation studies were performed for both drugs (Ibuprofen and Ketopfrofen)
before development into matrix tables.
3.2.1.1 Drugs identity conformation: Conformation of the drug was done according
British Pharmacopeia (BP, 2007). Accordingly, the melting point, optical rotation and IR
spectra of the drug were determined, using digital melting point apparatus, optical
rotation and FT-IR machine, respectively. The results were compared with the standard
as given in British Pharmacopeia (2007).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 78
3.2.1.2 Percentage purity determination of model drugs: Before formulation of matrix
tablets the Ibuprofen and Ketoprofen, samples were evaluated for their percentage purity.
The samples were compared with standards Ibuprofen and Ketopofen supplied by Abbott
Pharmaceutical Company, Karachi, Pakistan and Sanofi-Aventis Pharmaceutical
Company, Islamabad, Pakistan, respectively. In each case 50mg of drug was dissolved in
suitable quantity of phosphate buffer solution (pH 7.4) and the final volume (100ml) was
made with the same buffer solution. From this solution 1ml was taken and diluted up to
10ml. The absorbance of Ibuprofen was determined at λ max 223nm and that of
Ketoprofen at λ max 258nm using UV/Visible double beam spectrophotometer
(Shimadzu, 1601, Japan). The following formula was used for %age purity
determination:
%age Purity = )()(
)()(
SampleWstdAbsorbance
stdWSampleAbsorbance
× 100 (3.1)
Where, (std) = Standard, W = Weight.
3.2.1.3 Particles size analysis: The particles size analysis of the drugs was performed
with the Particle size analyzer (LA-300, HORIBA, Japan) using distilled water as a
circulating solvent. After setting different parameters (Circulation Speed: 2min, Ultra
sonic time: 5min, T%: 75%-85%, Form of distribution: standard, R.R.Index; 1.16-0.001)
small quantity of the drug was incorporated into the loading chamber and mean particles
size was determined.
3.2.1.4. Selection of suitable wavelength of model drugs: For this purpose 50 mg of
either drugs powder was dissolved in suitable volume of phosphate buffer solution (pH
7.4) in volumetric flasks and the final volume was made up to 100ml. The drug solution
was scanned between 190.0 nm to 500 nm using UV/Visible double spectrophotometer
(Shimadzu, 1601, Japan) and the λ mas was noted in each case.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 79
3.2.1.5. Powder’s flow properties: The compactibility and flowability of a powder are
critical process parameters that must be determined and investigated prior to tablets
preparation. The flow properties of powders are affected by physicochemical and
mechanical properties of powder, in addition to operational processing conditions.
Moreover, the interparculate attractive forces between the components of powder may
affect the flow properties of powder (Li et al., 2004). Therefore, in order to maximize the
chances of success in formulation development accurate assessment and investigation of
the flow characteristic of powder is essential.
There are a number of methods which have been used for the assessment and
investigation of flow properties of powders such as Angle of Repose (Liu et al., 2001).
Compressibility Index (Liu et al., 2001; Kumar et al., 2001) and Hausner Ratio (USP,
2005; Li et at., 2004; Wong et al., 2002; Abdullah and Geldart, 1999)
3.2.1.6. Angle of Repose: Angle of repose is a parameter which is used for measurement
of characterization of powder flow and properties (Wong et al., 2002; Abdullah and
Geldart, 1999; Liu et al., 2004). A schematic representation of the angle of repose is
shown in the figure (3.1) (Wong et al., 2002).
Figure 3.1 Schematic representation of angle of repose
The funnel method was used for determination of angle of repose (α). The powders were
taken in a funnel. The funnels was fixed with a stand and bellow the funnel tip the Petri
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 80
dish was kept in such a way that the tip of the funnel was exactly at the center and just
above the apex of the heap of powder. The powders were fallen freely on to the Petri dish
and then measured the height of heap and diameter of the powder cone i.e. the diameter
of Petri dish and the following equation was used for calculation of angle of repose (α).
Tan (α) = base
heapofHeignt
5.0 (3.2)
Table 3.1 Angle of repose and flow properties according to B.P 2007.
Flow Property Angle of repose
Excellent 25-30
Good 31-35
Fair 36-40
Passable (May hung up) 41-45
Poor 46-55
Very poor 56-65
Very very poor >66
3.2.1.7. Compressibility index and Hausner Ratio: By measuring the bulk and taped
volume of powder, Compressibility Index and Hausner Ratio were determined. The
Husner value is the measure of propensity of the powder to be compressed and it is
determined using bulk and tapped bulk densities of a powder (USP, 2005). In this study,
first the powders were taken up to the volume of 100 ml in a graduated cylinder of 250ml
and it was the apparent or bulk volume (Vo) and then the cylinder was tapped on flat
surface until there was no further changes observed in powder volume, it was the final
volume or tapped volume (Vf) and the values were put in the following equations.
Compressibility Index = 100×
V
VfV (3.3)
Hausner Ratio = Vf
V (3.4)
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 81
Table 3.2 Compressibility Index and Hausner Ratio limits according to B.P 2007.
Compressibility Flow Character Hausner Ratio
1-10 Excellent 1.00-1.11
11-15 Good 1.12-1.18
16-20 Fair 1.19-1.25
21-25 Passable 1.26-1.34
26-31 Poor 1.35-1.45
32-37 Very poor 1.46-1.59
>37 Very very poor > 1.60
3.2.1.8. Differential scanning calorimetry (DSC) studies: The differential scanning
calorimetry (DSC) study was performed for the determination of drug interaction with
polymers and excipients, using DSC instrument (Mettler Toledo DSC 822e, Greifensee,
Switzerland) equipped with Stare computer program. Approximately 3-6mg of sample
was weighed in aluminum pan and then sealed with punched lid. The temperature ranged
between 20-300oC with heating rate of 10
oC/min under nitrogen gas flow.
3.2.1.9. Fourier transform Infrared (FT-IR) studies: The FT-IR spectra of pure,
Ibuprfofen, ketoprofen and its mixture with polymers and different excipients were taken
to observe the drug-polymer and excipient interaction, using FT-IR SpectrumOne
spectrophotometer (Perkin Elimer, UK) in the range of 650 to 4000 cm-1
. The sample of
several milligrams was placed on the stage of machine and then handle of the machine
was placed on the sample for generation of enough pressure. Then sharp peaks with
reasonable intensities were obtained. The spectra obtained were the result of 4 scans at 1
cm-1
resolution.
3.2.1.10. Preparation of Phosphate Buffer solutions (pH 7.4): For the preparation of
phosphate buffer solution (pH 7.4), firstly 0.2 M monobasic potassium phosphate
solutions and 0.2M sodium hydroxide (NaOH) solution were prepared. 0.2M monobasic
potassium phosphate solution was prepared by dissolving 27.218g of monobasic
potassium phosphate (KH2PO4) in 1000ml of double distilled water and 0.2M NaOH
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 82
solution was prepared by dissolving 8gram of NaOH in 1000ml of double distilled water,
followed by mixing the required volume of 0.2M sodium hydroxide and 0.2M monobasic
potassium, according to the United State Pharmacopeia (USP, 2007).
3.2.1.11. Construction of standard curves: For this purpose stock solutions of the model
drugs (Ibuprofen and Ketoprofen) were prepared in phosphate buffer solution of pH 7.4
having concentration of 0.2mg/ml and then from the stock solution of the respective drug
different dilutions were prepared. The standard curves were constructed by plotting
absorbance values of the dilutions against their respective concentrations.
3.2.1.12 Calculation of concentration of Ibuprofen and Ketoprofen: Regression
equations obtained from the standard curve of Ibuprofen and Ketoprofen were used for
the calculation of concentration of Ibuprofen and Ketopfofen.
Y= MC+B (3.5)
After rearranging the equation:
C= (Y-B)/M (3.6)
Where, Y = Absorbance of solution containing Ibuprofen and ketoprofen at λ max 223nm
and λ max 258nm, respectively.
M = Slope of Ibuprofen or Ketopfrofen Standard Curve of known concentrations
C = Concentration to be calculated
B = Intercept of the Curve
3.2.1.13 Solubility study: Solubility studies of Ibuprofen and Ketoprofen were performed
in different solvents (Phosphate buffer of pH 6.8, 7.2, 7.4, distilled water and 0.1N HCL)
at different temperatures (Room temperature (25oC), 37
oC and 40
oC) according to a
published method by Higuchi and Connors (1965). Accordingly, surplus amount (100mg)
of Ibuprofen and Ketoprofen were placed in 100ml volumetric flasks and then made the
final volume with the desired solvent up to 100ml. The flasks were sealed with aluminum
foils using rubber bands to avoid solvent loss. Then these flasks were kept on shaking
using thermostatically controlled shaking water bath (Shel Lab, 1217-2E, USA) for 24
hours at room temperature (25oC). The oscillation speed was kept at 100 oscillations per
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 83
minute. After 24 hours all flasks were kept undisturbed on flat surface for three hours. A
few ml supernatant from each flask was taken and filtered through membrane filter
(0.45µm). One ml each filtrate was diluted with the same solvent up to 25ml to achieve
suitable dilutions. The diluted samples were analyzed to determine the Ibuprofen and
Ketoprofen concentrations, using a UV/Visible double beam spectrophotometer
(Shimadzu, 1601, Japan) at λ max 223nm and 258nm, respectively. The calibration
curves were used for the determination of the quantity of soluble drug per ml. The same
procedure was repeated for other temperatures such as 37oC and 40
oC. All the solubility
measurements were performed in triplicate.
3.2.1.14. Preparation of solid dispersions: Solid dispersions of Ibuprofen Ketoprofen
were prepared with drug and carrier (Glucosamine HCL) ratio 1:1, 1:2 and 1:3 by weight,
using solvent evaporation technique (Prasad et al., 2010; Jain et al., 2009). The drug was
dissolved in ethanol followed by the addition of carrier dispersion in ethanol. The solvent
was then removed by evaporation keeping at 40o
C under stirring condition (100rpm) for
24 hours. The solid dispersions prepared were then collected and kept at room
temperature for 48 hours. Then the mass was pulverized in porcelain mortar and pestle
and passed through sieve no 100, and stored at room temperature in a desiccator until
further use.
3.2.1.15. Preparation of physical mixtures: For comparative studies of solid dispersions,
physical mixtures were also prepared. The physical mixtures prepared were having the
same composition of the solid dispersions; however, they were prepared by simple
trituration of drugs and carrier in porcelain mortar followed by thorough blending in poly
bags. The mixtures were then sieved and stored in desiccator at room temperature until
further evaluation.
The composition of physical mixtures and solid dispersions of the model drugs is shown
in tables 3.3 and 3.4.
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Table 3.3 Composition of solid dispersions and physical mixtures of Ibuprofen
Formulation
Code Carrier Drug : Carrier Method
F1IBF Glucosamine HCL 1:1 Physical mixture (trituration)
F2 IBF Glucosamine HCL 1:2 Physical mixture (trituration)
F3 IBF Glucosamine HCL 1:3 Physical mixture (trituration)
F4 IBF Glucosamine HCL 1:1 Solid dispersion (solvent evaporation)
F5 IBF Glucosamine HCL 1:2 Solid dispersion (solvent evaporation)
F6 IBF Glucosamine HCL 1:3 Solid dispersion (solvent evaporation)
Table 3.4 Composition of solid dispersions and physical mixtures of Ketoprofen
Formulation
Code Carrier Drug : Carrier Method
F1KTP Glucosamine HCL 1:1 Physical mixture (trituration)
F2 KTP Glucosamine HCL 1:2 Physical mixture (trituration)
F3 KTP Glucosamine HCL 1:3 Physical mixture (trituration)
F4 KTP Glucosamine HCL 1:1 Solid dispersion (solvent evaporation)
F5 KTP Glucosamine HCL 1:2 Solid dispersion (solvent evaporation)
F6 KTP Glucosamine HCL 1:3 Solid dispersion (solvent evaporation)
3.2.1.16. Evaluation of solid dispersions and physical mixtures: The evaluation of solid
dispersion and physical mixture was performed using the following different techniques:
3.2.1.16.1. Determination of drug content: The drug content in each formulation was
determined by taking the solid dispersions or physical mixturesthe equivalent to 50mg of
the respective model drug (Ibuprofen or Ketoprofen) and transferring it to volumetric
flask of 100ml and then small volume of phosphate buffer (pH 7.4) was added to hydrate
the samples. Finaly the volume was made upto the mark. The samples were shaked for
some time to dissolve the drugs completely and were filtered carefully. The absorbance
values of standard (Ibuprofen and Ketoprofen standard, supplied by Abott Labortory,
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 85
Karachi, Pakistan and Sanofi Aventis, Pharmaceutical Company, Islamabad, Pakistan,
respectively) and the samples were determined at λmax 223 nm and 258nm for Ibuprofen
and Ketoprofen, respectively, using double beam spectrophotometer (UV-1601,
Shimadzu, Japan). Three reading were taken and then mean and standard deviation were
calculated.
3.2.1.16.2. Differential scanning calorimetry (DSC) studies: The differential scanning
calorimetry (DSC) study of carier Glucosamine, pure Ibuprofen, Ketoprofen, the solid
dispersions and physical mixtures of the model drugs was performed according to the
method described above in section 3.2.1.8, for determination of drugs-carrier interaction.
3.2.1.16.3. Fourier transform Infrared (FT-IR) studies: The FT-IR spectra of carrier
Glucosamine, pure Ibuprofen, Ketoprofen, the solid dispersions and physical mixtures
were taken to observe the drugs-carrier interation, using the same method as described in
section 3.2.1.9 of this thesis.
3.2.1.16.4. X-ray powder diffractometory studies: X-ray patterns of pure Ibuprofen, pure
Ketoprofen, physical mixtures and solid dispersions were taken using a Philips PW 1830
powder diffractometor (Philips, Eindhoven, Netherlands). The prepared samples were
exposed to Cu Kα radiation (λ= 1.5418 Å) in the range of 00
≤ 2θ ≤ 500. The step size was
0.050 and the time for each step was kept two secods.
3.2.1.16.5. Scanning electron microscope (SEM) analysis: Electron micrographs of
carrier Glucosamine, pure Ibuprofen, pure Ketoprofen, physical mixtures and solid
dispersions were obtained using scanning electron microscope (SEM; Joel JSM-5910,
Japan) operating at 10 kV. The samples were mounted on a metal stub using adhesive
tape with double sided and coated with gold for conductivity in an organ atmosphere
before observation. To study the morphology of active drugs, physical mixture and solid
dispersions, micrographs with different magnification were obtained.
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3.2.1.16.6. Solubility measurement: The solubility measurements of pure Ibuprofen,
Ketoprofen, physical mixtures and solid dispersions in distilled water were performed
according to the well published method by Higuchi and Connors (1965), as described
above in section 3.2.1.13.
3.2.1.16.7. In –vitro dissolution studies: The in-vitro dissolution studies were performed
by USP method II (Paddle method) using eight stations dissolution apparatus Pharma
Test (PTWS-11/P, TPT, Hunburg, Germany) and the rotation speed of paddles was set at
100 r. p.m. Each station or flask of the dissolution apparatus was filled with 900ml of
distilled water, used as dissolution medium to study percentage dissolution of model
drugs (Ibuprofen and Ketoprofen), physical mixtures and solid dispersions. The
temperature of dissolution medium was kept 37oC ± 0.5
oC. Samples of five ml were
withdrawn at selected time intervals (5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100,
110, 120 min) with the help of syringes consisting of 0.45um filters. After each sampling
equal volume of fresh dissolution medium was replaced to maintain the dissolution
medium constant. Then after appropriate dilution the samples were analyzed for
Ibuprofen and Ketoprofen using double beam spectrophotometer (UV-1601, Shimadzu,
Japan) at λmax 223nm and 258nm, respectively. Percent drug dissolution of Ibuprofen
and Ketoprofen was calculated by using calibration standard curves of respective drugs.
The study was conducted in triplicate.
3.2.2 Formuation studies
3.2.2.1 Formulation of matrix tablets containing Ibuprofen and ketoprofen by direct
compression method: Matrix tablets of Ibuprofen and Ketoprofen were prepared using
polymers (Ethocel®
standard premium and Ethocel® standard FP premium) of different
viscosity grades, as drug release controlling agents. HPMC K100M, CMC, Starch and
Lactose were used as co-excipient to determine their influence on the release patterns and
release mechanism of the drugs and Magnesium stearate was use as lubricant. Direct
compression method was used for the preparation of matrix tablets and drug-to-polymer
ratio (D: P) was kept 10:1, 10:2 and 10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
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Table 3.5 Different matrix tablets composition of Ibuprofen
D:P
Ratio
Drug Polymer Filler
(Lactose)
Lubricant Co-excipients
200 mg Ibuprofen -Ethocel matrices
10:1 100mg
7 Premium
10 mg 89 mg
0.5 %
------
7 FP Premium
1 mg
10 Premium
10 FP Premium
100 Premium
100 FP Premium
10:2 100mg
7 Premium
20 mg 79 mg 1 mg ------
7 FP Premium
10 Premium
10 FP Premium
100 Premium
100 FP Premium
10:3 100 mg
7 Premium
30 mg 69 mg 1 mg ------
7 FP Premium
10 Premium
10 FP Premium
100 Premium
100 FP Premium
200 mg Ibuprofen -Ethocel matrices having Co-excipients ( CMC, HPMC, Starch)
10:3 100mg
7 Premium
30 mg 48.3 mg
0.5 % 30 % of filler
7 FP Premium
1 mg 20.7 mg
10 Premium
10 FP Premium
100 Premium
100 FP Premium
All ingredients excepte magnesium stearate were mixed according to dilution principle of
powders and then polybags were used for further mixing. After this, for thorough mixing,
the powder mixtures were passed through No 30-mesh size screen and then the required
amount of magnesium stearate (0.5%) was added as lubricant and mixed well. Later on
each resultant mixture was passed twice through the same mesh screen, and then each
mixture was directly compressed into tablets, using single punch machine (Erweka,
Germany) equipped with 8 mm punch and die set. The composition of various
formulations is given in the tables 3.5 and 3.6.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 88
Table 3.6 Different matrix tablets composition of Ketoprofen
D:P
Ratio Drug Polymer
Filler
(Lactose) Lubricant Co-excipients
200 mg Ketoprofen -Ethocel matrices
10:1 100mg
7 Premium
10 mg 89 mg
0.5 %
------
7 FP Premium
1 mg
10 Premium
10 FP Premium
100 Premium
100 FP Premium
10:2 100mg
7 Premium
20 mg 79 mg 1 mg ------
7 FP Premium
10 Premium
10 FP Premium
100 Premium
100 FP Premium
10:3 100 mg
7 Premium
30 mg 69 mg 1 mg ------
7 FP Premium
10 Premium
10 FP Premium
100 Premium
100 FP Premium
200 mg Ketoprofen -Ethocel matrices having Co-excipients ( CMC, HPMC, Starch)
10:3 100mg
7 Premium
30 mg 48.3 mg
0.5 % 30 % of filler
7 FP Premium
1 mg 20.7 mg
10 Premium
10 FP Premium
100 Premium
100 FP Premium
3.2.2.2. Physical evaluation of matrix tablets: In order to assess whether the tablets
fulfill the desired specifications of United States Pharmacopeia 2007. The USP range for
hardness, friability, thickness, diameter and drug content uniformity is 5-10kg/cm3,
0.8%, 2-4 mm, 4-13 mm and 90-110%, respectively (USP, 2007). Different physical and
dimensional tests such as weight variation, thickness and diameter, hardness test, content
uniformity and friability (Augsburger et al.,2002) were performed, as mentioned below.
3.2.2.2.1 Weight variation test: For this purpose 20 tablets were taken from each batch
and weighed individually, using analytical balance (AX-200, Shimadzu, Japan). The
mean and standard deviation were calculated, using computer based excel programme
and the results were recorded accordingly.
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 89
3.2.2.2.2 Thickness and diameter: The thickness and diameter of 20 tablets from each
batch were observed by varnier caliper (Varnier caliper, Germany) and then mean and
standard deviation were calculated.
3.2.2.2.3 Crushing strength or Hardness test: Crushing strength or Hardness of a tablet
is an indication of the resistance of the solid dosage form to withstand fracturing/ or
attrition (Alton, 2000). For this test, 10 tablets were taken from each batch and their
hardness was determined by using hardness tester (Erweka, Germany). The mean and
standard deviation were calculated and noted accordingly.
3.2.2.2.4 Friability test: It is evaluated under specific conditions. It is used to determine
whether any damage may occur to surface of tablets or whether lamination or tablet
failure may take place when a dosage form is subjected to a mechanical shock (USP,
2005; BP, 2002). Different official guidelines are given by USP and BP. To determine
the friability of the prepared matrix tablets, pre-weighed/de-dusted 20 tablets (W1) from
each formulation were used. For this test, Roche friabilator (Erweka, Germany) was used
at speed of 25 r.p.m for four minutes. Then the tablets were de-dusted well with the help
of a blower and re-weighed (W2) to determine the loss in their weight. Friability was
calculated using the following formula:
1
21%
W
WWF
×100 (3.7)
Where, W1= Initial weight of tablets; W2= Final weight of tablets
3.2.2.2.5 Content Uniformity Assay: For this purpose 10 tablets were taken randomly
from each batch and pulverized into powder, using pastle and mortar. The powder
samples equivalent to 20 mg of the drug were transferred to a volumetric flask (100ml)
followed by addition of a small volume of phosphate buffer (pH 7.4) to hydrate the
samples and final volume was made upto the mark. The samples were shaked for some
time to dissolve the drug completely and were passed through membrane filter paper
(0.45µm). The absorbance values of standar standard (Ibuprofen and Ketoprofen
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 90
standard, supplied by Abott Labortory, Karachi, Pakistan and Sanofi Aventis,
Pharmaceutical Company, Islamabad, Pakistan, respectively) and the samples were
determined at λmax 223 nm and 258nm for Ibuprofen and Ketoprofen, respectively,
using double beam spectrophotometer (UV-1601, Shimadzu, Japan). Three reading were
taken and then mean and standard deviation were calculated.
3.2.2.3. In vitro dissolution studies
In vitro dissolution studies were conducted for the determination of drug release rate
from the formulations to USP method-1 (basket method), using eight stations dissolution
apparatus Pharma Test (PTWS-11/P, TPT, Hunburg, Germany) and the rotation speed of
basket was set at 100 r.p.m. Each station or flask of the dissolution apparatus was filled
with 900ml of 0.2M phosphate buffer (pH7.4) used as dissolution medium to study the
release rate and pattern of drug from tablets matrices up to 24 hrs. The temperature of
dissolution medium was kept 37ºC ± 0.5ºC. Samples of five ml were withdrawn at pre-
dermined time of interval 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 hrs with the help of
syringes consisting of 0.45um filters. After each sampling equal volume of fresh
dissolution medium was replaced to maintain the dissolution medium constant. Then all
samples were diluted with the same buffer solution. The absobance values of model drugs
(Ibuprofen and Ketoprofen) were recorded, using spectorophtometerl (UV/Visible-1601,
Shimadzu, Japan) at λmax 223 and 258nm for Ibuprofen and Ketoprofen, respectively.
Finally percent release of drugs was calculated, using their respective calibration standard
curves. The release study for all formulations was conducted in triplicate.
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Figure 3.2 Pharma-test dissolution apparatus
3.2.2.4. Drug Release kinetics
The following various kinetic models were applied on the data obtained from in vitro
dissolution studies of different matrix tablets formulations to determine the release
kinetics:
3.2.2.4.1 Zero-order kinetics (Xu and Sunada, 1995; Najib and Suleiman, 1985): Zero
order kinetic equation or model may be used for the constant release rate characterization
or representation of any active pharmaceutical ingredient (API) from a dosage form that
do not disintegrate or deaggregate (Costa and Lobo, 2001; Chang RK, 1986). Those
dosage forms which follow zero order kinetic, release the API in a constant amount per
unit time. To achieve prolong pharmacological action in sustained release dosage forms,
zero order model is an ideal kinetic model (Costa and Lobo, 2001; Chang RK, 1986).
This model is representing in the following equation.
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 92
W = k1t (3.8)
Where,
W = the amount of drug release at time = t
k1 = the zero-order release rate constant
t = time
3.2.2.4.2 First-order kinetics equation (Merchant et al., 2006; Avachat and Kotwal,
2007; Donbrow and Samueloy, 1980; Higuchi, 1963): The first order kinetic equation or
model was first proposed by Gibaldi and Feldman (Gibaldi and Feldman, 1967) and later
by Wagner (Wagner, 1969), where this model was used for description and
Characterization of absorption and release or elimination of certain drugs from biological
systems. This kinetic equation or model may be applied in those dissolution situation
where sink conditions exist (Wagner, 1969). This has shown in the following equation.
In (100-W) = In100-k2t (3.9)
Where,
W= the amount of drug release at time = t;
k2= the first order release rate constant
t= time
3.2.2.4.3 Hixon Crowel’s Equation(Erosion model) (Costa et al.,2003; Hixon and
Crowell, 1931): This model was developed by Hixon and Crowell (Hixon and Crowell,
1931). It is represented in the following equation.
(100-W)1/3
=1001/3
– k3t (3.10)
Where, W= the amount of drug release at time = t;
k3= a constant incorporating the surface volume relationship;
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 93
3.2.2.4.4 Higuchi’s Squre of Time Equation (Diffusion model) (Higuchi, 1963;
Korsmeyer et al., 1983): The Higuchi or Diffusion model describes the dissolution of
drugs in suspension from non-eroding matrix such as ointment base (Higuchi, 1963;
Higuchi, 1961). This model is also applicable for description of dissolution rates of other
pharmaceutical dosage forms other than ointment and also for description of dissolution
process and release mechanism of modified drug delivery systems (Higuchi, 1963;
Higuchi, 1961). The simple form of Higuchi model is shown in the following equation.
W = k4t1/2
(3.11)
Where,
W= the amount of drug release at time = t
k4= Higuichi dissolution rate constant
t= time
3.2.2.4.5 Power law equation or Korsmeyer- Peppas equation for mechanism of drug
release (Brabander et al., 2003; Korsmeyer et al., 1983; Rigter and Peppas, 1987): It is a
simple semi-empirical model that creates a relationship between drug release and elapsed
time with an exponential function. It is represented mathematically in the following
equation.
Mt / M∞ = k5t n
(3.12)
Where,
Mt / M∞= the fraction of drug release at time = t
k5= kinetic constant compromising the structural and geometric characteristics of the
device; n= the diffusion exponent for drug release
This model has been used for different systems in which the value for n is used to
describe different release mechanisms. For cylindrical matrix tablets if the n value is
equal to 0.45, then it indicates that the drug release mechanism is Fickian diffusion, and if
the n value is more than 0.45 and less than 0.89 it indicates that it is non-Fickian or
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anomalous diffusion and if n value 0.89 is the indication of case II transport or typical
zero order release (Siepmann and Peppas, 2001) and greater than 0.89 is super case II
transport (Vueba et al., 2004)
Table 3.7 Interpretation of release exponent “n” in power law for release
mechanism of different geometries (Rigter RL and Peppas, 1987a; Retger and Peppas,
1987b). Exponent “n” for
Thin film Cylinder Sphere
Drug release mechanisms
≤ 0.5 ≤ 0.45 ≤ 0.43 Fickian diffusion
0.5 < n < 1.0 0.45 < n < 0.89 0.45 < n < 0.89 Anomalous
1.0 ≥ 0.89 0.85 Zero order
Note: The word cylinder refers to tablets
3.2.2.5 Testing dissolution equivalency
To test dissolution equivalency model independent method was used as such, suggested
by shah (Shah et al., 1998) and Fassihi and Pillay (Fissihi and Pillay, 1998). This model
was recommended for use by the US FDA (US FDA, 1997). Model independent method
is a simple approach to compare the dissolution profiles using difference factor ƒ1 and
similarity factor ƒ2. These are commonly known as ƒ1 and ƒ2 fit factors, originally
reported by Moore and Flanner (Moore and Flanner, 1996). To calculate the percent
difference between the two dissolution profile at each time point and relative error
between the two curves difference factor ƒ1 is used. The difference factor ƒ1 was
calculated using the following formula:
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 95
ƒ1 = (3.13)
Where “n” is the number of pull points, Rt is the dissolution profile of the reference
tablets at time t and Tt is the dissolution profile of the test tablets at the same time “t”.
The similarity factor ƒ2 is a measurement of the similarity in the percent dissolution
between the curves and logarithmic reciprocal square root transformation of the sum of
squared error.
The following formula was used for similarity factor ƒ2.
ƒ2 = 50 log (3.14)
Where n is the number of points collected, Rt and Tt are the percent drug released at each
time point for reference and test tablets, respectively. If the value of difference factor ƒ1
is close to zero and similarity factor is close to 100 then the release profiles between two
formulations are considered similar. Generally, ƒ1≤15 and ƒ2 ≥50 indicates an average
difference of not more than 10% at the sample time points. (Gohel and Panchal, 2002;
Shah et al., 1998; US FDA, 1997)
3.2.2.6. Accelerated stability and reproducibility studies
The selected optimized matrix tablets formulations of each drug were stored at room
temperature, using stability chamber (Ti-Sc-THH-07-0400, Pakistan) and also tested for
stability under the short term accelerated storage conditions. Short term stability study
was carried out under the International Commission for Harmonization (ICH) guidelines
for accelerated storage conditions i.e. at 40 ±2
oC and Relative humidity (HR) 75 ±5 %.
The tablets were evaluated for their physical appearance, hardness, friability, weight
variation, content uniformity, dissolution profile at predetermined intervals of 0, 1, 2, 3,
6, 9, and 12 months.
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Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 96
3.2.2.7. Preparation of matix tablets containing solid dispersions of model drugs
Solid dispersions of models drugs (Ibuprofen and Ketoprofen) corresponding to 100mg
of drugs, using Ethocel® standard 7 FP premium polymer as release controlling agent, at
D: P ratio 10: 3 were poured into die. Tablets were compressed according to the method
as described above in section 3.2.2.1 and physicochemical evaluation and in-vitro
dissolution study were carried out according to section 3.2.2.2 and 3.2.2.3, respectively.
3.2.2.8. In-vivo evaluation
3.2.2.8.1. Study Protocol and Design: The study protocol was approved by Research and
Ethical Committee. The Animal Scientific Procedure Act, 1986 was followed for the
procedure used. The pharmacokinetic parameters of the reference sustanined release
tablets and optimized controlled release test tablets for comparison were studied in two
animal groups, each comprising 12 rabbits in a parallel study design. The in-vitro and in-
vivo correlation was carried using suitable formulas. The dose study design has been
given in table (3.8)
Table 3.8 Dosing Schedule design of test tablets and reference tablets for
pharmacokinetics study
Treatment Description Dose
1 Ibuprofen Taiji SR®, Sustained release Ibuprofen tablets
(300 mg)
1 tablet
2 Test CR matrix tablets of Ibuprofen (300 mg) 1 tablet
3 Profenid SR®, Sustained release Ketoprofen tablets (200
mg)
1 tablet
4 Test CR matrix tablets of Ketoprofen (200mg) 1 tablet
Note: Treatment 1, 2, 3, and 4 with dose 1 tablet means that one tablet of each
formulation of test and reference was administered to each rabbit of the group (n=12)
As shown in the table (3.8). In the first trial period, each rabbit of one group (n=12) was
given reference tablets of Ibuprofen and each rabbit of the other group (n=12) was given
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test tablets. And then after washout period of one week, each rabbits of both the groups
were given reference Ketoprofen tablets and test tablets.
3.2.2.8.2. Animals used for in-vivo studies: For in-vivo studies, local breed rabbits of
either sex, weighing 3 ± 0.5Kg were used as were used by Ishikawa (Ishikawa et
al.,2000) Maeda (Maeda et al.,1979) and Jing (Jing et al.,2006).
The rabbits were divided into two groups each one consisting 12 rabbits for assessment of
the pharmacokinetics evaluation of the test and reference formulations. The rabbits used
were kept on fasting for 24 hours before administration of test and reference tablets and
the same fasting condition was maintained until 24 hours post dosing. However, water
was allowed at libitum during this period.
3.2.2.8.3. Food, animal housing and maintenance for rabbits: The standard food was
given to the rabbits used for this study at least three days before administration of the
formulations. The standard food was prepared according to a published recipe composed
of 10% White fish meat, 18% Middlings, 20% Grass meal, 40% Bran (Kelley et al.,
1992)
3.2.2.8.4. Tablets administration to rabbits: For administration of tablets to rabbits 3ml
syringe with its barrel smoothly cut at the needle end to avoid the damage to oral mucosa
of rabbit was used. Before administration of tablets the rabbits were kept on fasting for
24hours and then the rabbits were shifted to wooden holder and tablets were administered
orally with help of syringe as mentioned. After conformation of tablets swallowing tap
water was given to rabbits with the help of 10ml syringe fitted with oral tube in order to
mimic human dosing.
3.2.2.8.5. Blood sample’s withdrawal or collection from rabbits: The blood samples of
1ml were collected in centrifuged tubes (Containing sodium heparin as anti-coagulant) at
0 (before dosing) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 42 and 48 hours after
dosing via an in-dwelling cannula placed in the marginal ear vein (Fig. 3.3) of rabbits for
the test and reference formulations of Ibuprofen and Ketoprofen. The blood samples
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collected were centrifuged for 15min at 3500 rpm and the plasma was transferred to new
glass tubes and kept frozen at -200 C until analysis.
Figure 3.3 Marginal ear vein of rabbit
3.2.2.9. Extraction of drugs from plasma
3.2.2.9.1. Extraction procedure for Ibuprofen and Ketoprofen from plasma: For the
extraction of drugs from the plasma a simple one step liquid liquid extratction procedure
was used. For the extraction of Ibuprofen from plasma the method used by
Ntawukulilyayo et al (Ntawukulilyayo et al., 1996) was used with slight modification.
Briefly, 500µl of plasma containing drug Ibuprofen was taken into a glass tube with
Teflon lined screw cap and 4ml hexan/ether mixture (4:1, v/v) was used as extracting
solvent. For Ketoprfofen extraction the method reported by Satterwhite and Boudinot
(Satterwhite and Boudinot, 1988) was used with some modification. In this the same
volume of plasma (500µl) was taken and then the samples were extracted with 4ml
diethyl ether. Then the samples prepared were vortexed 1-5 minutes with help of vortex
mixer (Gyromixer, Pakistan). After vortex mixing the samples were centrifuged 3500
rpm for 15 minutes by centrifuge (Kubota, Japan). Then the upper supernatant layer was
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transferred into React vial (React vial, Germany). Then the extraction solvents were
evaporated to dryness under nitrogenous atmosphere at 40o C. The resulting residues in
react vial were reconstituted with 100µl of respective mobile phases for Ibuprofen and
Ketoprofen.
3.2.2.10. HPLC analysis of drugs in rabbit plasma
For the determination and analysis of Ibuprofen and Ketoprofen concentration in plasma
the already published methods were used with slight modification.
3.2.2.10.1. Analysis of plasma Ibuprofen concentration: The Ibuprofen plasma samples
were analyzed, using a reversed-phase high performance liquid chromatographic (HPLC)
technique according to the method reported by (Paul et al.,1998) with slight modification.
Briefly, the HPLC system comprised of an HPLC (Perkin Elmer series 200, USA) with
binary pump solvent delivery system (Perkin Elmer Series 200, USA), UV/ Visible
variable wave length detector (Perkin Elmer Series 200, USA), Integrator NCI 900,
Degasser (Perkin Elmer Series 200, USA) and TCNav software. The samples of 20µl
were injected with the help of 50µl syringe into a 20µl sample loop in Rheodyne
injection port. The eluted chromatographic peaks were detected at λ max 220nm by UV
detector (Perkin Elmer Series 200, USA), using a reverse phase C-18 (ODS Hypersil, 4.6
×250mm, 5µm) stainless steel analytical column (Thermo Electron Corporation, UK)
fitted with a refillable guard column. The solvent used were degassed with help of
sonicator (Elma D 78224, Germany) before operation of HPLC and the pH of the mobile
was adjusted by pH meter (Inolab Series, Germany). The mobile phase consisted of
acetonitrile and phosphate buffer (60:40 v/v) with pH 3.0 ±0.2 was used. The pH of the
mobile phase was adjusted with orthophosphoric acid. The mobile phase prepared was
filtered through the 0.45µl membrane filter (Sartorius, Germany) and was then degassed
by ultrasonication. The analysis of was performed isocratically with mobile phase flow
rate of 1.0ml/min. And then quantification was done by linear regression equation
derived from standard curve.
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3.2.2.10.2. Analysis of plasma Ketoprofen concentration: The chromatographic analysis
of Ketoprofen samples was performed using the same HPLC system and procedure which
were used for Ibuprofen, but the mobile phase composition and the λ max for eluted
chromatographic peaks detection were different. The Ketoprofen in plasma was
determined according to the method described by Roda et al (Roda et al., 2002). For the
elution of Ketoprofen the mobile phase consisted of acetonitrile and 0.1M KH2PO4
(40:60 v/v) was used. The pH was adjusted to apparent pH 3.5 with H3PO4. The peaks
were detected at λ max 254nm.
3.2.2.11. Pharmacokinetic analysis
The most common pharmacokinetic parameters such as peak plasma concentration
(Cmax), time to reach maximum plasma concentration (Tmax) and total area under the
plasma concentration-time curve (AUC0-∞) were determined from the plasma
concentration time profile of the reference and test formulation for twelve rabbits. The
peak plasma concentration (Cmax) and time of its occurrence (Tmax) were calculated
directly from each plasma concentration data (Weiner, 1981). The plasma concentration-
time data for both drugs Ibuprofen and Ketoprofen in each animal was analyzed by well-
known pharmacokinetic computer software, WinNolin® Ver 5.2.1(Pharsight Corporation,
Mountain View, CA, USA). The total area under the plasma concentration-time curve
(AUC0-∞) was estimated by adding the area from time zero to the last sampling time
(AUC0-t) and the area from the last sampling point to infinity (AUCt-∞). The (AUC0-∞)
and momen plasma level time curves (AUMC) were calculated by trapezoidal method.
The ratio of (AUCt-∞) and (AUMC) was used for the calculation of mean residence time
(MRT). The (AUCt-∞) was determined by dividing the last measurable plasma drug
concentration with total elimination rate constant (Kel). All other parameters such as
terminal rate constant (Lz), half-life (t1/2), clearance (Clt), volume of distribution (Vd)
were calculated using the following formulas:
t1/2= In2/Lz, Cltotal= Dose/(AUC0-∞), and Vd= Cltotal/Lz, respectively.
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3.2.2.11.1. In-vitro and In-vivo correlation: The in-vitro and in-vivo correlation was
determined by plotting the percent drug absorbed (Fa) against percent drug released (Fr).
The values of percent drug released were taken from the in-vitro release data while
percent drug absorbed was determined by using Wagner and Nelson equation (Wagner
and Nelson, 1964).
Fa (3.16)
Where,
Fa= fraction of drug absorbed;
Ct= plasma drug concentration at time = t
Kel= the total elimination rate constant;
AUC0-t= area under the curve between time zero and time t;
AUC0-∞= area under the curve between tie zero and infinity
3.2.2.12. Statistical analysis
The parameters obtained were further processed for individual rabbit statistically for
getting mean and standard deviation and level of significance, using computer based
programs SPSS 17.
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CHAPTER 4
RESULTS AND DISCUSSION
Ibuprofen and Ketoprofen are Non-steroidal anti-inflammatory drugs, used for
rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute musculoskeletal injury
and dysmenorrhea. Due to their short half-life, dosage frequency, patient non-compliance
and side effects such as gastrointestinal disturbance, peptic ulceration and gastrointestinal
bleeding, they are considered to be good candidates for formulation into controlled
release dosage forms. Different drug delivery systems were developed such as controlled
release matrices, solid dispersionS and nanoparticle to avoid the above mentioned
problems.
4.1. Drugs identity conformation studies
During the preformulation studies, both drugs were evaluated physically in order to
confirm their identity, using British Pharmacopoea, 2007 as reference standard. As shown
in table 4.1, the melting point and optical rotation for Ibuprofen are 76.1oC and 0.03,
respectively and for Ketoprofen the melting point determined is 94oC, which are within
BP limits.
Table 4.1 Results of identity conformation tests
Chemical Test
performed
Result Official limit Comments
Ibuprofen Melting point
&
Optical rotation
76.1 °C
&
+ 0.03
75 to 78°C
&
-0.05° to + 0.05°
Identity
confirmed
Ketoprofen Melting point
94oC
94 to 97oC
Identity
confirmed
For further conformation FT-IR spectra for both drugs were taken and compared with the
standard spectra given in BP, 2007.
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Figure 4.1 FT-IR spectra of (a) BP Standard (b) Pure Ibuprofen sample
Figure 4.2 FT-IR spectra of (a) BP Standard (b) Pure Ketoprofen sample
Table 4.2 Percentage purity of Ibuprofen and Ketoprofen
Drug Absorbance %age purity
determined
BP 2007 limit comments
Ibuprofen Sample= 2.232
Standard= 2.237
99.78
99% to 101% Within limit
Ketoprofen Sample= 3.01
Standard= 3.019
99.701 99% to 101% Within limit
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As shown in Figs. 4.1 and 4.2, the FT-IR spectra of Ibuprofen and Ketoprofen samples
were similar, in all respects, to standard spectra of the same drugs as given in the BP,
2007, indicating the identity conformation and purity of the samples/model.
Table 4.2 shows the % age purity of the sample Ibuprofen and Ketoprofen as compared to
those of the BP standards. It may be observed that the % age purity of the sample drugs
lies within the acceptable BP limits.
4.2. Particle size analysis
After determination of percentage purity of the drugs, particle size analysis was
performed because particle size and size distribution of any drug play an important role in
the release pattern as well as the release mechanism of a drug from controlled release
formulations (Velasco et al., 1999). The details about mean particles size and size
distribution of Ibuprofen and Ketoprofen are shown in the Figs. 4.3 and 4.4. As shown
the mean particle size distribution for Ibuprofen was 38.30µm while that for Ketoprofen
the 24.35µm. So it indicated that both drugs are suitable candidate for controlled release
formulations.
Figure 4.3 Particle size distribution of Ibuprofen
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Figure 4.4 Particle size distribution of Ketoprofen
4.3. Selection of suitable wavelength for model drugs (Ibuprofen and Ketoprofen)
The UV spectra of Ibuprofen and Ketoprofen in phosphate buffer solution (pH 7.4) are
shown in Figs. 4.5 and 4.6.
Figure 4.5 UV/Visible spectra of Ibuprofen with different wave lengths in phosphate
buffer solution pH 7.4
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Figure 4.6 UV/Visible spectra of Ketoprofen with different wave lengths in
phosphate buffer solution pH 7.4
The spectra demosnstrate primery maximas (peaks) at 223nm and 217nm for Ibuprofen
and Ketoprofen, respectively, while secondry maximas (peaks) for Ibuprofen and
Ketoprofen are shown at 264nm and 258nm, respectively. In case of Ibuprofen, the
primary maxima (223nm) was selected as suitable wavelength for further analysis due to
clear peak and stable and maximum absorbance at this wavelength, as shown in Fig. 4.5.
However, in case of Ketoprofen a secondry maximum (258nm) was selected because of
stability and maximum absorbance at this wave length (Fig. 4.6).
4.4. Powder’s flow properties
In order to obtain optimum flow of powder from bulk storage containers or hoppers into
dies and for achieving reproducible matrix tablets with acceptable content uniformity,
blends of each formulation and pure Ibuprofen and Ketoprofen were evaluated for
compressibility index, Hausner Ratio and angle of repose, before matrix tablets
formulation.
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As problem in flowability can cause variations in die filling and result in tablets that vary
in weight, drug content and strength; to ensure uniform feed from hopper into dies for
achieving reproducible tablets with acceptable content uniformity, weight variation and
physical consistency an optimum flow of powder blends is must (Navaneethan et al.,
2005) These studies were conducted according to BP, 2007.
As shown in table 4.3, the compressibility index, Hausner Ratio and angle of repose for
pure Ibuprofen are 28±0.03%, 1.39±0.02 and 48.5±0.03, respectively, indicating poor
flow properties and for pure Ketoprofen, the vlues of the said parameters viz.
compressibility index, Hausner Ratio and angle of repose were 31±0.01%, 1.45±0.01 and
49.7±0.02, respectively (table 4.4), conforming poor flow properties. For improvement of
flow properties, 0.5% magnesium stearate was added as lubricating agent during mixing
of the formulation ingredients for all formulations, which showed good results and
improved flow properties of the powder blends. The same remedy has been prescribed by
the B.P and U.S.P to resolve such problems in flow properties of powders.
As shown in table 4.3, the values of the above mentioned parameters changed
significantly in favor of better flow properties, where the compressibility index for
Ibuprofen formulations became 12.3±0.03% to 14.8±0.01%, the Hausner Ratio as
1.112±0.02 to 1.17±0.02 and the angle of repose as 32.1±0.03 to 34.9±0.04, indicating
better flow properties. Similar improvements in flow properties for all formulation of
Ketoprofen blended magnesium stearate were observed (table 4.4), where the values of
the flow parameters changed significantly and the compressibility index became
12.4±0.04% to 15±0.02%, the Hausner Ratio as 1.121±0.03 to 1.18±0.02 and angle of
repose as 32.2±0.02 to 35±0.01, indicating better flow properties. These improvements in
flow properties of the powder samples were attributed to the addition of magnesium
stearate which is used as lubricating agent (Row, 2003).
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Table 4.3 Micromeritics or flow properties of pure Ibuprofen and formulation blends
S/NO Formulation D:P Ratio Co-
Excipients
Compressibility
Index (%)
(Mean±SD)
Hausner
Ratio
(Mean±SD)
Angle of
Repose
(Mean±SD)
1 Pure Ibuprofen - - 28±0.03 1.39±0.02 48.5±0.03
2 Ethocel® Standard 7P 10:1 Nil 14.8±0.01 1.167±0.03 34.9±0.04
3 Ethocel® Standard 7 FP -do- Nil 14.4±0.01 1.152±0.01 34.6±0.01
4 Ethocel® Standard 7P 10:2 Nil 14±0.03 1.154±0.03 34±0.01
5 Ethocel® Standard 7 FP -do- Nil 13.7±0.03 1.14±0.04 33.8±0.03
6 Ethocel® Standard 7P 10:3 Nil 13.5±0.02 1.133±0.02 33.5±0.03
7 Ethocel® Standard 7 FP -do- Nil 13.3±0.03 1.131±0.03 33.2±0.04
8 Ethocel® Standard 7P -do- HPMC 14.6±0.01 1.17±0.02 35±0.01
9 Ethocel® Standard 7 FP -do- HPMC 14.3±0.05 1.163±0.02 34.9±0.03
10 Ethocel® Standard 7P -do- CMC 13.3±0.04 1.123±0.05 33.4±0.01
11 Ethocel® Standard 7 FP -do- CMC 13.1±0.03 1.123±0.04 33.1±0.02
12 Ethocel® Standard 7P -do- Starch 12.9±0.04 1.123±0.04 33±0.04
13 Ethocel® Standard 7 FP -do- Starch 12.7±0.01 1.112±0.03 33±0.01
14 Ethocel® Standard 10P 10:1 Nil 14.7±0.03 1.17±0.03 34.9±0.01
15 Ethocel® Standard 10 FP -do- Nil 14.3±0.05 1.15±0.04 34.4±0.04
16 Ethocel® Standard 10P 10:2 Nil 13.8±0.02 1.153±0.03 33.9±0.04
17 Ethocel® Standard10 FP -do- Nil 13.6±0.03 1.13±0.02 33.7±0.05
18 Ethocel® Standard 10 P 10:3 Nil 13.4±0.02 1.132±0.02 33.4±0.02
19 Ethocel® Standard 10 FP -do- Nil 13.2±0.02 1.13±0.04 33.1±0.03
20 Ethocel® Standard 10 P -do- HPMC 14.5±0.04 1.16±0.03 34.9±0.03
21 Ethocel® Standard 10 FP -do- HPMC 14.2±0.03 1.159±0.04 34.8±0.02
22 Ethocel® Standard 10P -do- CMC 13.2±0.06 1.122±0.02 33.3±0.02
23 Ethocel® Standard 10 FP -do- CMC 13±0.04 1.12±0.03 33±0.03
24 Ethocel® Standard 10 P -do- Starch 12.8±0.03 1.122±0.03 32.9±0.03
25 Ethocel® Standard 10 FP -do- Starch 12.6±0.02 1.121±0.03 32.8±0.03
26 Ethocel® Standard 100P 10:1 Nil 14.6±0.03 1.16±0.02 34.8±0.02
27 Ethocel® Standard 100 FP -do- Nil 14.1±0.04 1.153±0.01 34.7±0.02
28 Ethocel® Standard 100 P 10:2 Nil 13.5±0.03 1.146±0.01 33.8±0.04
29 Ethocel® Standard 100 FP -do- Nil 13.3±0.04 1.121±0.03 33.5±0.01
30 Ethocel® Standard 100 P 10:3 Nil 13.1±0.02 1.12±0.05 33.2±0.02
31 Ethocel® Standard 100 FP -do- Nil 13±0.02 1.12±0.04 32.1±0.03
32 Ethocel® Standard 100 P -do- HPMC 14.3±0.03 1.14±0.03 34.7±0.04
33 Ethocel® Standard 100 FP -do- HPMC 14.2±0.02 1.146±0.03 34.4±0.05
34 Ethocel® Standard 100 P -do- CMC 13.1±0.04 1.121±0.02 33.2±0.04
35 Ethocel® Standard 100 FP -do- CMC 12.9±0.05 1.12±0.04 32.9±0.01
36 Ethocel® Standard 100 P -do- Starch 12.5±0.04 1.121±0.03 32.7±0.01
37 Ethocel® Standard 100 FP -do- Starch 12.3±0.03 1.2±0.01 32.30.03
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 109
Table 4.4 Micromeritics or flow properties of pure Ketoprofen and formulation blends
S/NO Formulation D:P Ratio Co-
Excipients
Compressibility
Index (%) Hausner Ratio
Angle of
Repose
1 Pure Ketoprofen - - 31±0.01 1.45±0.01 49.7±0.02
2 Ethocel® Standard 7P 10:1 Nil 15±0.02 1.17±0.05 35±0.01
3 Ethocel® Standard 7 FP -do- Nil 14.7±0.01 1.171±0.02 34.7±0.02
4 Ethocel® Standard 7P 10:2 Nil 14.1±0.01 1.155±0.04 34.1±0.02
5 Ethocel® Standard 7 FP -do- Nil 13.8±0.02 1.141±0.02 33.9±0.03
6 Ethocel® Standard 7P 10:3 Nil 13.6±0.02 1.134±0.04 33.6±0.01
7 Ethocel® Standard 7 FP -do- Nil 13.4±0.03 1.132±0.01 33.3±0.01
8 Ethocel® Standard 7P -do- HPMC 14.7±0.01 1.18±0.02 35±0.01
9 Ethocel® Standard 7 FP -do- HPMC 14.4±0.03 1.164±0.02 34.9±0.01
10 Ethocel® Standard 7P -do- CMC 13.4±0.03 1.124±0.01 33.5±0.01
11 Ethocel® Standard 7 FP -do- CMC 13.2±0.04 1.124±0.02 33.2±0.02
12 Ethocel® Standard 7P -do- Starch 13±0.03 1.124±0.03 33.1±0.05
13 Ethocel® Standard 7 FP -do- Starch 12.8±0.04 1.113±0.03 33.1±0.04
14 Ethocel® Standard 10P 10:1 Nil 14.8±0.02 1.18±0.03 35±0.01
15 Ethocel® Standard 10 FP -do- Nil 14.4±0.01 1.16±0.01 34.5±0.01
16 Ethocel® Standard 10P 10:2 Nil 13.9±0.02 1.154±0.04 34±0.03
17 Ethocel® Standard10 FP -do- Nil 13.7±0.03 1.14±0.01 33.8±0.01
18 Ethocel® Standard 10 P 10:3 Nil 13.5±0.05 1.133±0.01 33.5±0.03
19 Ethocel® Standard 10 FP -do- Nil 13.3±0.03 1.14±0.01 33.2±0.01
20 Ethocel® Standard 10 P -do- HPMC 14.6±0.02 1.17±0.02 35±0.01
21 Ethocel® Standard 10 FP -do- HPMC 14.3±0.03 1.16±0.04 34.9±0.04
22 Ethocel® Standard 10P -do- CMC 13.3±0.04 1.123±0.05 33.4±0.02
23 Ethocel® Standard 10 FP -do- CMC 13.1±0.06 1.13±0.01 33.1±0.03
24 Ethocel® Standard 10 P -do- Starch 12.9±0.01 1.123±0.03 33±0.02
25 Ethocel® Standard 10 FP -do- Starch 12.7±0.03 1.122±0.03 32.9±0.02
26 Ethocel® Standard 100P 10:1 Nil 14.7±0.03 1.17±0.02 34.9±0.01
27 Ethocel® Standard 100 FP -do- Nil 14.2±0.03 1.154±0.01 34.8±0.03
28 Ethocel® Standard 100 P 10:2 Nil 13.6±0.04 1.15±0.03 33.9±0.04
29 Ethocel® Standard 100 FP -do- Nil 13.4±0.02 1.122±0.03 33.6±0.04
30 Ethocel® Standard 100 P 10:3 Nil 13.2±0.01 1.123±0.01 33.3±0.04
31 Ethocel® Standard 100 FP -do- Nil 13.1±0.04 1.123±0.02 32.2±0.03
32 Ethocel® Standard 100 P -do- HPMC 14.4±0.02 1.15±0.03 34.8±0.02
33 Ethocel® Standard 100 FP -do- HPMC 14.3±0.02 1.147±0.03 34.5±0.01
34 Ethocel® Standard 100 P -do- CMC 13.2±0.03 1.122±0.03 33.3±0.01
35 Ethocel® Standard 100 FP -do- CMC 13±0.04 1.121±0.02 33±0.03
36 Ethocel® Standard 100 P -do- Starch 12.6±0.02 1.122±0.02 32.8±0.02
37 Ethocel® Standard 100 FP -do- Starch 12.4±0.04 1.21±0.01 32.34±0.02
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 110
4.5. Differential scanning calorietry (DSC) studies
To investigate interactions between the drugs, polymers and different excipients, DSC
studies were conducted. Figure 4.7 shows DSC curves of pure Ibuprofen and its physical
mixtures with polymer ethyl cellulose ether and different co-excipients. A sharp
endothermic peak at 76.94oC was observed for pure Ibuprofen at the temperature
corresponding to its melting point (Fig. 4.7a). As shown, the endothermic peak of
Ibuprofen in its mixtures with either the polymers or the coexipients did not show any
major change as compared to that of the pure drug (Fig.4.7a-d), indicating no possible
interaction.
Figure 4.7 DSC thermogram of pure Ibuprofen (a) and physical mixtures of
Ibuprofen with polymer ethylcellulosel, magnesium stearate, lactose, using co-
excipients; HPMC (b); starch (c); and CMC (d).
Differential scanning calorimetry (DSC) studies were also performed for Ketoprofen to
investigate possible drug-polymers and excipients interactions. The DSC thermograms of
pure Ketoprofen and its physical mixtures with poymer and co-excipients are shown in
the figure 4.8. The thermal curve of ketoprofen (Fig. 4.8a) showed a single endothermic
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 111
peak at 94oC, corresponding to the melting point of ketorpfen (Mudit et al., 2010). As
shown in figure (4.8a-d) the endothermic peaks of ketoprofen in the physical mixture of
polymer ethylcellulose and different co-excipients such as lactose, magnesium sterate,
hydroxypropylmethylcellulose (HPMC), starch and corboxymethylcellulose (CMC) were
found at the same temperature as that of pure ketoprofen. This indicated that no possible
chemical interaction was found between ketoprofen and polymer and different excipients.
Our results are supported by findings in other studies previously conducted by several
invistigators (Shivakumar et al., 2006; Khan and Zhu, 1998; Nagarsenkar and Shenal,
1996).
Figure 4.8 DSC thermogram of pure Ketoprofen (a) and physical mixtures of
Ketoprofen with polymer ethylcellulosel, magnesium stearate, lactose, using co-
excipients; HPMC (b); starch (c); and CMC (d).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 112
4.6. Fourier transform infrared (FT-IR) studies
For further analysis FT-IR spectra of pure drugs and their respective physical mixtures
were also taken to assure the compatibility between pure drug and its physical mixtures
with polymer ethylcellulose and different excipients such lactose, magnesium stearate,
hydroxypropylmethylcellulso (HPMC), starch and corboxymethylcellulose (CMC). The
FT-IR spectrums of pure ibuprofen, its physical mixture with polymer ethylcellulose
ether and different excipients such as lactose, magnesium stearate,
hydroxypropylmethylcellulso (HPMC), starch and corboxymethylcellulose (CMC) are
shown in Figure 4.9a-c. Pure ibuprofen showed sharp characteristic peaks at 1706 cm-1
which corresponds to the carboxyl acid (COOH) present in ibuprofen. Other smaller
peaks in the region 1200-1000 cm-1
are the indication of benzene ring (Socrates, 1994).
As the sharp, characteristic peaks of ibuprofen did not change in physical mixture with
polymer and different excipients, indicating no possible interaction.
Figure 4.9 FT-IR spectra of of pure Ibuprofen (a) and physical mixtures of
Ibuprofen with polymer ethylcellulosel, magnesium stearate, lactose, using co-
excipients; HPMC (b); starch (c); and CMC (d).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 113
Similarly, FT-IR spectra of pure ketoprofen (Fig. 4.10a) showed characteristic symmetric
carbonyl peaks at 1693.8 cm-1
and 1654.0 cm-1
due to dimeric carboxylic and ketonic
group stretching vibrations, respectively (Sancin et al.,1999; Mura et al.,1998). The
characteristic acid corbonyl stretching band of ketoprofen unchanged in formulation with
polymer ethylcellulose and different excipients such as lactose, magnesium,
hydroxypropylmethylcellulso (HPMC), starch and corboxymethylcellulose (CMC) as
shown (Fig.4.10a-d). Hence, from these studies it was conformed that no possible
interaction was found between drug, polymer and different excipients. On the other hand,
another study was performed by Shivakumar et al (2008) who conducted FT-IR study for
investigation the chemical interaction between Ketoprofen and cellulose acetate and
Eudragit. According to their findings no chemical interaction was found because the IR
spectra of Ketoprofen and microcapsules were identical.
Figure 4.10 FT-IR spectra of pure Ketoprofen (a) and physical mixtures of
Ketoprofen with polymer ethylcellulosel, magnesium stearate, lactose, using co-
excipients; HPMC (b); starch (c); and CMC (d).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 114
4.7. Construction of standard curves
For further analysis and determination of solubility of drugs in different solvents,
standard curves were prepared for both drugs (Ibuprofen and Ketoprofen). The average
absorbance values of drug solutions with different concentration, in phosphate buffer (pH
7.4), are shown in tables 4.5-4.5 and and standard curves in Figs. 4.11-4.12. The straight
lines with R2 value of 0.9997 and 0.9998 for Ibuprofen and Ketoprofen were obtained,
respectively.
Table 4.5 Absorbance and concentration of Ibuprofen for different dilutions.
S. No Cont. (mg/ml) Abs1 Abs2 Abs3 Avg. Abs
1 0 0 0 0
2 0.00125 0.08 0.079 0.081 0.080
3 0.00312 0.160 0.162 0.158 0.160
4 0.00625 0.303 0.303 0.303 0.303
5 0.0125 0.586 0.585 0.587 0.586
6 0.025 1.166 1.166 1.168 1.167
Figure 4.11 Standard Curve for Ibuprofen in phosphate buffer 7.4
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 115
Table 4.6 Absorbance and concentration of Ketoprofen for different dilutions.
S. No Cont. (mg/ml) Abs1 Abs2 Abs3 Avg. Abs
1 0 0 0 0 0
2 0.00125 0.105 0.105 0.105 0.105
3 0.00312 0.206 0.205 0.207 0.207
4 0.00625 0.421 0.421 0.421 0.421
5 0.0125 0.847 0.847 0.847 0.847
6 0.025 1.700 1.702 1.698 1.700
Figure 4.12 Standard Curve for Ketoprofen in phosphate buffer 7.4
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 116
4.8. Solubility studies
The concentrations (mg/ml) of Ibuprofen and Ketoprofen determined from solubility
studies in phosphate buffer solutions (pH 6.8, 7.2 and 7.4), distilled water and 0.1 N HCL
solutions at 25oC, 37
oC and 40
oC are shown in tables 4.5 and 4.6.
As shown in tables 4.7 and 4.8, the solubility of the drugs (Ibuprofen and Ketoprofen) is
higher in phosphate buffer solution of pH 7.4 as compared to other solvents. Ibuprofen
and Ketoprofen are weekly acidic drugs with pKa value 5.3 and 4.6, respectively. This
increase in solubility of Ibuprofen and Ketoprofen in phosphate buffer solution of pH 7.4
may be due to weekly acidic properties of both these drugs, as the solubility of weak
acidic or basic drugs is often pH dependent. Solubility of weak acidic drug is increased
with increase in pH of the solvent (Loyd et al., 2005a).
Moreover, with the increase in temperature the solubility of both the drugs was enhanced
in different in all solvents as shown in tables 4.7 and 4.8. This increase in solubility of
drugs may be due to absorption of heat, as most chemical absorb heat when they are
dissolved and are said to have positive heat of solution, resulting in increased solubility
with an increase in temperature (Loyd et al., 2005b)
Table 4.7 Solubility of Ibuprofen in different solvents at different temperatures.
S/NO Solvent Temp Conc. Determined
(Mean±SD)
1 Phosphate Buffer 6.8 PH
25 °C 0.847±0.005
37 °C 0.856±0.003
40 °C 0.867±0.002
2 Phosphate Buffer 7.2 PH
25 °C 0.928±0.002
37 °C 0.931±0.009
40 °C 0.940±0.002
3 Phosphate Buffer 7.4 PH
25 °C 0.990±0.007
37 °C 0.999±0.006
40 °C 1.00±0.008
4 Distilled Water
25 °C 0.276±0.007
37 °C 0.285±0.003
40 °C 0.295±0.001
5 0.1N HCL solution
25 °C 0.027±0.005
37 °C 0.045±0.005
40 °C 0.053±0.009
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 117
Table 4.8 Solubility of Ketoprofen in different solvents at different temperatures.
4.9. Preparation of solid dispersions
Different methods such as salt formation, solubilization, particle size reduction, complex
formation, solvent evaporation, etc. are used to prepare solid dispersions to enhance the
dissolution rate and thereby improve the bioavailability of poorly water soluble drugs
(Galia et al., 1998), however, in this study solvent evaporation method was used due to
its inherent ease of handling and no more steps were required. The solid dispersions of
model drugs (Ibuprofen and Ketoprofen) with different drug and carrier ratios were
prepared. The respective physical mixtures with the same drug and carrier ratios were
prepared by simple trituration method for comparative evaluation.
For conformation of uniform dispersion of drug in solid dispersions and physical
mixtures drug content analysis was performed and it was found between 99.57±0.7 %
and 101.3 ±0.32 %. All the solid dispersions and physical mixtures indicated the high
content and uniformly dispersion of drugs. These findings conformed that the solvent
evaporation method appears to be reproducible for development and preparation of solid
dispersions. Similar studies were conducted by Prasad (Prasad et al., 2010; Rosario et al.,
S/NO Solvent Temp Conc.determined
(Mean±SD)
1 Phosphate Buffer 6.8 PH
25 °C 0.853±0.003
37 °C 0.858±0.007
40 °C 0.869±0.004
2 Phosphate Buffer 7.2 PH
25 °C 0.938±0.007
37 °C 0.941±0.004
40 °C 0.944±0.005
3 Phosphate Buffer 7.4 PH
25 °C 0.978±0.003
37 °C 0.998±0.004
40 °C 0.999±0.004
4 Distilled Water
25 °C 0.421±0.004
37 °C 0.425±0.002
40 °C 0.431±0.003
5 0.1N HCL solution
25 °C 0.158±0.001
37 °C 0.163±0.003
40 °C 0.169±0.003
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 118
2002) who prepared solid dispersions of Tebinanfine hydrochloride and NSAIDs by the
same method obtaining good results in terms of content analysis and uinform distribution
of the drugs used.
4.9.1. Solubility study: As shown in table 4.9, the aqueous solubility study of pure
Ibuprofen, pure Ketoprofen, their physical mixtures and solid dispersions was performed
in distilled water. The study showed that solubility of Ibuprofen and ketoprofen enhanced
in presence of carrier (Glucosamine HCL). This effect of solubility enhancement was
more prominent in case of solid dispersions as compared to that of their respective
physical mixtures. The enhancement of drugs solubility in presence of solid dispersions
may be due to conversion of drugs to amorphous form as amorphic forms of drug are
more soluble than their crystalline form (Parsad et al., 2010; Khan and Zhu, 1998). The
increase in solubility of drugs in solid dispersions might also be due to good wettability
and dispesrability (Khan and Zhu, 1998).
Table 4.9 Solubility data of different Ibuprofen and Ketoprofen formulations.
Formulations Solubility (mg/ml)
Ibuprofen
IBF Pure
F1 IBF
F2 IBF
F3 IBF
F4 IBF
F5 IBF
F6 IBF
0.285
0.297
0.313
0.333
0.320
0.357
0.398
Ketoprofen
KPT Pure
F1 KPT
F2 KPT
F3 KPT
F4 KPT
F5 KPT
F6 KPT
0.321
0.335
0.355
0.377
0.465
0.501
0.555
4.9.2. Differential scanning calorimetry (DSC) studies: Differential scanning
calorimetric (DSC) studies of pure ibuprofen, ketoprofen, their physical mixtures and
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 119
solid dispersions were conducted to investigate the crystillinity and drugs carrier
interaction. The DSC run of the pure Ibuprofen and carrier (glucosamine HCL) show
sharp endothermic peaks around 76.94oC and 210
oC, corresponding to the melting point
of Ibuprofen and Glucosamine HCL, respectively (Fig. 4.13a-d).
Figure 4.13 DSC Thermograms of (a) Glucosamine; (b) Pure ibuprofen; (c) Physical
mixture; and (d) Solid dispersions of ibuprofen with glucosamine.
Figure 4.14 DSC Thermograms of (a) Glucosamine; (b) Pure ketoprofen; (c)
Physical mixture; and (d) Solid dispersions of ketoprofen with glucosamine.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 120
The endothermic peak of Ibuprofen is of very high intensity, showing the crystalline form
of ibuprofen. The DSC thermograms of Ibuprofen-carrier (Glucosamine HCL) physical
mixture and solid dispersions showed both the endothermic peaks (Fig. 4.13c-d) with
some changes in the characteristics of the peaks shown by individual components; for
example the endothermic peaks of physical mixture and solid dispersions lost its
sharpness and distinctive appearance. It showed that no possible interaction was found
between drug and carrier but the loss of peaks sharpness may be due to conversion from
crystalline form to amorphous form of the drug.
As shown in (Fig. 4.14a-d), the DSC studies of pure Ketoprofen, its physical mixture and
solid dispersions exhibited similar interactive effects as found in case of Ibuprofen. The
pure Ketoprofen and carrier (Glucosamine HCL) showed sharp endothermic peaks round
94oC and 210
oC, corresponding to their melting points, while the DSC thermograms of
Ketoprofen in physical mixture and solid dispersions (Fig. 4.14c-d) did not exhibit any
major change in the endothermic peaks except disappearance of sharpness, indicating
occurance of no possible interaction between Ketoprofen and Glucosamine HCL.
Our results are supported by findings in other studies previously conducted by several
invistigators (Khan and Zhu, 1998; Nagarsenkar and Hira, 1996).
4.9.3. Fourier transform Infrared (FT-IR) studies: For the conformation of interaction
between drugs and carrier in presence of physical mixtures and solid dispersions FT-IR
studies were performed. The FT-IR spectrums of pure Ibuprofen, and Ibuprofen-
Glucosamine physical mixtures and solid dispersions were obtained as shown in the Fig.
4.15a-d. Pure Ibuprofen showed sharp characteristic peaks at 1706 cm-1
which
corresponds to the carboxyl acid (COOH) present in ibuprofen. Other smaller peaks in
the region 1200-1000 cm-1
are the indication of benzene ring (Socrates, 1994). These
peaks can also be seen in the ibuprofen-carrier physical mixture and solid dispersions, but
in this case IR spectrum for Ibuprofen-carrier mixture and solid dispersion shows the
overlapping of carboxyl acid group (Fig. 4.15c-d). Therefore, it can be concluded that no
chemical interaction occurred between Ibuprofen and glucosamine HCL.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 121
Figure 4.15 FT-IR spectra of (a) Glucosamine; (b) Pure ibuprofen; (c) Physical
mixture; and (d) Solid dispersions of ibuprofen with glucosamine.
Figure 4.16 FT-IR spectra of (a) Glucosamine; (b) Pure ketoprofen; (c) Physical
mixture; and (d) Solid dispersions of ketoprofen with glucosamine.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 122
Pure ketoprofen crystals show two carbonyl absorption bands at 1694.4 cm
-1 and 1654.2
cm-1
, indicating carboxyl carbonyl and ketonic carbonyl stretching, respectively (Sancin
et al., 1999, Mura et al., 1999) as shown in Fig. 4.16a-d. The characteristics stretching
band of pure ketoprofen with Glucosamine in physical mixture and solid dispersions did
not change, and on the basis of these observations no possible interaction was observed
between ketoprofen and Glucosamine HCL. The same findings were observed by other
researchers (Shivkumar et al., 2008).
4.9.4. X-ray diffractometory studies: Figure (4.17a-c) shows the diffractograms of pure
Ibuprofen, Ibuprofen-carrier physical mixture and solid dispersion.
Figure 4.17 X-ray diffractograms of (a) Pure Ibuprofen; (b) Physical mixture; and
(c) Solid dispersions of Ibuprofen and glucosamine.
The diffractograms of pure Ibuprofen with numerous distinctive peaks showed that the
drug is highly crystalline in nature, confirms the DSC studies as shown in figure (4.13b).
Four peaks with high intensity were present in the diffractogram of Ibuprofen around 17o,
20o, 23
o and 25
o along with some other peaks of lower intensity. The same peaks were
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 123
present in the diffractogarm of Ibuprofen-carrier physical mixture and solid dispersions,
but with lower intensity. This indicates that Ibuprofen crystallinity has been diminished.
As compared to pure Ibuprofen and physical mixture of Ibuprofen-carrier, the peaks in
the diffractogram of solid dispersions were of much reduced intensities, indicating the
amorphous nature of the Ibuprofen in presence of solid dispersions.
While in case of Ketoprofen, as shown in Figure (4.18a-c) different peaks with high
intensity were present in the diffractogram around 13o, 14
o, 18
o, 23
o, 24
o, 26
o and 29
o
along with some other peaks of lower intensity. The same peaks were present in the
diffractograms physical mixture and solid dispersion but with low intensities, indicating
the conversion of crystalline form of pure Ketoprofen to amorphous form in presence of
physical mixture and solid dispersions. Moreover, the peak intensity of Ketoprofen was
much more reduced as compared to pure Ketoprofen and physical mixture, as shown in
Figure 4.18b-c. Our results confirm the findings of other researchers (Shivakumar et al.,
2008; Nagarsenkar and Hira, 1996).
Figure 4.18 X-ray diffractograms of (a) Pure ketoprofen; (b) Physical mixture; and
(c) Solid dispersions of ketoprofen and glucosamine.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 124
4.9.5. Scanning electron microscope analysis: Figure 4.19a-d shows the scanning
electron micrographs of Glucosamine HCL, pure Ibuprofen, Ibuprofen-carrier physical
mixture and solid dispersions of Ibuprofen with glucosamine HCL. After analysis, the
scanning electron microscopy (SEM) revealed that Glucosamine has prismatic shape
(polygonal) and pure Ibuprofen has irregular crystalline shape. Both of these crystals can
easily be identified in the physical mixture, as shown in the Figure 4.19c. In physical
mixture, there are numerous small crystals of Ibuprofen which are responsible for more
solubility and enhanced dissolution rate as compared to pure compound, while in case of
solid dispersions the crystals of Ibuprofen are in smallest size and they have irregular,
circular and plate like shapes. The dissolution rate of Ibuprofen in solid dispersions was
rapid and more as compared to pure Ibuprofen and physical mixture because the particle
shape irregularity and small particle size increased the specific surface area and enhanced
the dissolution rate (Javadzadeh and Nokhodchi, 2009).
Figure 4.19 Scanning electron photomicrographs of (a) Carrier (Glucosamine HCL); (b)
Pure Ibuprofen; (c) Physical mixture of Ibuprofen-Glucosamine HCL; (d) Solid dispersion
of Ibuprofen-Glucosamine HCL.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 125
Similar SEM results were produced for Ketoprofen as shown in Fig. 4.20a-d.
Glucosamine and pure Ketoprofen has prismatic shape (polygonal) and irregular shape
crystals, respectively. The SEM analysis showed that relatively smaller polyhedral
crystalline forms of Glucosamine and Ketoprofen are clearly visible in physical mixture,
as shown in Fig. 4.20c, the Ketoprofen has smallest, irregular, circular and plate like
crystals in solid dispersions, which are responsible for enhanced dissolution rate. Similar
studies were conducted Nagarsenkar and Hira, (1996) and Shivakumar et al. (2008). Our
results confirm their findings.
Figure 4.20 Scanning electron photomicrographs of (a) Carrier (Glucosamine
HCL); (b) Pure Ketoprofen; (c) Physical mixture of Ketoprofen-Glucosamine HCL;
(d) Solid dispersion of Ketoprofen-Glucosamine HCL.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 126
4.9.6. In –vitro dissolution studies: The dissolution profiles of pure Ibuprofen, Ibuprofen
physical mixtures and solid dispersions prepared with Glucosamine HCL are shown in
Figs. 4.21 and 4.22. It is shown that pure Ibuprofen has the slowest dissolution rate and
22.3% of drug was dissolved after 120 minutes, while in case of physical mixtures and
solid dispersions with different Drug: Carrier ratios (1:1, 1:2 and 1:3) the dissolution rate
was linearly increased and 25%, 29.65, 32.8% and 27.1%, 40.75, 43.3% of drug was
dissolved after 120 minutes from formulations F1 IBF, F2 IBF, F3 IBF and F4 IBF, F5
IBF, F6 IBF, respectively. The fastest dissolution rate was obtained for the formulation
(F6 IBF) with the D: C ratio of 1:3 in carrer concentration dependent manners. The fast
and rapid dissolution rate of Ibuprofen in solid dispersion may be due to the presence of
Ibuprofen in amorphous form which is revealed by the results of different techniques as
mentioned above. On the other hand it may be that if the percentage of carrier is too high,
this may lead to increase in solubility and dissolution rate due to absence of crystallinity
of drug (Ford, 1986).
Figure 4.21 In-vitro dissolution profiles of pure Ibuprofen and physical mixture with
different drug-carrier (Glucosamine HCL) ratio; F1 IBF (1:1); F2 IBF (1:2); F3 IBF
(1:3)
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 127
Figure 4.22 In-vitro dissolution profiles of pure Ibuprofen and solid dispersions with
different drug-carrier (Glucosamine HCL) ratio
Similar study was performed for Ketoprofen and the dissolution profile of pure
Ketoprofen and Ketoprofen physical mixtures and solid dispersions with Glucosamine
HCL are depicted in Figs. 4.23 and 4.24. As shown 27.3% of pure Ketoprofen was
dissolved after 120 minutes, while in case of physical mixtures and solid dispersions with
different Drug: Carrier ratios (1:1, 1:2 and 1:3) the dissolution rate was linearly increased
and 30%, 33.1% and 34.2% and 32.5%, 42.7% and 46.9% of drug was dissolved after
120 minutes from formulations F1 KTP, F2 KTP, F3 KTP and F4 KTP, F5 KTP, F6
KTP, respectively. As shown in Figs. 4.23 and 4.24 the Ketoprofen dissolution rate from
formulations containing the same carrier with the same D: C ratios followed the same
dissolution rate pattern as described above in case of Ibuprofen, which further
authenticates the more prominent and effective role of the carrier Glucosamine HCl in
enhancing the dissolution rate of drugs such as IBF and KTP. The fast and rapid
dissolution rate of Ketoprofen in solid dispersions may be due to the presence of
Ketoprofen in amorphous form which is revealed by the results of different techniques as
mentioned above. On the other hand it may be that if the percentage of carrier is too high,
this may lead to increase in solubility and dissolution rate due to absence of crystallinity
of drug (Ford, 1986).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 128
Figure 4.23 In-vitro dissolution profiles of pure Ketoprofen and physical mixture
with different drug-carrier (Glucosamine HCL) ratio.
Figure 4.24 In-vitro dissolution profiles of pure Ketoprofen and solid dispersion with
different drug-carrier (Glucosamine HCL) ratio.
4.10. Physicochemical Assessment of Matrix Tablets
In order to assess whether the specific dosage form fulfills the desired specifications
different physicochemical, dimensional and quality control tests, such as weight
variation, thickness and diameter, hardness test, content uniformity and friability test
must be performed on solid dosage forms (Augsburger et al.,2002). These tests are
performed to ensure that tablets will have sufficient mechanical strength to tolerate forces
encountered during, packaging, shipping and handling. Moreover, test must be performed
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 129
to ensure, whether the tablets are physically and chemically stable to deliver the precise
amount of drug at the desired dissolution rate when administered by a patient. Any
change in these characteristics may significantly affect the safety and efficacy of the
product (Hwang et al., 2001).
As summarized in tables 4.10 and 4.11, the prepared matrix tablets containing model
drugs (Ibuprofen and Ketoprofen), polymer ethyl cellulose of different viscosity grades
and co-excipients, at several drugs to polymer ratio of 10:1, 10:2 and 10:3, were
evaluated for their physicochemical properties and appearance. Table 4.10 shows the,
weight variation, hardness, friability, thickness, diameter and drug content tests results,
applied to controlled release matrix tablets of Ibuprofen with Ethocel® standard 7, 10 and
100 premium and Ethocel® standard 7, 10 and 100 FP premium with or without co-
excipient ( HPMC, CMC and starch). All these tests were performed in strict compliance
of Good Laboratory Practice (GLP). Orgnolaptically, the tablets were having smooth
surfaces and were elegant in appearance. As shown in table 4.10, the average weight for
all formulations is 199.01±0.403mg to 200.95±0.401mg, indicating low weight variation,
which is within acceptable range of United States Pharmacopeia. Similar study was
conducted by Tiwari et al (2003). They prepared controlled-release formulations of
tramadol HCL, using HPMC K100M and calculated the weight variation of each
formulation. All the tablets prepared showed acceptable in-house specifications for
weight variation. The average hardness, friability, thickness, diameter and drug content
given in the table 4.10 are 6.98±0.041 kg/cm3 to 7.16±0.096 kg/cm
3, 0.11±0.01% to
0.29±0.05%, 3.4±0.032 mm to 3.51±0.031 mm, 7.985±0.031 mm to 7.995±0.035 mm
and 98.09±2.322% to 100.311±2.031%, respectively. The results obtained for the
physicochemical testing of all formulations divulged that the prepared matrix tablets
comply with the USP standards. The USP range for hardness, friability, thickness,
diameter and drug content uniformity is 5-10kg/cm3, 0.8%, 2-4 mm, 4-13 mm and 90-
110%, respectively (USP, 2007).
The hardness of matrix tablets containing FP grades was more as compared to the tablets
containing Premium grades. Moreover, it was observed that tablets containing FP grades
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 130
polymer (Ethocel® standard 7, 10 and 100 FP premium) were less thick as compared to
tablets containing Premium grades (Ethocel® standard 7, 10 and 100 premium). This is
probably due to fine particle size of FP grades which facilitates the compression of tablets
resulting into production of thinner tablets. These results conform the finding of Khan
and Median (2007), that Ethocel® standard FP premium tablets were more compressible,
harder and less thick as compared to tablets containing Ethocel® standard premium
because of the fine particle size of FP grades. The results showed that tablet diameter was
almost similar for all formulations because diameter of the tablets was not affected by the
polymer, lubricant, co-excipients as well as viscosity grade of polymer. On the other
hand, another study was performed by Ghorab et al (2004) who prepared meloxicam
tablets, using β-cyclodextrin as a vehicle, either alone or in blends with lactose, by direct
compression and wet granulation and subjected to thickness and diameter tests.
According to their findings no effect on diameter of tablets was observed with changing
the concentration of different excipients.
The same physicochemical tests were repeated for the assessment of controlled release
matrices of Ketoprofen. The tablets obtained were elegant in appearance and were having
smooth surfaces. The results of the average weight, hardness, friability, thickness,
diameter and drug content determination of the tablets are given in table 4.11. The
average weight, hardness, friability, thickness, diameter and drug content are
199.85±0.234 mg to 200.85±0.231 mg, 6.93±0.092 kg/cm3 to 7.17±0.095 kg/cm
3,
0.11±0.03% to 0.29±0.03%, 3.42±0.032 mm to 3.505±0.039 mm, 7.985±0.037 mm to
7.995±0.022 mm and 98.012±3.103% to 100.213±2.343, respectively. All formulations
were found to be uniform in weight, hardness, friability, thickness, and diameter and drug
content within acceptable limits of BP and USP. The results showed that no significant
variations were observed in physical tests applied except hardness and thickness. The
tablets containing FP grades were harder and less thick than the tablets containing
Premium grades of polymer. As mentioned above, this might be due to fine particle size
of FP grades. These results conform the finding of Khan and Median (2007).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 131
Table 4.10 Physicochemical characteristics of Ibuprofen controlled release matrices
S/NO Polymer D:P
Ratio
Co-
Excipi
ents
Wt variation
test (mg)
n=20
(Mean±SD)
Hardness
test(kg/cm3
)
n=10
Mean±SD
Friability
test (%)
n=3
Mean±SD
Thickness
(mm)
n=20
(Mean±SD)
Diameter
(mm)
n=20
(Mean±SD
)
Drug content
(%)
n=3
(Mean±SD)
1 Etho Std 7 10:1 Nil 199.01±0.403 7.11±0.056 0.21±0.02 3.5±0.021 7.99±0.032 100.211±2.03
2 Etho Std 7FP -do- Nil 199.01±0.305 7.13±0.032 0.11±0.01 3.4±0.054 7.99±0.035 99.216±2.035
3 Etho Std 7 10:2 Nil 199.03±0.201 7±0.092 0.28±0.01 3.5±0.034 7.985±0.03
1
99.223±2.023
4 Etho Std 7FP -do- Nil 200.02±0.203 7.14±0.095 0.12±0.03 3.4±0.032 7.99±0.036 99.212±2.037
5 Etho Std 7 10:3 Nil 199.7±0.403 6.99±0.049 0.25±0.04 3.5±0.032 7.99±0.035 99.231±2.043
6 Etho Std 7FP -do- Nil 200.02±0.303 7.16±0.096 0.12±0.01 3.4±0.022 7.995±0.03
2 98.09±2.825
7 Etho Std 7 -do- HPMC 199.05±0.421 6.98±0.041 0.24±0.04 3.5±0.032 7.99±0.036 99.025±2.143
8 Etho Std 7FP -do- HPMC 200.15±0.432 7.11±0.045 0.13±0.02 3.49±0.031 7.99±0.038 100.01±2.194
9 Etho Std 7 -do- CMC 200.04±0.321 6.99±0.043 0.29±0.02 3.495±0.039 7.995±0.03 99.032±2.213
10 Etho Std 7FP -do- CMC 199.85±0.323 7.11±0.049 0.12±0.05 3.4±0.032 7.985±0.03 99.08±2.211
11 Etho Std 7 -do- Starch 199.83±0.423 7±0.085 0.19±0.03 3.5±0.032 7.99±0.038 99.311±3.125
12 Etho Std 7FP -do- Starch 199.1±0.432 7.12±0.037 0.12±0.01 3.41±0.31 7.99±0.025 99.09±2.212
13 Etho Std 10 10:1 Nil 199.83±0.328 7.01±0.095 0.24±0.02 .5±0.032 7.99±0.033 99.221±2.035
14 EthoStd10FP -do- Nil 200.82±0.342 7.12±0.095 0.11±0.03 3.4±0.038 7.99±0.039 99.125±2.036
15 Etho Std 10 10:2 Nil 200.03±0.329 7.01±0.056 0.2±0.03 3.5±0.042 7.99±0.035 100.231±2.01
16 EthoStd10FP -do- Nil 200.75±0.432 7.12±0.098 0.14±0.01 3.4±0.046 7.995±0.03 99.211±2.033
17 Etho Std 10 10:3 Nil 200.01±0.521 7±0.085 0.23±0.04 3.505±0.039 7.995±0.02 99.311±1.912
18 EthoStd10FP -do- Nil 199.1±0.321 7.13±0.045 0.12±0.06 3.49±0.031 7.995±0.05 98.22±1.387
19 EthoStd 10 -do- HPMC 199.1±0.445 6.98±0.049 0.25±0.02 3.51±0.031 7.99±0.032 100.041±2.82
20 EthoStd10FP -do- HPMC 200.05±0.321 7.12±0.075 0.16±0.03 3.49±0.031 7.99±0.032 99.08±1.365
21 EthoStd 10 -do- CMC 199.75±0.543 7.02±0.096 0.21±0.02 3.49±0.31 7.995±0.02 99.152±3.19
22 EthoStd10FP -do- CMC 200.07±0.354 7.11±0.077 0.15±0.03 3.4±0.032 7.99±0.032 99.012±2.198
23 EthoStd 10 -do- Starch 200±0.454 7.01±0.076 0.21±0.04 3.51±0.031 7.995±0.02 99.05±2.355
24 EthoStd10FP -do- Starch 199.1±0.459 7.13±0.046 0.12±0.01 3.45±0.023 7.99±0.024 99.011±3.106
25 EthoStd 100 10:1 Nil 200.65±0.465 7.0±0.096 0.23±0.04 3.5±0.033 7.99±0.031 99.212±2.032
26 EthoStd100FP -do- Nil 200.43±0.232 7.11±0.092 0.12±0.01 3.43±0.067 7.99±0.035 100.311±2.03
27 EthoStd 100 10:2 Nil 200.85±0.234 7.0±0.095 0.23±0.04 3.5±0.043 7.995±0.03 99.215±2.031
28 EthoStd100FP -do- Nil 199.95±0.204 7.11±0.095 0.14±0.06 3.45±0.067 7.99±0.031 99.111±2.038
29 EthoStd 100 10:3 Nil 199.8±0.507 7±0.085 0.21±0.01 3.5±0.035 7.99±0.035 98.09±2.322
30 EthoStd100FP -do- Nil 199.9±0.506 7.11±0.098 0.18±0.01 3.42±0.022 7.995±0.02 99.22±1.321
31 EthoStd 100 -do- HPMC 200.95±0.401 6.98±0.042 0.25±0.02 3.5±0.031 7.99±0.024 99.211±2.165
32 EthoStd100FP -do- HPMC 199.8±0.543 7.12±0.096 0.16±0.04 3.4±0.034 7.99±0.033 100.01±1.153
33 EthoStd 100 -do- CMC 200.05±0.365 6.99±0.099 0.27±0.02 3.5±0.034 7.99±0.032 100.012±2.15
34 EthoStd100FP -do- CMC 199.95±0.54 7.11±0.075 0.15±0.01 3.4±0.045 7.99±0.033 99.231±2.217
35 EthoStd 100 -do- Starch 200.1±0.498 6.98±0.048 0.29±0.05 3.5±0.037 7.985±0.03 100.03±2.102
36 EthoStd100FP -do- Starch 199.05±0.35 7.12±0.099 0.17±0.01 3.49560.032 7.985±0.03 99.02±2.171
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 132
Table 4.11 Physicochemical characteristics of Ketoprofen controlled release matrices.
S/N Formulation D:P
Ratio
Co-
Excipie
nts
Weight
variation test
(mg)
n=20
(Mean±SD)
Hardness
test
(kg/cm3)
n=10
Mean±SD
Friability
test (%)
n=3
(Mean±SD)
Thickness
(mm)
n=20
(Mean±SD)
Diameter
(mm)
n=20
(Mean±SD)
Drug content
(%)
n=3
(Mean±SD)
1 Etho Std 7 10:1 Nil 200.01±0.501 7.02±0.083 0.23±0.03 3.5±0.022 7.99±0.031 99.217±2.234
2 Etho Std 7FP -do- Nil 199.01±0.602 7.11±0.023 0.15±0.01 3.496±0.065 7.995±0.022 100.03±2.201
3 Etho Std 7 10:2 Nil 200.03±0.301 6.99±0.095 0.24±0.03 3.5±0.023 7.995±0.022 100.213±2.34
4 Etho Std 7FP -do- Nil 200.01±0.101 7.14±0.091 0.16±0.01 3.497±0.023 7.995±0.022 100.04±2.321
5 Etho Std 7 10:3 Nil 199.9±0.308 6.97±0.048 0.25±0.03 3.5±0.032 7.99±0.031 99.211±2.037
6 Etho Std 7FP -do- Nil 200.05±0.605 7.17±0.095 0.17±0.01 3.495±0.022 7.995±0.022 98.09±2.823
7 Etho Std 7 -do- HPMC 200.05±0.394 6.97±0.048 0.25±0.01 3.5±0.032 7.99±0.031 99.024±2.172
8 Etho Std 7FP -do- HPMC 200.15±0.587 7.02±0.042 0.18±0.02 3.49±0.031 7.99±0.031 100.01±2.193
9 Etho Std 7 -do- CMC 200.05±051 6.98±0.042 0.26±0.02 3.495±0.039 7.995±0.022 99.032±2.523
10 Etho Std 7FP -do- CMC 199.95±0.394 7.11±0.042 0.17±0.03 3.42±0.032 7.985±0.037 99.09±2.213
11 Etho Std 7 -do- Starch 199.85±0.489 7±0.082 0.26±0.01 3.5±0.032 7.99±0.031 99.312±3.121
12 Etho Std 7FP -do- Starch 200.1±0.447 7.12±0.032 0.13±0.01 3.43±0.31 7.995±0.022 99.07±2.201
13 Etho Std 10 10:1 Nil 199.85±0.489 6.93±0.092 0.27±0.01 3.5±0.024 7.995±0.022 99.09±2.206
14 EthoStd10FP -do- Nil 199.82±0.345 7.11±0.03 0.15±0.0.4 3.5±0.027 7.99±0.031 99.04±2.301
15 Etho Std 10 10:2 Nil 200.05±0.483 6.97±0.093 0.27±0.05 3.48±0.046 7.99±0.031 100.07±2.201
16 EthoStd10FP -do- Nil 199.75±0.483 7.12±0.034 0.15±0.02 3.499±0.029 7.99±0.031 99.217±2.503
17 Etho Std 10 10:3 Nil 200.01±0.512 6.97±0.093 0.25±0.01 3.505±0.039 7.995±0.022 99.321±1.994
18 EthoStd10FP -do- Nil 200.1±0.447 7.12±0.082 0.12±0.03 3.49±0.031 7.995±0.022 98.22±1.322
19 EthoStd 10 -do- HPMC 200.1±0.447 6.97±0.048 0.26±0.05 3.51±0.031 7.99±0.031 98.041±2.813
20 EthoStd10FP -do- HPMC 200.05±0.51 7.11±0.074 0.16±0.01 3.49±0.031 7.99±0.031 99.05±1.334
21 EthoStd 10 -do- CMC 199.85±0.489 7.0±0.095 0.21±0.03 3.49±0.31 7.995±0.022 99.122±3.183
22 EthoStd10FP -do- CMC 200.05±0.394 7.11±0.074 0.14±0.04 3.47±0.032 7.99±0.031 99.012±2.135
23 EthoStd 10 -do- Starch 200±0.459 7.01±0.074 0.2±0.01 3.51±0.031 7.995±0.022 99.03±2.356
24 EthoStd10FP -do- Starch 200±0.459 7.12±0.042 0.12±0.04 3.49±0.022 7.995±0.022 98.012±3.103
25 EthoStd 100 10:1 Nil 200.85±0.483 6.97±0.093 0.23±0.03 3.5±0.076 7.99±0.031 100.07±2.298
26 EthoStd100FP -do- Nil 200.85±0.231 7.11±0.089 0.15±0.01 3.498±0.022 7.985±0.037 99.07±2.522
27 EthoStd 100 10:2 Nil 199.85±0.234 7±0.098 0.27±0.03 3.5±0.028 7.99±0.031 100.07±2.431
28 EthoStd100FP -do- Nil 199.95±0.203 7.12±0.01 0.14±0.04 3.499±0.035 7.985±0.037 99.237±2.201
29 EthoStd 100 10:3 Nil 199.9±0.553 7±0.082 0.25±0.01 3.5±0.032 7.99±0.031 98.08±2.327
30 EthoStd100FP -do- Nil 199.9±0.553 7.11±0.082 0.15±0.02 3.495±0.022 7.995±0.022 98.22±1.322
31 EthoStd 100 -do- HPMC 199.95±0.51 6.98±0.042 0.28±0.01 3.505±0.022 7.995±0.022 99.221±2.163
32 EthoStd100FP -do- HPMC 199.9±0.553 7.12±0.082 0.13±0.01 3.48±0.034 7.99±0.031 100.02±1.163
33 EthoStd 100 -do- CMC 200.05±0.394 6.99±0.088 0.27±0.02 3.5±0.032 7.99±0.031 100.042±2.15
34 EthoStd100FP -do- CMC 199.95±0.51 7.11±0.074 0.11±0.03 3.495±0.032 7.99±0.031 98.231±2.211
35 EthoStd 100 -do- Starch 200.1±0.447 6.98±0.042 0.29±0.03 3.5±0.032 7.985±0.037 100.03±2.113
36 EthoStd100FP -do- Starch 200.05±0.394 7.13±0.095 0.17±0.03 3.495±0.039 7.985±0.037 99.04±2.136
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 133
4.11. In-vitro dissolution study of directly compressed matrix tablets
An ideal extended release tablet should release the requisite quantity of drug with
predetermined kinetics, in order to uphold effective drug plasma concentration. To
achieve this, the tablet should be formulated in such a way to release the drug in
predetermined and reproducible manner. To achieve the predetermined release profile,
various formulation factors like polymer, polymer concentration, polymer grades and
excipients should be modified to get the required release (Saravanan et al., 2002). The in-
vitro dissolution study was carried out to examine the release profile of model drugs
(Ibuprofen and Ketoprofen) from the formulations containing polymer ethyl cellulose of
different viscosity grades (Ethocel® standard 7, 10 and 100 premium and Ethocel
®
standard 7, 10 and 100 FP premium). Moreover, the effect of polymer concentration and
partial incorporation of co-excipients (HPMC, CMC and starch) on the release profile of
model drugs from different formulations was also studied.
4.11.1. Effect of Ethocel® viscosity grade (Molecular weight) on drug release: The
release profiles of Model drugs (Ibuprofen and Ketoprofen) from Ethocel® matrices with
different viscosity grades, at D: P ratios of 10:3 are shown in Figs. 4.25 and 4.26. It can
be observed that Ethocel® 7-cp showed the slowest release rate and Ethocel
® 100-cp the
fastest release rate among the formulations studied. This is because that tablets containing
Ethocel®
with higher viscosity grades (granular polymer with larger particle size and thus
higher porosity) might not have produced a matrix with pores or openings small enough
to trap the drug and retard its release rate. The reason cited is that the smaller particle size
and fragmentation rate of Ethocel® with lower molecular weight (viscosity grade) are
more effective than those with higher molecular weights (higher viscosity) (Nystrem and
Alderborn, 1993).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 134
Figure 4.25 Release profile of Ibuprofen from Ethocel
® matrices with different
viscosity grades and D: P ratio of 10:3.
These results ratify the findings of Shlieout and Zessin. (1996) and that of Upadrashta et
al. (1993) that ethylcellulose with lower viscosity grades produce slower release rates.
However, our results oppose the declaration of Shaikh et al. (1987a and 1987b) stating
that higher the viscosity grades of ethylcellulose the slower the release of water soluble
and sparingly soluble drugs from the tablets.
Figure 4.26 Release profile of Ketoprofen from Ethocel
® matrices with different
viscosity grades and D: P ratio of 10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 135
4.11.2. Effect of drug-to- polymer (D: P) ratio on release rate: Figs. 4.27 to 4.32 show
the percentage release of model drugs (Ibuprofen and Ketoprofen) in 24 hours from
matrix tablets containing ethylcellulose derivative polymer, Ehocel® standard premium
(7, 10 and 100) and Ethocel® standard FP premium (7,10 and 100) at different D:P ratios.
It can be observed that an increase in the quantity of Ethocel® decreased the drug release
rates. This might be due to the strength of matrix because the matrix at higher amount of
Ethocel®
should be, expectedly, stronger. This kind of matrix would cause a reduction of
water or solvent penetration through the micropores and drug diffusion, resulting in
slower release rate. Similar study was performed by Velasco et al. (1999). They observed
that release rate of Diclofenac sodium from matrix tablets containing HMPC was reduced
by an increase in the amount of the polymer. Our results also conform the findings of
Espinoza et al. (2000), showing that slower release rates of Pelanserin HCL were
observed with higher HPMC proportion.
Figure 4.27 Release profiles of Ibuprofen from Ethocel® standard 7 premium and
Ethocel® standard 7 FP premium matrices with different D: P ratios.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 136
Figure 4.28 Release profile of Ibuprofen from Ethocel® standard 10 premium and
Ethocel® standard 10 FP premium matrices with different D:P ratios.
Figure 4.29 Release profiles of Ibuprofen from Ethocel® standard 100 premium and
Ethocel® standard 100 FP premium matrices with different D: P ratios.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 137
Figure 4.30 Release profiles of Ketoprofen from Ethocel® standard 7 premium and
Ethocel® standard 7 FP premium matrices with different D: P ratios.
Figure 4.31 Release profiles of Ketoprofen from Ethocel® standard 10 premium and
Ethocel® standard 10 FP premium matrices with different D:P ratios.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 138
Figure 4.32 Release profiles of Ketoprofen from Ethocel® standard 100 premium
and Ethocel® standard 100 FP premium matrices with different D: P ratios.
4.11.3. Ethocel® standard premium vs. Ethocel
® standard FP premium: Figures 4.33
and 4.34 show the comparative release patterns of model drugs (Ibuprofen and
Ketoprofen) from the matrix tablets containing Ethocel® Standard 7 premium and 7 FP
premium, Standard 10 premium and 10 FP premium, Standard 100 premium and 100 FP
premium polymers at 10: 3, D:P ratio. It could be observed that Ethocel®
standard FP
polymers had a more pronounced effect on the release rates of Ibuprofen and Ketoprofen
from all the formulations studied as compared to to simple Ethocel® standard premium
polymers. As shown in Fig. 4.33, granular Ethocel® Standard 7, 10 and 100 Premium
released 50% of Ibuprofen after 10, 8 and 6 hours, respectively.
On the other hand Ethocel® Standard 7, 10 and 100 FP Premium with similar D: P ratio
(10:3) released 50% of the drug after 18, 12 and 10 hours, respectively. As shown the
Ethocel® FP polymers extended the release rates of the drug more efficiently than the
conventional granular forms (Ethocel® Standard Premium), indicates that particle size of
the polymer has more effective role in controlling/retarding the release rate of the model
drugs. This effect of Ethocel®
standard FP grades might be due to the small particle size
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 139
and decreased porosity as compared to the granular Ethocel® Standard Premium grades of
polymer. Our results also conform the finding of Katikaneni et al. (1995), where tablets
prepared of polymer ethylcellulose with different particle sizes, revealed different release
profiles and showed that the porosity of the tablets increased with increase of particle size
of polymer and resulted in faster drug release. It may be seen that 100% drug was
released from all formulation after 24 hours, however, the percentage release from
formulation containing Ethocel® standard 7 FP Premium was 95.5% after 24 hours. This
distinctive effect of polymer Ethocel® standard FP 7 Premium could be due to the
smallest or fine particles size of the polymer as compared to all other types of the
granular as well as FP grades of Ethocel®, used in this study. Similar findings were
observed by Khan and Meidan (2007) in a previous study.
As demonstrated in Fig. 4.34, the Ketoprofen release from matrix tablets containing the
same polymers with the same D: P ratio followed the same release patterns as observed in
case of Ibuprofen, which further authenticates the more effective role of Ethocel® FP
grades, sepecially of the Ethocel®
standard 7 FP premium polymer in controlling the
release rate of drugs such as Ibuprofen and Ketoprofen.
Figure 4.33 Release profiles of Ibuprofen from Ethocel® standard 7, 10 and 100
premium and Ethocel® standard 7, 10 and 100 FP premium matrices with D: P ratio
10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 140
Figure 4.34 Release profiles of Ketoprofen from Ethocel® standard 7, 10 and 100
premium and Ethocel® standard 7, 10 and 100 FP premium matrices with D: P ratio
10:3.
4.11.4. Influence of co-excipietns on drug release rate: Preparation of tablets may
require the addition of co-excipients to acquire the tablets with appropriate size and
properties or to modify the drug release rates. Therefore, the influence of different co-
excipients, such as HPMC K100M, CMC and Starch was studied on the release rates of
model drugs (Ibuprofen and Ketoprofen) from the matrix tablets containing Ethocel®
Standard 7, 10, and 100 Premium and Ethocel®
Standard 7, 10 and, 100 FP Premium, at
D:P ratio 10:3. The release study was performed after physicochemical evaluation of all
formulation containing co-excipients. Tablets with acceptable physical properties were
obtained in all cases, studied. Moreover, excellent content uniformity was observed in all
the tablets with the above mentioned co-excipients.
As depicted in Figs. 4.35 to 4.46, all the co-excipients used in this study showed
significant enhancement in the drugs release rates from the tablets formulated. Drugs
release was found to be most rapid from tablets containing co-excipients as compared to
those without co-excipients. As shown in the figures, 90% of Ibuprofen was released
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 141
after 18, 12 and 10 hours from the formulations containing Ethocel® Standard 7, 10 and
100 Premium, respectively, on the other hand, the amount (90%) of the drug was released
after 24, 18 and 12 hours from the formulations having Ethocel® Standard 7, 10, and 100
FP Premium, respectively. It can also be seen from the same Figs. (4.35-4.40), that all
formulations with co-excipients displayed much higher release rates of the Ibuprofen.
The formulations containing Ethocel® Standard 7, 10, and 100 Premium and Ethocel
®
Standard 7, 10, and 100 FP Premium with co-excipient HPMC K100M, showed fast
release of Ibuprofen, as 90% of drug was released after 8, 6, 5, 18, 12 and 10 hours,
respectively. However, when CMC and Starch were used as co-excipients the release
rates of the drug were further increased, where 90% of the drug was released only within
2-3hours.
The same procdure was repeated for the tablet formulations containing Ketoprofen. It can
be observed form the figures 4.41-4.46 that 90% of Ketoprofen was released from the
formulations containing Ethocel® Standard 7, 10, 100 Premium and Ethocel
® Standard 7,
10 and 100 FP Premium after 7, 6, 5 and 24, 18, 12 hours, respectively. But after
incorporation of HMPMC K100M as co-excipient to the formulation containing Ethocel®
Standard 7, 10, 100 Premium and Ethocel®
Standard 7, 10 and 100 FP Premium, the
release rates were increased and 90% of Ketoprofen was released after 6, 5, 4, 12, 10 and
8 hours, respectively. Much faster release the drug was observed from the tablets when
CMC and Starch were replaced as co-excipients and 90% of the drug was released within
2-3 hours.
As the release rates of the model drugs (Ibuprofen and Ketoprofen) from the formulations
containing HPMC K100M as co-excipient was fast as compared to formulation without
co-excipients, but it was more extended as compared to formulations containing co-
excipients CMC and Starch. This more extended release may be due to the less hydration
capacity of HPMC K100M (Luana et al., 2004), but the higher release rates from the
tablets having HPMC K100M as compared to the formulations containing Ethocel®
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 142
standard Premium and Ethocel® FP Premium without co-excipient may be due to the
development of osmotic pressure because HPMC creates osmotic forces following
penetration of water with in matrices. These results conform the finding of Alderman.
(1984), Ford et al. (1987), Khan GM and Zhu. (1998a and 1998b) and Gohal et al. (2003)
that HPMC in small quantity may act as channeling agent and can increase the release
rate.
As shown in the figures, more than 90% of drug is released within 2-3hours from the
formulation containing starch as co-excipient, it is because that starch is insoluble in
water and due to insoluble nature of starch it may cause non-uniformity of polymeric
material around the drug and due to this property mostly imperfection in membranes
takes place, which causes the quick release of drug from tablets and it may be due to
water-swellable nature of starch in water. Similar findings were reported by Khan and
Zhu. (1998b) who quoted that reason for enhancement of drug from formulations
containing starch could be the water-swellable property of starch and due to this property;
it might cause to rupture the polymeric membrane around the drug contents and causing
the enhancement of drug release rate.
The same findings were observed when CMC was used as co-excipient (Figs. 4.41-4.46)
where the entire drug was released from the formulations containing CMC within 2
hours. These results might be attributed to the relatively lower viscosity of CMC which
led to low swellability and rapid dilution and erosion of the diffusion gel layer
(Alderman, 1984; Hamdy et al., 2007). It may also be due to the disintegrating property
of CMC (Khan and Rhodes, 1975; Shah and Jarwoski, 1981), and the disintegration
properties might contribute to this effect. Furthermore, this drastic release may be due to
the water soluble property of CMC because according to Khan and Zhu. (1998b) the
water soluble co-excipient may break up the polymeric membrane around the drug
contents due to the creation of osmotic forces within matrices, causing higher release rate
of drug.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 143
Figure 4.35 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ibuprofen from tablets containing
Ethocel® standard 7 premium with D: P ratio, 10:3.
Figure 4.36 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ibuprofen from tablets containing
Ethocel® standard 7 FP premium with D: P ratio, 10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 144
Figure 4.37 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ibuprofen from tablets containing
Ethocel® standard 10 premium with D: P ratio, 10:3.
Figure 4.38 Influence of partial replacement (30%) of lactose with various co-
excipients (HPMC K100M, CMC and Starch) on release profiles of Ibuprofen from
tablets containing Ethocel® standard 10 FP premium with D: P ratio, 10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 145
Figure 4.39 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ibuprofen from tablets containing
Ethocel® standard 100 premium with D: P ratio, 10:3.
Figure 4.40 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ibuprofen from tablets containing
Ethocel® standard 100 FP premium with D: P ratio, 10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 146
Figure 4.41 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ketoprofen from tablets
containing Ethocel® standard 7 premium with D: P ratio, 10:3.
Figure 4.42 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ketoprofen from tablets
containing Ethocel® standard 7 FP premium with D: P ratio, 10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 147
Figure 4.43 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ketoprofen from tablets
containing Ethocel® standard 10 premium with D: P ratio, 10:3.
Figure 4.44 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profiles of Ketoprofen from tablets
containing Ethocel® standard 10 FP premium with D: P ratio, 10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 148
Figure 4.45 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profile of Ketoprofen from tablets containing
Ethocel® standard 100 premium with D: P ratio, 10:3.
Figure 4.46 Influence of partial replacement (30%) of lactose with various co-excipients
(HPMC K100M, CMC and Starch) on release profile of Ketoprofen from tablets containing
Ethocel® standard 100 FP premium with D: P ratio, 10:3.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 149
4.12. In-vitro release study of the matrix tablets containing solid dispersions
Solid dispersions of model drugs (Ibuprofen and Ketoprofen) showing better dissolution
rate were formulated into matrix tablets, using Ethocel® standard 7 FP premium, at D: P
ratio 10: 3. Ethocel® standard 7 FP premium was selected for preparation of these
formulations due to its more effective role in controlling the release rate of drugs
Ibuprofen and Ketoprofen as mentioned above. As shown in Figs. 4.47 and 4.48, the
formulated matrix tablets containing solid despersions of model drugs showed complete
(100%) release of Ibuprofen and Ketoprofen in 12 and 8 hours, respectively, whereas the
matrix tablets of Ibuprofen and Ketoprofen were found to release 87.6% and 95.4% of
drug after 24 hours, respectively. The fast and rapid release of drugs in solid dispersions
form could be due to the presences of drugs in amorphous form. These results well
conform to those obtained in this study, from the DSC, X-ray diffractometry, IR and
SEM. The other factors such as absence of aggregation, good wettability and
dispersability might contribute to the increase in release rate (Parsad et al., 2010)
Figure 4.47 Comparative dissolution release profile of Ibuprofen and Ibuprofen solid
desperisons from matrix tablets containing Ethocel® standard 7 FP premium polymer.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 150
Figure 4.48 Comparative dissolution release profile of Ketoprofen and Ketoprofen solid
desperisons from matrix tablets containing Ethocel® standard 7 FP premium polymer.
4.13. Analysis of drugs release kinetics
Tables 4.12 to 4.27 show the data of the parameters of the kinetic models (Zero-order
kinetics, First-order kinetics, Hixon Crowel‟s Cube-root Equation, Higuchi‟s Square Root
of Time Equation and Power Law Equation) as applied to test formulations for model
drugs (Ibuprofen and Ketoprofen) release profiles from tablets containing Ethocel®
Standard Premium and Ethocel® Standard FP Premium polymers of different grades, at
different D: P ratios with or without and co-excipients (HPMC K100M, Starch and
CMC). Based on the kinetic models, linear relation was found for all the formulations
containing conventional Ethocel® Standard Premium polymers, at different D: P ratios.
Among them, the Ethocel® Standard 10 and 100 Premium polymers demonstrated
maximum r values, at D: P ratios of 10:2 and 10:3, when the release data was fitted to Eq.
5 but the best linear relation as well as maximum r values were found for Ethocel®
Standard 7 Premium, as compared to Ethocel® Standard 10 and 100 Premium, when the
percentage release data for both drugs (Ibuprofen and Ketoprofen) was fitted to the same
equation 5 (Power Law equation).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 151
However, in case of tablets containing Ethocel®
Standard FP Premium (the lattest among
the ethyl cellulose ether derivative polymers), at different D: P ratios, good linear relation
was observed in all the cases when the data was fitted to any one of the above equations
(Eqs. 1-5) and the best linear relation with maximum r values was observed for Ehtocel®
Standard 7 FP Premium, at D: P ratio of 10:3. Nevertheless, maximum linearity was
found for all formulations when the data was fitted to Eq. 5.
In case of formulations containing co-excipients, linear relation was found for
formulations containing co-excipient HPMC K100M along with Ethocel® Standard FP 7
Premium, at D: P ratio 10:3, when the data was fitted to Eq. 1-5. However, fluctuations
were observed in the release mechanisms of drugs in those formulations containing other
co-excipients, such as CMC and Starch when the data was fitted to the said equations
(Eqs. 1-5) and non-linear relation was found with minimum r values.
As shown in the tables 4.12 to 4.27 majority of the formulations have diffusional
exponent value “n” in between 0.469 and 0.855, indicating that these formulations follow
non-fickian anomalous release mechanism (n value between 0.45 and 0.89). This means
that the drug is released in pure diffusion controlled mechanism coupled with swelling
and erosion mechanisms; while the remaining formulations showed „„n‟‟ value less than
0.45. This smaller value may be due to drug diffusion partially through swollen matrix
and water filled pores in the formulation (Roshan et al., 2008). The formulations
containing Ethocel®
standard FP 7 Premium showed better release kinetics as compared
to other formulations containing different grade of ethylcellulose polymer and
formulations containing co-excipients, as shown in tables 4.12 to 4.27.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 152
Table 4.12 Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Sandard Premium polymer of
different viscosity grade, (meanSD of three determinations).
Formulation
IBF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
Ibuprofen- Ethocel
standard 7 Premium
10:1
9.7339.042
0.9321
0.3140.152
0.9212
0.3390.117
0.9301
8.3517.864
0.9321
0.0160.048
0.9531
0.632
10:2
5.2661.841
0.9582
0.1180.040
0.9521
0.1500.037
0.9513
5.8662.537
0.9532
0.0760.152
0.9632
0.721
10:3
4.5681.160
0.9853
0.0960.033
0.9652
0.1190.027
0.9762
5.3622.171
0.9854
0.2080.412
0.9941
0.758
Ibuprofen Ethocel
standard 10 Premium
10:1
9.8329.751
0.8639
0.2990.165
0.9174
0.3390.114
0.9324
8.3778.250
0.9639
0.0110.032
0.9603
0.618
10:2
6.0372.553
0.963
0.1340.035
0.9224
0.1710.033
0.9415
6.3952.935
0.9631
0.0560.121
0.9929
0.721
10:3
5.3151.909
0.941
0.1120.030
0.9247
0.1480.036
0.9163
5.9102.361
0.9751
0.0800.165
0.9912
0.722
Ibuprofen- Ethocel
standard 100 Premium
10:1
9.76810.484
0.7966
0.3490.200
0.6755
0.3720.153
0.7557
8.2299.150
0.7955
0.0090.027
0.973
0.583
10:2
6.903 4.224
0.9539
0.1780.076
0.7995
0.2120.052
0.8701
6.8944.911
0.9541
0.0320.070
0.9878
0.712
10:3
6.42.999
0.9604
0.1450.047
0.7892
0.1830.039
0.8661
6.6233.597
0.9654
0.0430.089
0.9899
0.716
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 153
Table 4.13 Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard FP Premium
polymer of different viscosity grades, (meanSD of three determinations).
Formulation
IBF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
Ibuprofen- Ethocel
standard 7 FP Premium
10:1
6.1613.138
0.9494
0.1290.033
0.9778
0.1670.036
0.9612
6.4613.326
0.9494
0.0500.104
0.9682
0.715
10:2
5.0381.490
0.9236
0.1000.034
0.9681
0.1310.025
0.9517
5.7722.218
0.9236
0.1790.353
0.992
0.775
10:3
3.6130.490
0.9932
0.0750.039
0.9935
0.0890.026
0.9901
4.5322.016
0.9992
0.5571.103
0.9995
0.855
Ibuprofen- Ethocel
standard 10 FP Premium
10:1
6.6633.222
0.9453
0.1590.059
0.9254
0.1970.041
0.9767
6.8043.688
0.9653
0.0380.082
0.9893
0.715
10:2
5.371.805
0.9614
0.1130.033
0.6599
0.1400.025
0.9862
5.9612.188
0.9714
0.1320.267
0.9924
0.761
10:3
3.8870.347
0.9746
0.0720.032
0.9856
0.0980.030
0.9845
4.9672.490
0.9846
0.4120.774
0.9944
0.762
Ibuprofen- Ethocel
standard 100 FP Premium
10:1
6.9053.873
0.9616
0.1720.060
0.8263
0.2100.045
0.8922
6.8794.289
0.9616
0.0310.066
0.9902
0.704
10:2
6.4240.013
0.9612
0.1370.043
0.7837
0.1730.031
0.8659
6.6763.586
0.9641
0.0790.170
0.9897 0.755
10:3
4.7261.558
0.9882
0.1000.046
0.9082
0.1280.033
0.9021
5.5393.251
0.8922
0.1960.403
0.9935
0.772
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 154
Table 4.14 Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard Premium polymer
of different grades and co-excipient HPMC K100M, (meanSD of three
determinations).
Formulation
IBF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
Ibuprofen- Ethocel
standard 7 Premium and HPMC K100M
10:3
8.8067.046
0.9163
0.2470.111
0.8821
0.2890.075
0.8176
7.9116.275
0.9061
0.0180.045
0.9184
0.666
Ibuprofen- Ethocel
standard 10 Premium and HPMCK100M
10:3
9.431 8.732
0.8648
0.2860.145
0.755
0.3180.110
0.8275
8.0997.695
0.8654
0.0110.029
0.9824
0.623
Ibuprofen- Ethocel
standard 100 Premium and HPMC K100M
10:3
9.321 8.519
0.8523
0.3040.151
0.7637
0.3350.116
0.8312
8.0387.643
0.8552
0.0080.021
0.9791
0.600
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 155
Table 4.15 Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard FP polymer of
different grades and HPMC K100M, (meanSD of three determinations).
Formulation
IBF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
Ibuprofen- Ethocel
standard 7 FP Premium and HPMC K100M
10:3
4.2990.753
0.9921
0.0890.036
0.9908
0.1080.026
0.9951
5.1711.880
0.9923
0.3100.631
0.9961
0.761
Ibuprofen- Ethocel
standard 10 FP Premium and HPMC K100M
10:3
5.8872.546
0.9522
0.1240.039
0.743
0.1580.030
0.9387
6.3443.270
0.9513
0.0890.176
0.9887
0.759
Ibuprofen- Ethocel
standard 100 FP Premium and HPMC K100M
10:3
6.631 3.904
0.9473
0.1590.070
0.7937
0.1910.048
0.8604
6.7924.973
0.9479
0.0570.120
0.9901
0.748
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 156
Table 4.16 Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard Premium
polymer of different grades and co-excipient Starch, (meanSD of three
determinations).
Formulation
IBF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
Ibuprofen- Ethocel
standard 7 Premium and Starch
10:3
11.36715.197
0.6923
0.4520.314
0.689
0.4740.229
0.7189
9.04112.102
0.6959
0.0150.052
0.9485
0.537
Ibuprofen- Ethocel
standard 10 Premium and Starch
10:3
11.41218.118
0.6152
0.4720.333
0.4383
0.4790.279
0.536
8.84014.366
0.6144
0.0100.031
0.9715
0.515
Ibuprofen- Ethocel
standard 100 Premium and Starch
10:3
11.54317.572
0.6103
0.5300.412
0.3591
0.5160.308
0.4994
8.88313.956
0.6112
0.0070.024
0.9517
0.469
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 157
Table 4.17 Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
standard FP polymer of
different grades and co-excipient Starch, (meanSD of three determinations).
Formulation
IBF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
Ibuprofen- Ethocel
standard 7 FP Premium and Starch
10:3
9.0987.628
0.9107
0.2540.112
0.8882
0.2980.078
0.9202
8.0566.628
0.9119
0.0180.050
0.9743
0.657
Ibuprofen- Ethocel
standard 10 FP Premium and Starch
10:3
9.5019.110
0.8352
0.3040.148
0.7697
0.3380.121
0.8221
8.1268.081
0.8343
0.0110.030
0.9764
0.607
Ibuprofen- Ethocel
standard 100 FP Premium and Starch
10:3
9.64910.376
0.7982
0.3500.205
0.6645
0.3720.154
0.7509
8.1619.170
0.7965
0.0080.023
0.9759
0.580
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 158
Table 4.18 Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
Standard simple Premium
polymer of different grades and co-excipient CMC, (meanSD of three
determinations).
Formulation
IBF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
Ibuprofen- Ethocel
standard 7 Premium and CMC
10:3
6.92616.420
0.3339
0.6730.678
0.4048
1.0270.835
0.2624
4.86711.625
0.3331
0.0000.000
0.7495
0.092
Ibuprofen- Ethocel
standard 10 Premium and CMC
10:3
6.57716.778
0.2127
1.0360.932
0.0079
0.9900.860
0.0685
4.52411.921
0.2123
0.0000.000
0.7051
0.075
Ibuprofen- Ethocel
standard 100 Premium and CMC
10:3
6.44616.686
0.1987
1.0340.939
0.0049
0.9930.870
0.0587
4.41911.861
0.2984
0.0000.000
0.6972
0.071
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 159
Table 4.19 Different kinetic models applied to determine the release profile of
controlled release matrices of IBF consisting Ethocel
standard FP polymer of
different grades and co-excipient CMC, (meanSD of three determinations).
Formulation
IBF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
Ibuprofen- Ethocel
standard 7 FP Premium and CMC
10:3
8.14116.140
0.4125
0.6280.628
0.3982
0.8920.652
0.3958
5.71911.434
0.4128
0.0000.000
0.844
0.128
Ibuprofen- Ethocel
standard 10 FP Premium and CMC
10:3
7.74 17.846
0.2849
0.9060.720
0.0804
0.9010.722
0.1635
5.34412.144
0.2749
0.0000.000
0.7818
0.106
Ibuprofen- Ethocel
standard 100 FP Premium and CMC
10:3
7.59317.725
0.2712
0.9200.746
0.06
0.9120.740
0.142
5.23812.599
0.2717
0.0000.000
0.7728
0.101
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 160
Table 4.20 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
simple Premium polymer of
different grades, (meanSD of three determinations).
Formulation
KTF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
KTF- Ethocel
standard 7 Premium
10:1
9.14611.727
0.8146
0.4450.257
0.8364
0.4710.217
0.8391
7.49110.275
0.8146
00 0.009
0.9823
0.417
10:2
8.987510.362
0.9098
0.4020.192
0.9236
0.4360.176
0.9086
7.5329.093
0.9298
0.0010.001
0.9851
0.449
10:3
9.076610.1347
0.9343
0.2960.160
0.9633
0.3230.126
0.9211
8.0569.443
0.9343
0.0240.071
0.9873
0.662
KTF- Ethocel
standard 10 Premium
10:1
9.081 11.901
0.7218
0.4380.245
0.5694
0.4710.216
0.6621
7.42010.080
0.7219
0.0000.001
0.9813
0.406
10:2
9.29511.049
0.7462
0.4150.197
0.6736
0.4500.186
0.7268
7.6459.319
0.7465
0.0000.001
0.9829
0.436
10:3
7.7910.043
0.8142
0.3220.174
0.7452
0.3470.140
0.7961
8.3278.901
0.8147
0.0200.059
0.9869
0.633
KTF- Ethocel
standard 100 Premium
10:1
9.02811.585
0.8225
0.4170.207
0.8945
0.4680.215
0.6581
7.2969.667
0.7029
0.0000.000
0.9814
0.387
10:2
9.28811.504
0.8275
0.4310.220
0.8159
0.4620.201
0.6482
7.5999.755
0.7243
0.0000.000
0.9842
0.424
10:3
9.710.275
0.8621
0.3360.192
0.8069
0.3580.149
0.7717
8.2639.222
0.9876
0.0150.046
0.9847
0.619
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 161
Table 4.21 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
FP polymer of different
grades, (meanSD of three determinations).
Formulation
KTF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
KTF- Ethocel
standard 7 FP Premium
10:1
8.337 7.179
0.9016
0.2740.101
0.9014
0.3160.094
0.9805
7.4486.637
0.9216
0.0030.008
0.9898
0.571
10:2
8.09755.191
0.985
0.1790.050
0.9892
0.2190.037
0.9976
7.5654.067
0.975
0.0710.185
0.9945
0.741
10:3
4.7931.454
0.9923
0.0930.017
0.9904
0.1280.022
0.997
5.6691.063
0.9923
0.1670.343
0.9991
0.843
KTF- Ethocel
standard 10 FP Premium
10:1
8.031 6.332
0.9176
0.2610.093
0.9277
0.3050.088
0.9082
7.2695.836
0.9176
0.0030.007
0.9891
0.568
10:2
8.4156.362
0.9319
0.2250.092
0.9502
0.2600.067
0.9022
7.6935.862
0.9319
0.0340.086
0.9769
0.704
10:3
5.8822.271
0.957
0.1180.032
0.9679
0.153.022
0.9335
6.3252.561
0.957
0.1260.265
0.9982
0.776
KTF- Ethocel
standard 100 FP Premium
10:1
8.5377.539
0.8773
0.2960.112
0.8182
0.3420.111
0.619
7.4596.857
0.8773
0.0020.004
0.9819
0.528
10:2
8.9017.082
0.8151
0.2620.114
0.8399
0.2880.078
0.9025
7.8916.289
0.9151
0.0250.065
0.9829
0.684
10:3
6.6433.153
0.9119
0.1440.058
0.9783
0.1770.037
0.9632
6.8323.806
0.9219
0.0880.188
0.9853
0.771
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 162
Table 4.22 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
simple Premium polymer of
different grades and co-excipient HPMC K100M , (meanSD of three
determinations).
Formulation
KTF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
KTF- Ethocel
standard 7 Premium and HPMC K100M
10:3
9.7509.438
0.813
0.3110.152
0.7634
0.3430.124
0.8183
8.2638.167
0.8323
0.0140.042
0.6979
0.612
KTF- Ethocel
standard 10 Premium and HPMC K100M
10:3
9.70510.472
0.7998
0.3460.214
0.6451
0.3660.157
0.7442
8.2219.301
0.7876
0.0110.033
0.9702
0.596
KTF- Ethocel
standard 100 Premium and HPMC K100M
10:3
7.1724.483
0.9536
0.1850.082
0.8004
0.2180.053
0.8773
7.0494.901
0.9532
0.0370.081
0.9861
0.723
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 163
Table 4.23 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
stand FP polymer of
different grades and co-excipient HPMC K100M, (meanSD of three
determinations).
Formulation
KTF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
KTF- Ethocel
standard 7 FP Premium and HPMC K100M
10:3
6.092.564
0.9836
0.1310.036
0.9615
0.1680.028
0.9585
6.4462.946
0.9636
0.0730.151
0.9924
0.745
KTF- Ethocel
standard 10 FP and HPMC K100M
10:3
6.9773.900
0.9625
0.1710.063
0.8324
0.2060.043
0.8956
6.9683.825
0.9637
0.0440.097
0.9914
0.730
KTF- Ethocel
standard 100 FP and HPMC K100M
10:3
7.1724.483
0.9536
0.1850.082
0.8004
0.2180.053
0.8773
7.0494.901
0.9512
0.0370.081
0.9867
0.723
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 164
Table 4.24 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
Standar simple Premium
polymer of different y grades and co-excipient Starch, (meanSD of three
determinations).
Formulation
KTF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
KTF- Ethocel
standard 7 Premium and Starch
10:3
3.6888.171
0.1953
1.0410.890
0.0313
1.0501.005
0.0815
2.4745.853
0.1952
0.0000.000
0.8373
0.037
KTF- Ethocel
standard 10 Premium and Starch
10:3
0.2539.270
0.0052
1.3061.632
0.026
1.2461.584
0.0074
0.0486.565
0.0052
0.0000.000
0.2768
0.004
KTF- Ethocel
standard 100 Premium and Starch
10:3
3.6149.330
0.1767
1.1441.054
0.0056
1.0981.068
0.047
2.4436.679
0.1723
0.0000.000
0.7529
0.035
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 165
Table 4.25 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
Standard FP 7, 10, 100
polymers of different grades and co-excipient Starch, (meanSD of three
determinations).
Formulation
KTF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
KTF- Ethocel
standard 7 FP Premium and Starch
10:3
6.0952.564
0.9636
0.1310.036
0.7615
0.1680.028
0.8585
6.4462.946
0.9612
0.0730.151
0.9914
0.745
KTF- Ethocel
standard 10 FP Premium and Starch
10:3
3.7147.890
0.209
1.0110.864
0.038
1.0300.986
0.0915
2.4715.668
0.2213
0.0000.000
0.8693
0.039
KTF- Ethocel
standard 100 FP Premium and Starch
10:3
3.7319.086
0.1718
1.1671.077
0.2007
1.1021.058
0.0286
2.5166.990
0.1732
0.0000.000
0.7664
0.037
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 166
Table 4.26 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
standar Simple Premium
polymer of different grades and co-excipient CMC, (meanSD of three
determinations).
Formulation
KTF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
KTF- Ethocel
standard 7 Premium and CMC 10:3
2.1486.306
0.0174
1.223 1.215
0.0382
1.1761.254
0.0078
1.3834.519
0.0172
0.0000.000
0.6721
0.010
KTF- Ethocel
standard 10 Premium and CMC
10:3
2.1566.344
0.0201
1.2611.247
0.0411
1.1941.268
0.008
1.3934.544
0.0232
0.0000.000
0.6637
0.012
KTF- Ethocel
standard 100 Premium and CMC
10:3
2.0616.182
0.0083
1.2511.269
0.0566
1.1941.290
0.0182
1.3134.428
0.0076
0.0000.000
0.6201
0.001
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 167
Table 4.27 Different kinetic models applied to determine the release profile of
controlled release matrices of KTF consisting Ethocel
FP polymer of different
grades and co-excipient CMC, (meanSD of three determinations).
Formulation
KTF:Ethocel
W=k1t
k1SD r1
(100-W)=ln100-k2t
k2SD r2
(100-W)1/3=1001/3-k3t
k3SD r3
W=k4t1/2
k4SD r4
Mt/M=k5tn
k5SD r5 n
KTF- Ethocel
standard 7 FP Premium and CMC
10:3
2.7857.541
0.0869
1.3751.410
0.0453
1.1991.212
0.0009
1.8365.394
0.8543
0.0000.000
0.734
0.021
KTF- Ethocel
standard 10 FP Premium and CMC
10:3
2.947.975
0.0972
1.1591.090
0.0007
1.1251.137
0.0102
1.9475.722
0.0932
0.0000.000
0.7183
0.023
KTF- Ethocel
standard 100 FP Premium and CMC
10:3
2.8927.912
0.0731
1.2191.162
0.0147
1.1541.169
0.0004
1.9095.656
0.0712
0.0000.000
0.7023
0.020
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 168
4.14. Selection of the optimized test tablets
The Ibuprofen and Ketoprofen formulations containing Ethocel® standard 7 FP premium,
at D:P ratio 10:3 were selected as the optimized and the best formulations on the basis of
their prolonged release rates of 87.66% and 95.4% of Ibuprofen and Ketoprofen,
respectively, after 24 hours (Figs. 4.25 to 4.46). The formulations also followed near to
zero order release profile, as shown in tables 4.12 to 4.27. These formulations were
further used for stability study and in- vivo evaluation.
4.15. Reproducibility and accelerated stability study
The selected tablets (best formulations) were stored for stability study in ambient
conditions or room temperature (temperature = 25 0C and Relative humidity 65%) as well
as at accelerated storage conditions (400C and RH 75%) for one year. The tablets were
evaluated for their physical appearance, hardness, friability, weight variation, content
uniformity and dissolution profile at predetermined intervals of time 0 (pre-storage), 1, 2,
3, 6, 9 and 12 months. As shown in tables 4.28 and 4.29, the percent drug content for
Ibuprofen in ambient conditions or room temperature at 0 time (pre-storage) and after 1,
2, 3, 6, 9 and 12 months are 101±3, 101±2, 100±1, 100.1±2, 99.5±2, 99±2 and 99±1, and
in accelerated conditions as 101±3, 100±1, 99.5±1, 99.2±2, 99±3 and 99±1, respectively
showing no significant difference in drug content. The weight variation in both
conditions in ambient and accelerated conditions at the same time interval was noted to
be 199.85±0.421, 199.05±0.12, 199.1±0.231, 199.12±0.121, 200.05±0.231,
200.05±0.654, 200.01 and 199.85±0.421, 200±0.12, 200.01±0.231, 200.02±0.121,
200.05±0.231, 200.1±0.654, 200.15±0.132, respectively. The friability for optimized
Ibuprofen formulation in ambient conditions was noted to be 0.12±0.01, 0.13±0.0.5,
0.13±0.02, 0.12±0.09, 0.14±0.01, 0.14±0.02, 0.14±0.03 and in accelerated conditions it
was 0.12±0.01, 0.14±0.0.6, 0.14±0.09, 0.14±0.01, 0.15±0.01, 0.15±0.01 and 0.15±0.02 at
0 time (pre-storage) and after 1, 2, 3, 6, 9 and 12 months, respectively. Moreover,
hardness was also evaluated at 0 time (pre-storage) and after 1, 2, 3, 6, 9 and 12 months
in ambient and accelerated conditions and the results obtained are 7.15±0.092,
7.15±0.098, 7.15±0.043, 7.16±0.012, 7.17±0.017, 7.17±0.091, 7.17±0.098 and
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 169
7.15±0.092, 7.15±0.012, 7.16±0.043, 7.16±0.052, 7.16±0.019, 7.17±0.078, 7.17±0.099,
respectively. The percentage release profile at 0 time (pre-storage) and after 1, 2, 3, 6, 9
and 12 months was also studied in ambient and accelerated conditions and the results
obtained are 87.91±0.111, 87.01±0.213, 86.09±0.112, 86.05±0.123, 86.04±0.12,
86.01±0.312, 86±0.114 and 87.91±0.111, 87.06±0.341, 86.08±0.431, 86.07±0.123,
86.05±0.171, 86.02±0.211, 86.01±0.141, respectively. The whitish appearance was
retained the whole year.
Similar stability studies were performed for optimized Ketoprofen matrix tablets. As
shown in tables 4.30 and 4.31, no significant changes were observed in the percent drug
content in ambient conditions (101±1, 100.5±2, 100.5±1, 100±2, 99.85±1, 99.5±1, 99±2);
weight variation (200±0.123, 199.85±0.13, 199.85±0.141, 200±0.122, 200.05±0.231,
200.1±0.113, 200.75±123); percent friability (0.14±0.02, 0.15±0.0.1, 0.15±0.03,
0.16±0.08, 0.16±0.05, 0.16±0.01, 0.16±0.02); hardness (7.14±0.093, 7.14±0.095,
7.15±0.031, 7.15±0.0141, 7.16±0.0117.17±0.012, 7.17±0.0312); percent drug release
(94.9±0.121, 94.5±0.214, 94.5±0.112, 94.5±0.121, 94.1±0.11, 94±0.316, 93.9±0.125) and
appearance (whitish), tested at 0 time (pre-storage) and after storage at 1, 2, 3, 6, 9 and 12
months, respectively and same results were found when the tablets were stored in
accelerated conditions. Moreover, no significant effects were observed in accelerated
conditions on the percent drug content (101±1, 100.5±1, 100±2, 99.5±2, 99.1±2, 99.1±1,
99±2); weight variation (200±0.123, 200±0.568, 200±0.145, 200±0.172, 200.05±0.231,
200.1±0.112, 200.1±0.112); percent friability (0.14±0.02, 0.15±0.07, 0.15±0.09,
0.16±0.04, 0.16±0.08, 0.16±0.09, 0.17±0.01); hardness (7.14±0.093, 7.15±0.098,
7.15±0.0842, 7.17±0.095, 7.17±0.098, 7.17±0.101, 7.17±0.123); percent release
(94.9±0.121, 94.5±0.124, 94.5±0.234, 94.5±0.157, 94.1±0.217, 94.1±0.452, 94±0.161);
appearance (whitish), tested at 0 time (pre-storage) and after storage at 1, 2, 3, 6, 9 and 12
months, respectively
As shown (tables 4.28 to 4.31), no significant difference was noted in the % drug
released. This indicates that controlled release matrix tablets of Ibuprofen and Ketoprofen
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 170
were reliable and reproducible. Also the release kinetics remained unchanged up to one
year of storage in ambient and accelerated conditions and no significant changes were
observed in all physical characteristics, suggesting that Ibuprofen and Ketoprofen were
stable in Ethocel® standard 7 FP premium polymer compressed tablets. These results are
similar to a previously reported study of Chandran et al. (2008), wherein no significant
changes were observed in physical characteristics and release profiles of Ibuprofen
matrix tablets after storage for one year.
Difference factor ƒ1 and Similarity factor ƒ2 were also calculated as shown in tables 4.32
and 4.33 during stability studies for Ibuprofen and Ketoprofen controlled release matrix
tablets at different time intervals after 1, 2, 3, 6, 9 and 12 months, while comparing the
release profile with dissolution profiles at zero time (pre-storage). As shown in tables
4.32 and 4.33 the difference factor ƒ1 for Ibuprofen and Ketoprofen matrix tablets in
ambient and accelerated conditions was in the range of 0.014-0109 and 0.011-0.101,
respectively, while similarity factor ƒ2 was in the range of 96.305-99.161 for Ibuprofen
and 98.856-99.809 for Ketoprofen, indicating a good level of equivalence of dissolution
profiles determined at 0 time (pre-storage) and after storage at 1, 2, 3, 6, 9 and 12 months.
Generally, ƒ1 up to 15 and ƒ2 > 50 indicates similar dissolution profile (Shah et al., 1998;
US FDA, 1997).
Table 4.28 Stability indicating parameters (drug content, weight variation, friability,
hardness, % release after 24 hours and appearance) for Ibuprofen matrices in ambient
conditions (25oC and RH 65%).
Reading taken for
determination of
stability
Drug
content(%)
n= 3
(mean±SD)
Weight variation
test (mg)
n=20
(Mean±SD)
Friability
test (%)
n=3
(Mean±SD
Hardness
test kg/cm3)
n=10
(Mean±SD
% Release after
24 hours
n=3
(Mean±SD)
Appearance
(Colour)
At 0 time (prestorage) 101±3 199.85±0.421 0.12±0.01 7.15±0.092 87.91±0.111 Whitish
After 1 month 101±2 199.05±0.12 0.13±0.0.5 7.15±0.098 87.01±0.213 Whitish
After 2 months 100±1 199.1±0.231 0.13±0.02 7.15±0.043 86.09±0.112 Whitish
After 3 months 100.1±2 199.12±0.121 0.12±0.09 7.16±0.012 86.05±0.123 Whitish
After 6 months 99.5±2 200.05±0.231 0.14±0.01 7.17±0.017 86.04±0.12 Whitish
After 9 months 99±2 200.05±0.654 0.14±0.02 7.17±0.091 86.01±0.312 Whitish
After 12 months 99±1 200.01 0.14±0.03 7.17±0.098 86±0.114 Whitish
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 171
Table 4.29 Stability indicating parameters (drug content, weight variation, friability,
hardness, % release after 24 hours and appearance) for Ibuprofen matrices in accelerated
conditions (40oC and RH 75%).
Reading taken for
determination of
stability
Drug content
(%)
n= 3
(mean±SD)
Weight variation
test (mg)
n=20
(Mean±SD)
Friability
test (%)
n=3
(Mean±SD
Hardness
test (kg/cm3)
n=10
(Mean±SD
% Release after
24 hours
n=3
(Mean±SD)
Appearance
(Colour)
At 0 time (prestorage) 101±3 199.85±0.421 0.12±0.01 7.15±0.092 87.91±0.111 Whitish
After 1 month 100±1 200±0.12 0.14±0.0.6 7.15±0.012 87.06±0.341 Whitish
After 2 months 99.5±1 200.01±0.231 0.14±0.09 7.16±0.043 86.08±0.431 Whitish
After 3 months 99.2±2 200.02±0.121 0.14±0.01 7.16±0.052 86.07±0.123 Whitish
After 6 months 99.1±2 200.05±0.231 0.15±0.01 7.16±0.019 86.05±0.171 Whitish
After 9 months 99±3 200.1±0.654 0.15±0.01 7.17±0.078 86.02±0.211 Whitish
After 12 months 99±1 200.15±0.132 0.15±0.02 7.17±0.099 86.01±0.141 Whitish
Table 4.30 Stability indicating parameters (drug content, weight variation, friability,
hardness, % release after 24 hours and appearance) for Ketoprofen matrices in ambient
conditions (25oC and RH 65%).
Reading taken for
determination of
stability
Drug
content (%)
n= 3
(mean±SD)
Weight variation
test (mg)
n=20
(Mean±SD)
Friability
test (%)
n=3
(Mean±SD
Hardness
test (kg/cm3)
n=10
(Mean±SD
% Release after
24 hours
n=3
(Mean±SD)
Appearance
(Colour)
At 0 time (prestorage) 101±1 200±0.123 0.14±0.02 7.14±0.093 94.9±0.121 Whitish
After 1 month 100.5±2 199.85±0.13 0.15±0.0.1 7.14±0.095 94.5±0.214 Whitish
After 2 months 100.5±1 199.85±0.141 0.15±0.03 7.15±0.031 94.5±0.112 Whitish
After 3 months 100±2 200±0.122 0.16±0.08 7.15±0.0141 94.5±0.121 Whitish
After 6 months 99.85±1 200.05±0.231 0.16±0.05 7.16±0.011 94.1±0.11 Whitish
After 9 months 99.5±1 200.1±0.113 0.16±0.01 7.17±0.012 94±0.316 Whitish
After 12 months 99±2 200.75±123 0.16±0.02 7.17±0.0312 93.9±0.125 Whitish
Table 4.31 Stability indicating parameters (drug content, weight variation, friability,
hardness, % release after 24 hours and appearance) for Ketoprofen matrices in accelerated
conditions (40oC and RH 75%).
Reading taken for
determination of
stability
Drug
content (%)
n= 3
(mean±SD)
Weight variation
test (mg)
n=20
(Mean±SD)
Friability
test (%)
n=3
(Mean±SD
Hardness test
(kg/cm3)
n=10
(Mean±SD
% Release after
24 hours
n=3
(Mean±SD)
Appearanc
e
(Colour)
At 0 time (prestorage) 101±1 200±0.123 0.14±0.02 7.14±0.093 94.9±0.121 Whitish
After 1 month 100.5±1 200±0.568 0.15±0.07 7.15±0.098 94.5±0.124 Whitish
After 2 months 100±2 200±0.145 0.15±0.09 7.15±0.0842 94.5±0.234 Whitish
After 3 months 99.5±2 200±0.172 0.16±0.04 7.17±0.095 94.5±0.157 Whitish
After 6 months 99.1±2 200.05±0.231 0.16±0.08 7.17±0.098 94.1±0.217 Whitish
After 9 months 99.1±1 200.1±0.112 0.16±0.09 7.17±0.101 94.1±0.452 Whitish
After 12 months 99±2 200.15±121 0.17±0.01 7.17±0.123 94±0.161 Whitish
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 172
Table 4.32 Difference factor ƒ1 and Similarity factor ƒ2 calculated for Ibuprofen controlled release
matrix tablets, while comparing their dissolution profile at different time intervals with dissolution
profile at zero time (pre-storage) during stability study.
Time Difference factor ƒ1 Similarity factor ƒ2
25oC/RH 65% 40
oC/RH 75% 25
oC/RH 65% 40
oC/RH 75%
After 1 month 0.014 0.01 99.064 99.161
After 2 months 0.121 0.12 96.597 96.565
After 3 months 0.112 0.13 96.468 96.533
After 6 months 0.111 0.11 96.436 96.468
After 9 months 0.109 0.107 96.338 96.370
After 12 months 0.103 0.109 96.305 96.338
Table 4.33 Difference factor ƒ1 and Similarity factor ƒ2 calculated for Ketoprofen controlled release
matrix tablets, while comparing their dissolution profile at different time intervals with dissolution
profile at zero time (pre-storage) during stability study.
Time Difference factor ƒ1 Similarity factor ƒ2
25oC/RH 65% 40
oC/RH 75% 25
oC/RH 65% 40
oC/RH 75%
After 1 month 0.011 0.011 99.809 99.809
After 2 months 0.011 0.011 99.809 99.809
After 3 months 0.011 0.011 99.809 99.809
After 6 months 0.012 0.012 99.254 99.254
After 9 months 0.014 0.012 99.064 99.254
After 12 months 0.101 0.012 98.856 99.064
The selected formulations were further used for in-vivo studies. In this case the sustained
release tablets of Ibuprofen and Ketoprofen available in market were used as reference, as
the strength of SR Ibuprofen and SR Ketoprofen available in market was 300mg and
200mg, respectively, so the test formulations were developed according to market
strength, for this purpose the same D:P ratio was used (10:3). Therefore, controlled
release matrix tablets of Ibuprofen and Ketoprofen were developed containing 300mg
Ibuprofen and 200 mg Ketoprofen active. After satisfactory physical evaluation and in-
vitro dissolution studies the tablets were used for in-vivo evaluation. As shown in Fig.
4.49, the in-vitro dissolution studies depicted that more than 90% of drug was release
from reference SR tables of Ibuprofen in 18 hours, while 90% of drug was released from
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 173
test tablets in 24 hours. Similar comparative studies were performed for SR Ketoprofen
tablets available in market and test tablets. As shown in Fig. 4.50, more than 90% of drug
was released in 18 hours from reference tablets of Ketoprofen, while from the test tablets
more than 90% of drug was released in 24 hours. It can be seen that both test tablets of
Ibuprofen and Ketoprofen had a slower in-vitro release when compared with the
commercially available reference products.
Figure 4.49 Drug-release profiles for Ibuprofen from test and reference tablets up to 24
hours.
Figure 4.50 Drug-release profiles for Ketoprofen from test and reference tablets up
to 24 hours.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 174
4.16. In-vivo evaluation
Selecting the formulations for in-vivo evaluation was done after a inclusive in-vitro
development study. Figures 4.51 to 4.56 are typical chromatograms of standard solution
containing 5µg/mL of Ibuprofen and Ketoprofen, rabbit plasma spiked with 10µg/mL of
Ibuprofen and Ketoprofen, rabbit plasma collected from blood withdrawn 4 hours after
administration of test tablets of Ibuprofen and Ketoprofen. As shown, sharp peaks with
retention times of 7.3min and 5.2min for Ibuprofen and Ketoprofen are observed,
respectively. The mean absolute recovery of Ibuprofen and Ketoprfen determined from
six aliquot samples was more than 90% at 0.25µg/mL to 10µg/mL. The mean plasma
concentration curve was found to be linear with correlation coefficient R2 of 0.9988 and
0.9992 for Ibuprofen and Ketoprofen, respectively (Figs. 4.57 and 4.58).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 175
Figure 4.51 A representative chromatogram of standard solution consisting of
5µg/mL of Ibuprofen
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 176
Figure 4.52 A representative chromatogram of Ibuprofen extracted from a sample
of rabbit plasma spiked with 10µg/mL of Ibuprofen.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 177
Figure 4.53 A representative chromatogram of Ibuprofen extracted from a sample
of rabbit plasma with drawn 4 hours after administration of Ibuprofen Test tablet.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 178
Figure 4.54 Representative chromatogram of standard solution consisting of
5µg/mL of Ketoprofen
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 179
Figure 4.55 A representative chromatogram of Ketoprofen extracted from a sample
of rabbit plasma spiked with 10µg/mL of Ketoprofen.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 180
Figure 4.56 A representative chromatogram of Ketoprofen extracted from a sample
of rabbit plasma with drawn 4 hours after administration of Ketoprofen Test tablet
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 181
Figure 4.57 Standard curve for Ibuprofen in plasma.
Figure 4.58 Standard Curve for Ketoprofen in plasma.
The mean plasma concentration versus time profiles of reference and test tablets of
Ibuprofen and Ketoprofen are shown in figures 4.59 and 4.60, respectively. As shown,
the in-vivo plasma concentration for both test and reference formulations of Ibuprofen
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 182
and Ketoprofen are reflective of a slow and extended release rate of drug absorption.
However, more extended release rates were observed in case of test formulations
compared to reference formulations of Ibuprofen and Ketoprofen, as for reference
formulations the active moieties remained in the body for 30 hours, while for test
formulations the active moieties remained in the body for longer period of 42 hours.
The pharmacokinetic parameters based on the plasma level time curve are presented in
tables 4.34 and 4.35. The two tailed t-test was applied on results using SPSS 12.0
software to test for the treatment effect i.e. Test tablets vs reference tablets. As shown in
table 4.34, the mean elimination rate constants (Kel) of reference SR Ibuprofen tablets and
test tablets were 0.274±0.311 h-1
and 0.0767±0.006 h-1
, respectively and significant
difference (P<0.05) in Kel values of the two formulations was found. The mean half-life
(t1/2) of Ibuprofen reference and test tablets were 4.858±2.301 and 9.913±1.032,
respectively and significant difference was observed (P<0.001). The mean Tmax values for
reference and test tablets of Ibuprofen were 3±0.003 hours and 4±0.001 hours and Cmax
were 414.21±3.211µg/mL and 411.03±1.322 µg/mL. Statistical analysis showed
significant difference between Tmax values of reference and test tablets (P<0.05), while
there was no significant difference observed between Cmax values of reference and test
tablets of Ibuprofen (P>0.05).
Figure 4.59 Mean plasma concentration of Ibuprofen from test tablets and reference
tablets (n=12).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 183
Figure 4.60 Mean plasma concentration of Ketoprofen from test tablets and
reference tablets (n=12).
In this study the values of AUC0-t for reference and test tablets were noted 3391.54±70.04
µg.hr/mL and 6593.9±48.43 µg.hr/mL, respectively and statistically significant difference
was noted between reference and test formulations (P<0.001). The mean resident time
(MRT0-t) values, calculated for reference and test tablet of Ibuprofen were 3.647±0.76
hours and 13.053±0.43 hours, respectively and significant difference was observed
(P<0.0001). Similarly, the mean volume of distribution (Vd) values for reference and test
formulations were 0.609±0.002 Litters and 0.612±0.001 Litters, respectively, and no
significant difference was observed (P>0.05). The mean of total clearance, calculated for
reference tablets was higher 0.087±0.003µg×hr/(µg/mL) than that of test tablets
0.05±0.0002µg×hr/(µg/mL) with significant difference (P<0.05). The means apparent
volume of distribution at steady state (Vss) values and absorption rate constant for
reference and test formulations were 0.71±0.004 Litters and 0.698±0.001 Litters and
0.348±0.213 and 0.478±0.321, respectively and no significant difference was observed
(P>0.05). Similar in-vivo study for Ibuprofen mini matrices was conducted by Caroline et
al. (2004), using human volunteers, but our results were contradicting with their findings.
This might be due to subject difference, as in our study rabbits were used as experimental
animals while they had used human volunteers for their in-vivo evalution.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 184
Table 4.34 Pharmacokinetic parameters for Ibuprofen, following oral administration of
300mg Reference and 300mg Test tablets of Ibuprofen to two separate groups of rabbits
(Mean±SD, n=12).
Pharmcokinetic parameters calculated for Reference Tablets
(Ibuprofen, 300mg)
Test Tablets
(Ibuprofen, 300mg)
Elimination rate constant (Kel) (hr-1
) 0.274±0.311 0.077±0.006
Half-life (t1/2) (hours) 4.858±2.301 9.913±1.032
Time of maximum plasma concentration (tmax) (hours) 3±0.003 4±0.001
Maximum plasma concentration (Cmax) (µg/ mL) 414.21±3.211 411.03±1.322
Area under curve (AUC0-t) (µg×hr/mL) 3391.54±70.04 6593.9±48.43
Mean residence time (MRT0-t) (hours) 3.647±0.76 13.053±0.43
Volume of distribution (Vd) (Liters) 0.609±0.002 0.612±0.001
Clearance (Cl) (µg×hr/(µg/mL) 0.087±0.0031 0.049±0.0002
App. vol of distribution at steady state (Vss) (µg/(µg/mL) 0.710±0.004 0.698±0.001
Absorption rate constant (Ka) 0.348±0.213 0.478±0.321
Similarly, table 4.35 represents mean values of pharmacokinetic parameters obtained
after oral administration of reference SR and test tablets of Ketoprofen to rabbits (n=12).
The elimination rate constant (Kel) of the experimental formulation was significantly
lower 0.080±0.134 h-1
than the corresponding value of reference formulation
0.380±0.213 h-1
, combined with significant difference (P<0.001) in half-life (t1/2), as half-
life for reference was noted to be 4.133±1.431hr, while that for test formulation it was
10.309±2.103 hr. Maximum plasma concentration (Cmax) of reference formulation was
283.42±2.431 µg/mL, while that for test formulation it was 281.77±1.321 µg/mL and no
significant difference was observed (P>0.05). As shown in fig () the maximum plasma
peak reference was not significantly higher than that of test formulation, but reach in
short time as compared to test formulation. As Tmax for reference was noted 2±0.001 hr,
while that for test 4±0.002 hr. statistically, there is significant difference between Tmax of
reference and test formulations (P<0.05). In this study the values of AUC0-t for reference
and test formulations were observed 1596.24±64.21 µg.hr/mL and 4159.36±37.21
µg.hr/mL, respectively and statistically, significant difference was noted between
reference and test formulations (P<0.001). The mean resident time (MRT0-t) values,
calculated for reference and formulations of Ketoprofen were 2.631±0.45 hours and
12.469±0.57 hours, respectively and significant difference was observed (P<0.0001).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 185
Similarly, the mean volume of distribution (Vd) values for reference and test
formulations were 0.741±0.003 Litters and 0.745±0.001 Litters, respectively, and no
significant difference was observed (P>0.05). The mean of total clearance, calculated for
reference tablets was higher 0.124±0.001 µg×hr/(µg/mL) than that of test tablets
0.045±0.001 µg×hr/(µg/mL) with significant difference (P<0.05). The means apparent
volume of distribution at steady state (Vss) values and absorption rate constant for
reference and test formulations were 0.827±0.001 Litters and 0.743±0.004 Litters and
0.455±0.113 and 0.568±0.211, respectively and no significant difference was observed
(P>0.05). Similar study was also performed by Roda et al. (2002), using human
volunteers and evaluated different pharmacokinetic parameters. Our results were different
in respect of different pharmacokinetic parameters. This might be due to subject
difference, as in our study rabbits were used as experimental animals while they had used
human volunteers for their in-vivo evaluation.
Table 4.35 Pharmacokinetic parameters for Ketoprofen, following oral administration of
200mg Reference and 200mg Test tablets of Ketoprofen to two separate groups of rabbits
(Mean±SD, n=12)
Pharmcokinetic parameters calculated Reference Tablets
(Ketoprofen, 200mg)
Test Tablets
(Ketoprofen, 200mg)
Elimination rate constant (Kel) (hr-1
) 0.380±0.213 0.080±0.134
Half-life (t1/2) (hours) 4.133±1.431 10.309±2.103
Time of maximum plasma concentration (tmax) (hours) 2±0.001 4±0.002
Maximum plasma concentration (Cmax) (µg/mL) 283.42±2.431 281.77±1.321
Area under curve (AUC0-t) (µg×hr/mL) 1596.24±64.21 4159.36±37.21
Mean residence time (MRT0-t) (hours) 2.631±0.45 12.469±0.57
Volume of distribution (Vd) (Liters) 0.741±0.003 0.745±0.001
Clearance (Cl) (µg×hr/(µg/mL) 0.124±0.001 0.045±0.001
Apparent volume of distribution at steady state (Vss)
(µg/(µg/mL))
0.827±0.001 0.743±0.004
Absorption rate constant (Ka) 0.455±0.113 0.568±0.211
Relatively wide inter subjects (rabbits) variation was observed in the values of AUC0-t,
which could be attributed to difference in body weight and drug disposition among
subjects (rabbits).
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 186
4.17. In-vitro and in-vivo correlation
In-vitro and in-vivo correlation (IVIVC) is an analytical mathematical model used for
unfolding the relationship between an In-vitro behavior of a product and corresponding
In-vivo response. Typically, the In-vitro behavior is the rate or extent of a drug release,
while the In-vivo is the plasma drug concentration (US FDA, 1997).
Five correlation levels such as, level A, B, C, D and E have been introduced for the In-
vitro and In-vivo correlation in the FDA guidance (US FDA, 1997). The level A
correlation is the best class of correlation and reports a point-to-point relationship
between In-vitro dissolution rate and In-vivo absorption rate of the drug from the dosage
form (US FDA, 1997). Therefore, to demonstrate a IVIVC, fraction of percent drug
absorbed (Fa, Y-axis) was plotted against fraction of percent drug released (Fr, X-axis)
(Amir et al., 2010).The values of percent drug released were obtained from In-vitro
release data and percent drug absorbed was calculated, using the well-known Wagner and
Nelson equation (Wagner and Nelson, 1964). As shown in figures 4.61 and 4.62, a good
in-vitro and in-vivo correlation of level A was achieved for test formulations of Ibuprofen
and Ketoprofen with coefficient of determination (R2) 0.9658 and 0.9643, respectively,
which indicate that the formulations were successful enough for further clinical
evaluation and promotion. However, the reference SR formulations of Ibuprofen and
Ketoprofen showed less linearity with coefficient of determination (R2) 0.8651 and
0.7868, respectively (Figs. 4.63 and 4.64) Moreover, Ibuprofen and Ketoprofen test
formulations showed good linear relationship between In-vitro drug released and In-vivo
drug absorption, prolonged MRT0-t and t1/2 values as compared to reference formulations.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 187
Figure 4.61 Percent of drug absorbed (Fa, Y-axis) plotted against percent of drug
released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 hours to
show the In-vitro and In-vivo correlation of Ibuprofen Test tablets.
Figure 4.62 Percent of drug absorbed (Fa, Y-axis) plotted against percent of drug
released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 hours to
show the In-vitro and In-vivo correlation of Ketoprfofen Test tablets.
CR Matrices of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 188
Figure 4.63 Percent of drug absorbed (Fa, Y-axis) plotted against percent of drug
released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 hours to
show the In-vitro and In-vivo correlation of Ibuprofen Reference tablets.
Figure 4.64 Percent of drug absorbed (Fa, Y-axis) plotted against percent of drug
released (Fr, X-axis) at times 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 hours to
show the In-vitro and In-vivo correlation of Ketoprofen Reference tablets.
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 189
CHAPTER 5
NANOPARTICLES MATERIALS AND METHODS
5.1. MATERIALS
5.1.1. Chemical and reagent
The chemicals and reagents used for nanoparticles preparation are.
Ibuprofen sodium salt, Ibuprofen and Ketoprofen (Sigma, UK), Poly glycerol adipate
(0% C-18 PGA), Modified 40% C-18 PGA and Modified 100% C-18 PGA (Provided by
Dr. Paraskevi Kallinteri), Tween 0.01% (Sigma, UK), Sepharose (Sigma, UK) Acetone
(Fisher Scientific, UK), Methanol (Fisher Scientific, UK), HPLC grade water (Fisher,
UK), Acetonitrile HPLC grade (Fisher, UK), Ethanol (Fisher Scientific, UK), Sodium
Hydroxide (NaOH) (Sigma, UK), Monobasic Potassium Phosphate (KH2PO4) (Sigma,
UK).
5.1.2. Instrumentation and equipment
The following instruments and equipment were used in this research work.
Glass Vials (Fisherbrand, UK), Glass pipettes (Fisherbrand, UK), Accurate pipette
(micropipette) (Gilson, France), Pipette tips (Gilson, France), Nitrogen Pump and
Cylinder (Boc, UK), Beakers, Flasks, Gloves, Magnetic stirrers, Stands, test tubes
(Fisherbrand, UK), Eppendorfs (Eppendorf, UK), Size Exclusion Chromatography
column and plastic tubing for SEC (Coludin: GE Healthcare, France), Fraction Collector
and Pump P1 ( GE Healthcare, France), Viva Spin Centrifuge tubes (Sartorius Stedim
Biotech, Germany), Dialysis Membrane (M.W. cut off 12-14kDa), (SLS,UK), Hot Plate
(IKA WERK, RT 10 P,Germany), Fume hood (UK), Freez Drier (SCANVAC,
DENMARK), Bench Centrifuge (Hettich Rotina, 3812, Germany), Microcentrifuge
(Hettich, Mikro 120, Germany), HPLC (Millipore water, France), GPC (PL-GPC50Plus,
Varian), Water bath (shaker)(Grant, OLS 200, UK), Sonicator (Ultrawave, UK), Balance
(Sartorious, ED1245, Germany), Vapour Venting Wash Bottles (Bibby Sterilin, UK),
Parafilm M (PARAFILM, Chicago), Marvlen Zitasizer (Marveln, nano ZS, UK), pH
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 190
meter (Denver, USA), DSC instrument (Mettler Toledo DSC 822e, Greifensee,
Switzerland), FT-IR SpectrumOne spectrophotmer (Perkin Elmer, UK).
5.2. METHODS
5.2.1. Nanoparticles formulation
5.2.1.1. Differential scanning calorimetry (DSC) studies: The differential scanning
calorimetry (DSC) study was performed for the determination of drugs interaction with
polymer, using DSC instrument (Mettler Toledo DSC 822e, Greifensee, Switzerland)
equipped with Stare computer program according to the method described above in
section 3.2.1.8.
5.2.1.2. Fourier transform Infrared (FT-IR) studies: The FT-IR spectra of pure
Ibuprofen, pure ketoprofen, pure Ibuprofen sodium salt and polymers, were taken to
observe the drugs-carrier interation, using FT-IR SpectrumOne spectrophotometer
(Perkin Elimer, UK), using the same method as described in section 3.2.1.9 of this thesis.
5.2.1.3. Preparation of Stock Solution: Polymer (20 mg/ml in acetone) and drug
(4mg/ml) stock solutions were prepared. Drugs used were Ibuprofen, Ibuprofen sodium
salt and Ketoprofen. Ibuprofen and Ketoprofen were dissolved in Methanol while
Ibuprofen sodium salt was dissolved in deionised water.
5.2.1.4. Preparation of Empty Nanoparticles: Nanoparticles were prepared using the
interfacial deposition method (Fessi et al., 1965). Empty particles were prepared by
adding dropwise the polymer solution (20 mg in 2 ml of acetone) into 5ml deionised
water under mild stirring at room temperature. The dispersion was left in the fume hood
overnight for the organic solvent to evaporate. Then, agglomerated polymer was
separated from the particles by centrifugation at 5000rpm for five minutes and then
particles were passed through PD-10 column with distilled water as an eluent. Particle
size, polydispersity index and zeta-potential were determined using NanoZS by Malvern.
5.2.1.5. Preparation of drug-loaded particles: For the formation of nanoparticles loaded
with the lipophilic drugs, 1 ml of drug stock solution was mixed with 1 ml polymer
solution in a glass vial and then the organic solvents were evaporated using nitrogen gas
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 191
stream till the formation of a matrix in the vial. Then, that was dissolved in 2ml of
acetone which was added dropwise in 5 ml of distilled under mild stirring at room
temperature. Then, the particle dispersion was left in the fume hood overnight for the
organic solvent to evaporate. In case of the water-soluble Ibuprofen sodium salt, 1ml of
drug solution in water was added in 4 ml of distilled water. To that solution, 2 ml of
polymer solution (20 mg) was added. Polymer aggregates were separated from the
particles by centrifugation as mentioned above.
5.2.1.6. Separation of free drug from nanoparticles: Nanoparticles were separated from
the free drug using size exclusion chromatography Sepharose 4B-CL (16mm x 24 cm)
Fig. 5.1. Distilled water was used as an eluent. Fractions of 1 ml were collected at a flow
rate 1ml/min. The fractions that contained the nanoparticles were pooled together, the
exact volume was measured and the preparation was split in half. One half was freeze
dried so to estimate the drug incorporation while the other half was placed in dialysis
bags to study the drug release.
Figure 5.1 Size Exclusion Chromatography column packed with Sepharose 4B-CL.
Column length ~24 cm, diameter 16 mm
5.2.1.7. Freeze-drying study: For freeze-drying the glass vials were weighed before and
after placing the samples for freeze drying. The difference of the two weights (weight
after – weight before) was the mass of the freeze dried polymer + drug matrix.
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 192
5.2.1.8. Drug Release study: For the determination of drug release from the
nanoparticles, the samples were concentrated to approximately 2.5ml in viva spin
concentrators at 11,000 r.p.m at 25C0 for 30 minutes Fig. 5.2.
Figure 5.2 Viva spine Concentrator tubes
Then, the samples were transferred in dialysis bags and put into a glass vial with 2ml of
0.01% Tween. The samples were placed in a shaking water-bath (25 oscillation, 37°C)
and drug release study was carried out for 17 days. Samples (2ml) were withdrawn at
various time intervals (0 min, 15 min, 30 min, 1hr, 2hr, 3hr, and then daily till 17 days)
while they were replaced with fresh 0.01% Tween solution.
The analysis of the samples was carried out using HPLC. All formulations were prepared
in triplicate for statistical purposes.
5.2.1.9. HPLC analysis of the nanoparticles: Percentage drug release from polymer
nanoparticles was determined using HPLC (Waters, Millipore Instrument), consisting of
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 193
Waters 717plus autosampler, Waters 486 UV-detector, Waters 600 controller and
GALAXIE Varian software. An analytical column (Lichrospher C-18) was used.
The mobile phase for ibuprofen analysis was 0.05M phosphate buffer (pH:
3.5)/acetonitrile (30/70 v/v) respectively. Detection wavelength was 220nm and the drug
retention time was 3.9 minutes.
The moblile phase for ketoprofen was 0.05M phosphate buffer (pH: 7.4)/acetonitrile
(22/78 v/v). The drug was detected at 258nm while the retention time was 4.1nm.
The mobile phase for ibuprofen sodium salt was 0.05M phosphate buffer (pH:
6.5)/acetonitrile (66/34 v/v). The drug was detected at wavelength 236nm and the
retention time was 4.1 minutes.
5.2.1.10. Preparation of standard solutions and construction of calibration curves: So
for construction of calibration curves, stock solutions of all three drugs were prepared
with concentration of 1mg/ml in HPLC grade solvents. From these stock solutions
reference solutions of 0.25ppm, 0.5ppm, 1ppm, 2ppm, 5ppm and 10ppm were prepared.
Then standard curve for all three drugs were constructed using HPLC (Figs. 5.3, 5.4 and
5.5).
Figure 5.3 Standard curve for Ibuprofen
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 194
Figure 5.4 Standard curve for Ketoprofen
Figure 5.5 Standard curve for Ibuprofen sodium salt
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 195
5.2.1.11. Determination of drug loading: In order to estimate the drug loading on the
nanoparticles, the following process was carried out: the freeze-dried samples containing
ibuprofen and ketoprofen were first dissolved in 0.5 ml of methanol and 1 ml of acetone
(1:2 v/v) and then diluted with same solvent upto 10ml for HPLC anaylsis, but in case of
ibuprofen sodium salt water and acetone was used for dissolution of freeze-dried sample
with the same ratio (1:2 v/v) as mentioned above.
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 196
CHAPTER 6
NANOPARTICLES RESULTS AND DISCUSSION
6.1. Drug-polymer interaction studies
6.1.1. Differential scanning calorimetry (DSC): To investigate the possible interactions
between drugs and polymers DSC studies were performed. Figures 6.1, 6.2 and 6.3 depict
DSC curves of each drug alone, polymer and drug-polymer combination (mixture)
separately.
The thermal curves or peaks of pure Ibuprofen, polymer PGA (Poly glycerol adipate) and
drug-polymer combination are depicted in Fig. 6.1a-c. A sharp endotherm (Tpeak=
76.94oC) was observed for pure ibuprofen at the temperature corresponding to its melting
point (Fig. 6.1c). The polymer peak was observed at 37.18oC which is the melting point
of PGA polymer (Fig.6.1a). As shown, the thermogram of ibuprofen did not show any
major change in the endothermic peak with the polymer PGA (Fig. 6.1b), indicating no
possible interaction but the broadness and low melting point of polymer indicates that the
polymer has amorphous structure.
Figure 6.1 DSC thermograms of (a) PGA polymer; (b) Ibuprofen-polymer (PGA);
(c) pure Ibuprofen.
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 197
The thermal curves of pure ketoprofen, polymer and ketoprofen-polymer (PGA) are
reported in Fig. 6.2a-c. The thermogram of ketoprofen showed a single endothermic peak
at 94oC, corresponding to the melting point of this drug (Fig. 6.2c). The DSC themogram
for Ketoprofen-polymer combination (mixture) showed prominent peaks at the same
temperature range as their melting points (Fig. 6.2b). There were not extra thermal events
found in the corresponding thermograms and the ketoprofen signal appears unaffected,
which means that there is no incompatibility between ketoprofen and polymer PGA.
Figure 6.2 DSC thermograms of (PGA polymer); (b) Ketoprofen-polymer (PGA)
mixture; (c) pure Ketoprofen.
The DSC thermogram of ibuprofen sodium salt and its combination with polymer PGA,
40% C18 PGA, and 100% C18 PGA are shown in the Fig. 6.3a-d. The pure ibuprofen
sodium salt shows two endothermic peaks at 197.76oC and 100.57
oC, indicating melting
point and the loss of crystal water (dehydration peak), respectively (Fig. 6.3d). It is
obvious that the mixture of drug with all polymers did not show any peaks indicating
possible interaction between the two components, while mixtures of Ibuprofen sodium
salt with the said polymers showed disappearance of sharp melting peak and dehydration
peak. Thus on the bases of these observations it can be concluded that Ibuprofen sodium
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 198
salt has possible interaction with polymers. The same findings were observed by other
investigator Gruber et al. (2009) about Ibuprofen sodium salt.
Figure 6.3 DSC thermograms of (a) Ibuprofen sodium salt-Polymer (100% C-18
PGA) mixture; (b) Ibuprofen sodium salt-Polymer (40%C-18 PGA) mixture; (c)
Ibuprofen sodium salt-Polymer (PGA C-18) mixture; (d) Ibuprofen sodium salt
pure.
6.1.2. Fourier transforms infrared spectroscopy (FT-IR): To rule out any possible
interaction between different drugs, such as ibuprofen, ketoprofen, and mixtures of these
drugs with the polymers used, FT-IR study was performed.
The FT-IR spectrums of pure ibuprofen, polymer and ibuprofen-polymer (PGA)
combination (mixture) were obtained as shown in the Fig. 6.4a-c. Pure ibuprofen showed
sharp characteristic peaks at 1706 cm-1
which corresponds to the carboxyl acid (COOH)
present in ibuprofen. Other smaller peaks in the region 1200-1000 cm-1
are the indication
of benzene ring (Socrates, 1994). These peaks can also be seen in the ibuprofen-polymer
(PGA) mixture, but in this case IR spectrum for ibuprofen-polymer (PGA) mixture shows
the overlapping of carboxyl acid group (Fig. 6.4b). Therefore, it can be concluded that no
chemical interaction occurred between ibuprofen and polymer (PGA).
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 199
Figure 6.4 FT-IR spectra of (a) PGA polymer; (b) Ibuprofen-polymer (PGA)
mixture; (c) pure Ibuprofen.
Similar results were observed for the combination of Ketoprofen with the polymer.
Infrared spectra of ketoprofen, as well as those of ketoprofen-polymer (PGA) mixture are
depicted in Fig. 6.5a-c. Pure ketoprofen crystals show two carbonyl absorption bands at
1694.4 cm-1
and 1654.2 cm-1
, indicating carboxyl carbonyl and ketonic carbonyl
stretching, respectively (Sancin et al., 1999, Mura et al., 1999) as shown in Fig. 6.5a.
PGA polymer also contains carboxyl carbonyl group, therefore the IR spectra showed
overlapping carboxyl vibration of carboxyl group at 1694.4 cm-1
. The characteristics
stretching band of pure ketoprofen with polymer did not change, and on the basis of these
observations it may be suggested no possible interaction was observed between
ketoprofen and polymer (PGA).
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 200
Figure 6.5 FT-IR spectra of (PGA polymer); (b) ketoprofen-polymer (PGA)
mixture; (c) pure Ketoprofen
Ibuprofen sodium salt peaks of FT-IR are shown in Fig. 6.6a-d. Pure ibuprofen sodium
salt shows a peak at 1697.6 cm-1
, indicating the carbonyl stretch (COOH). Figure 6.6a-c
showed a significant difference in the FT-IR spectra of ibuprofen sodium salt and its
mixture with polymers when compared with spectra of pure ibuprofen sodium salt. The
characteristic carbonyl-stretching band of ibuprofen sodium salt was changed in the case
of ibuprofen sodium salt-polymer mixtures. This study revealed that there was a possible
interaction between ibuprofen sodium salt and polymers, as the change was from lower
wave number to higher wave number, indicating the change from more crystalline form
to amorphous.
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 201
Figure 6.6 FT-IR spectra of (a) Ibuprofen sodium salt-Polymer (PGA C-18)
mixture; (b) Ibuprofen sodium salt-Polymer (40%C-18 PGA) mixture; (c)
Ibuprofen sodium salt-Polymer (100 C-18 PGA) mixture; (d) pure Ibuprofen
sodium salt.
6.2. Preparation of empty and drug loaded nanoparticles
The main objective of this study was to prepare ibuprofen, ibuprofen sodium salt and
ketoprofen nanoparticles using the newly synthesized polymer PGA (poly glycerol
adipate) (Kallinteri et al., 2005) and its acylated derivatives in absence of surfactant. As
mostly surfactants are used as stabilizing agent for nanoparticles. But the removal of
surfactants from nanoparticles surface is not easy and the presence of surfactants on the
surface of nanoparticles may cause toxicity (Vu-giang et al., 2004)
Empty and drug-loaded nanoparticles of Ibuprofen, Ibuprofen sodium salt and
Ketoprofen were prepared, using biodegradable polymer, Poly (glycerol adipiate) (PGA)
and its acylated derivatives 40% C-18 PGA and 100%C-18 PGA by interfacial deposition
method without using surfactans (Fessi et al., 1995). Empty nanoparticles and drug-
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 202
loaded nanoparticles of Ibuprofen sodium salt were successfully developed with polymer
PGA and its acylated derivatives, while massive aggregartion and precipitation was
observed during the preparation of drug-loaded nanoparticles of Ibuprofen and
Ketoprofen with acylated derivaties 40% C-18 PGA, 100% C-18 PGA and combination
of PGA with 40% C-18 PGA and 100% C-18 PGA. The aggregation or precipitation may
be due to lipophilicity of polymer as 0% PGA is less lipophilic than its acylated
derivatives. The increased lipophilicity (hydrophobicity) may cause a subsequent increase
in the aggregation number of polymer molecules leading to a rapid precipitation (Puri et
al., 2008)
6.2.1. Physical evaluation of nanoparticles: The size, zeta potential and polydispersity
of empty as well as loaded nanoparticles were determined. The zeta potential is an
indicator of surface charge, which determines particles stability in the dispersion using
the principle of elecrophoretic mobility in electric field. Polydisperity index is the
dimensionless number indicating the width of the size distribution (Chandr et al., 2010).
The average particle size of empty nanoparticles 0% C-18P PGA, 40% C-18 PGA,
combination of 0% C-18 PGA with 40% C-18 PGA and 100% C-18PGA were found to
be in the range of 197.07±2.6 nm, 240.5±3.061 nm, 234.6±3.58 nm, 252.4±3.732 nm,
respectively, while drug-loaded nanoparticles of Ibuprofen and Ketoprofen with 0% C-18
PGA were having average particle size 207.333±3.85 nm and 202.6±2.18 nm,
respectively. Moreover, drug-loaded nanoparticles of Ibuprofen sodium salt with 0% C-
18 PGA, 40% C-18PGA, combination of 0% with 40% C-18 PGA and 100% C-18 PGA
were found to be in the range 192.767±3.204 nm, 231.33±2.804 nm, 226.933±2.312 nm,
and 240.633±2.150 nm, respectively. As shown in the Table 6.1 that the particle size of
empty nanoparticles of 0% C-18 PGA was smaller than the loaded nanoparticles of
Ibuprofen and Ketoprofen with 0% C-18PGA. This increase in size may be due to
packing arrangement of the drug in the polymeric matrix. Some authors have reported
that larger size of drug loaded particles than empty particles is due to the presence of drug
in the polymeric matrix based on the assumption that presence of drug in the matrix is
responsible for expansion of matrix volume and hence size (Stolnik et al., 1995). It may
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 203
also depend on the properties of different functional groups of polymer. As ibuprofen and
ketoprofen are sparingly soluble drugs and increase in the number of hydrophobic
domains was found to be associated with larger nanoparticles (Piskin, 1995).While in
case of ibuprofen sodium salt the nanopaticles formed with 0% PGA, 40% C-18 PGA,
combination of 0% C-18 PGA with 40% C-18 PGA and 10% C-18PGA were smaller
than empty nanoparticles as shown in Table 6.1. There could be two possibilities for this
difference in particle size: Change in the aggregation number of polymer molecules or
change in the particles density due to interaction between drug and polymer, but in this
case it is more likely to be due to drug-polymer interaction (Fig. 6.3a-d). As some time
interaction between drug and polymer may cause more compact and condense particles, it
may be due to the solubility of drug, as ibuprofen sodium salt is water soluble, it may
also play a role at the interface; there could be a steep concentration gradient at the
interface or migration of drug from more viscous phase, both leading to a decrease in the
interfacial tension and turbulence leading to rapid diffusion of acetone from organic
phase and result in more compact and condensed particles. The particles size data suggest
that it is possible to prepare the biodegradable nanoparticles of ketoprofen, ibuprofen and
ibuprofen sodium salt by interfacial deposition method without using surfactant. The zeta
potential for all empty and drug-loaded nanoparticles was -27.37 mV to -33.8mV and
polydispersity index was 0.116 to 0.860 as shown in the Table 6.1. As no more change in
the zeta potential and polydispersity was observed, but there was a slightly increased
negative zeta potential value with increase of acylation and incorporation of drug. This
increase in the negative value of zeta potential might be due to surface localization of
drug molecules (Alejandro et al., 1999).
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 204
Table 6.1 Physical characteristics (size , polydispersity index and zeta potential) of
empty and drug loaded nanoparticles prepared from various polymers by
interfacial deposition method.
Polymer Empty particles (+) Ibuprofen sodium salt (+) Ibuprofen (+) Ketoprofen
Size nm (SD) Polydispersity index
ζ-Potential mV(SD)
Size nm ( SD) Polydispersity index
ζ-Potential mV(SD)
Size nm (SD) Polydispersity index
ζ-Potential mV (SD)
Size nm (SD) Polydispersity
index
ζ-Potential mV (SD)
0%PGA-12kDa
197.07(2.6) 0.116
-27.37(2.011)
192.767(3.204) 0.148
-28.3(0.6)
207.33(3.85) 0.197
-29.57(1.42)
202.6(2.18) 0.185
-28.27(2.7)
40%C18-12kDa
240.5(3.06)
0.116
-28.67(1.96)
231.33(2.804)
0.132
-29.27(1.65)
-------
--------
-------
--------
0%+40%C18-12kDa
234.6(3.58)
0.176
-31.37(2.05)
226.93(2.312)
0.152
-32.2(0.4)
-------
-------
-------
--------
100%C18-12kDa
252.4(3.732)
0.189
-33.3(3.676)
240.633(2.150)
0.86
-33.8(1.308)
------
--------
-------
--------
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 205
6.3. Drug loading
As shown in the Fig. 6.7, the average amount of drug bound per mg of polymer was
determined. Ibuprofen and Ketoprofen loading on 0% C-18 PGA was 17.53± 7.15 µg/mg
and 19.6 ± 5.83µg/mg, respectively. Ibuprofen sodium salt loading on 0% C-18 PGA,
40%C-18PGA, combination of 0% with 40% C-18 PGA and 100% C-18 PGA was
10.59± 2.09, 18.28 ± 5.39, 14.12 ± 1.29 and 19.6 ± 2.7, respectively. As shown in
Fig.4.71 increase in acylation increase led to increase in drug loading for Ibuprofen
sodium salt. As maximum loading of Ibuprofen sodium salt was observed on 100% C-18
PGA.This maximum loading might be due to more interaction of drug with 100% C-18
PGA confirmed by different studies such as DSC and FT-IR. As the higher the
percentage of acyl groups, the greater the expected interactions between drug and
polymer (Puri et al., 2008). Similar finding were observed by other investigators
(Panyam et al., 2003). However, the exact opposite trend was observed for Ibuprofen and
Ketoprofen. As the loading of Ibuprofen and Ketoprofen on 0% C-18 PGA was more as
compared to Ibuprofen sodium salt. This might be due to some binding between drugs
and polymer that depends upon the collective properties of the two. As the drug loading
is not only the matter of drug-polymer interaction but it depends on the mechanism of
polymer assembly into nanoparticles (Kallinteri et al., 2005). It might be due to drug and
polymer nature as Ibuprofen and Ketoprofen are lipophilic drugs and Ibuprofen sodium
salt is hydrophilic. The loading of Ibuprofen and Ketoprofen was more on 0% C-18 PGA
which is less lipophilic as compared to its acylated derivatives, while loading of
Ibuprofen sodium salt on 100% C-18 PGA as compared to 0% C-18 PGA.
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 206
Figure. 6.7 Average drug contents on each plolymer
6.4. In-vitro drug release study
The in-vitro release profile of ibuprofen, ketoprofen and ibuprofen sodium salt from 0%
C-18 PGA, 40% C-18PGA, combination of 0% C-18 PGA with 40% C-18 PGA and
100% C-18 PGA are shown in Figures 6.8 and 6.9. As shown in Figures the drug release
from these particles is biphasic phenomenon but in some case triphasic profile is also
observed. In some formulations there is initial rapid removal of drug from nanoparticles,
it may be due to the loosely bonding of drugs to the surface of nanoparticles, mostly, and
this initial release is rapid and uncontrolled, termed burst release (Tse et al., 1999). The
initial release after 15 minutes of ibuprofen and ketoprofen from 0% C-18 PGA
nanoparicle was 7.09±0.7% and 2.54±1.13%, respectively and the release of Ibuprofen
sodium salt from different nanoparticles of 0% C-18PG, 40% C-18PGA, combination of
0% with 40%C-18PGA and 100% C-18PGA was 3.6±0.42%, 2.53±0.403%,
10.05±0.85% and 1.74±0.3%, respectively. The initial burst release in case of ibuprofen
from 0% C-18 PGA and Ibuprofen sodium salt from combination of 0% and 40% C-18
PGA may be the due to surface localization of drug. Other factors contributing to initial
burst release are larger surface area, high diffusion coefficient and low viscosity of matrix
(Akinobu, 2002). The release from other formulations was slow and no initial burst
release phenomenon was observed. At the end of in-vitro drug release study (17 days),
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 207
100% drug was released from all nanopartilces but on the basis of statistical calculation
the t50% for ibuprofen and ketoprofen from 0% C-18 PGA was 2 and 3 days, respectively,
but for ibuprofen sodium salt from 0% C-18PGA, 40%C-18PGA, combination of 0% and
40% PGA, and 100% C-18PGA was 4, 6, 2 and 3 days, respectively. Most commonly it
is reported that particles with higher drug loading have a fast release rate mainly
attributed to surface localization. (Peng, 2006). As shown in the Figs. 6.8 and 6.9, the
drug loading of ibuprofen, ketoprofen on 0%C-18PGA, and that of ibuprofen sodium salt
on 100%C-18 PGA is more as compare to other formulations.
Figure. 6.8 The release behavior of various formulations (the results are the mean
and standard deviation of three determinations).
Nanoparticles of Propionic Acid Derivatives By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 208
Figure. 6.9 The release behavior of various formulations (the results are the mean
and standard deviation of three determinations).
Conclusion By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 209
OVER ALL CONCLUSIONS
During the preformulation studies our results confirmed that no possible
interaction was found between the drugs (Ibuprofen and Ketoprofen) and
differenent polyemers and excipietns.
Solid Dispersions of Ibuprofen and/or Ketoprofen with Glucosamine HCl
markedly enhanced the dissolution rates and solubility of the drugs. Moreover,
DSC, FT-IR, X-ray diffractometory and SEM studies revealed the confirmation of
solid dispersions and that no possible interactions take place between the carrier
and drugs.
Ethocel polymers can be used for successful development of controlled-release
matrix tablets of sparingly soluble drugs such as Ibuprofen and Ketoprofen, using
direct compression method.
Ethocel polymers with lower viscosity grades are more compressible than their
counterparts with higher viscosity grades.
Particle size and concentration of the polymer are the determining factors in
controlling the release of Ibuprofen and Ketoprofen from the tablets.
Ethocel standard FP premium polymers are more efficient than conventional
Ethocel Standard premium polymers in extending and controlling the release rates
of the drugs. Our results revealed that Ethocel standar 7 FP premium showed
more effective role in controlling the release of drugs such as Ibuprofen and
Ketoprofen.
Conclusion By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 210
The release mechanisms of Ibuprofen and Ketoprofen from the tablets are
changeable, depending mainly on the particle size and amount of the polymer
used in the formulations.
Replacement of portions of lactose within the tablet formulation by the co-
excipients such as HPMC K100M, CMC and starch enhance the release rates of
Ibuprofen and Ketoprofen.
Matrices composed of Ethocel® standard 7 FP premium provide suitable
environment for stability of Ibuprofen and Ketoprofen like drugs and optimized
formulations demonstrating good stability of the Ibupofen and Ketoprofen in
Ethocel matrix tablets.
In-vivo pharmacokinetic parameters of test formulations showed more extended
release rates as compared to reference formulations of Ibuprofen and Ketoprofen.
Moreover, the test formulations showed good linear relationship between In-vitro
drug release and In-vivo drug absorption, and prolonged MRT0-t and t1/2 values as
compared to reference formulations.
Nanoparticles of the Ibuprofen and Ketoprofen with PGA (Poly glycerol adipate)
and its acylated derivates 40% C-18 PGA and 100% C-PGA could be used for
successful development of controlled release formulations of the drugs.
References By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 211
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List of publications
1. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq, Nauman Rahim Khan, Abid Hussain, Haroon Khan and
Muhammad Farid Khan (2011). Formulation and Evaluation of Controlled Release matrices of Ketoprofen and
influence of different Coexcipients on the Release Mechanism (Published in international journal “Die
Pharmazie”, Germany) Vol. 66: 677–683. Impact factor 1. (HEC recognized)
2. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq, Nauman Rahim Khan, Abid Hussain (2011). Pre-
formulation investigation and in vitro evaluation of directly compressed ibuprofen-ethocel oral controlled release
matrix tablets: A kinetic approach (Published in African journal of pharmacy and pharmacology). Vol. 5(19): 2118-2127. . Impact factor 0.667. (HEC recognized)
3. Muhammad Akhlaq, Gul Majid Khan and Abdul Wahab, Nauman Rahim Khan, Abid Hussain, Waqas Rabbani
(2011). Effect of ether derivative cellulose polymers on hydration, erosion and release kinetics of diclofenac
sodium matrix tablets. ( Published, in Archive of Pharmacy Practice) Vol.2(3): 123-128. (HEC recognized)
4. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, Hamdy Abdelkader, Raid Alany, Abid Hussain and
Nauman Rahim Khan (2011). Physicochemical characterization and in-vitro evaluation of flubiprofen oral
controlled release matrix tablets: Role of ether derivative polymer ethocel (Published in African journal of
Pharmacy and Pharmacology) Vol. 5(7): 862-873. . Impact factor 0.667. (HEC recognized)
5. Abdul Wahab, Muhammad Akhlaq, Waqas Rabbani, Asim Rehman, Abid Hussain, Kifayatullah Shah and Gul
Majid Khan (2010). Innovative transdermal drug delivery systems and technology: A review of current trends
with futuristic prospective (Published in GomaL, University, Journal of research) Vol. 26(2): 25-32. (HEC
recognized)
6. Khan Haroon, Khan Muhammad Farid, Wahab Abdul, Hussain Abid (2011). Cytosolic fraction of Glutathione
level after addition of aluminum metal human blood (Published in international journal of research and
Ayurveda and pharmacy) Vol. 2(2): 550-555. (HEC recognized)
7. Murad Ali Khan, Abdul Haleem Shah, Azhar Maqbool, Shakoor Ahmad, Zia Urrahman, Abdul Wahab (2011).
Epidemiological survey of scabies skin disease among different migrants in Khyber Pukhthoonkhwa, Pakistan
(published in IJCRB) Vol. 3 (2): 1378-1390. (HEC recognized)
8. Shah Shefaat Ullah, Shah Kifayat Ullah, Wahab Abdul, Khan Haroon, Khan Gul Majid (2011). Formulation
and evaluation of directly compressed ofloxacin-ethocel controlled release tablets: A kinetic approach (Published
in IJRAP) Vol. 2 (3): 801-809. (HEC recognized)
9. Nauman Rahim Khan, Gul Majid Khan, Abdul Wahab, Abdul Rahim Khan , Akhlaq Ahmad, Abid Husssain,
Asif Nawaz (2011). Formulation, Physical, In vitro and Ex-vivo evaluation of transdermal hydrogels of
Ibuprofen containing turpentine oil as penetration enhancer ( Published in Die Pharmazie, Germany ) Vol.
66(11): 849-852. . Impact factor 1. (HEC recognized)
10. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, Arshad Khan, Abid Hussain, Asif Nawaz, Hamdy
Abdelkader (2011). A simple High-Performance Liquid Chromatographic practical approach for determination
of Flurbiprofen (Published in, Journal of Advance pharmaceutical technology and research) Vol. 2(3): 151-155. .
Impact factor 0.332. (HEC recognized) 11. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, Abid Hussain, Arshad Khan and Asif Nawaz (2011).
Formulation and In-vitro evaluation of Flurbiprofen Controlled release matrix tablets using cellulose derivative
polymers. (published in, Pakistan journal of pharmacy) Vol. 21-23(1and 2): 3-9. (HEC recognized)
References By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 250
12. Muhammad Rafiq, Abdul Wahab, Nisar-ur-Rehman, Abid Hussain and Said Muhammad (2010) . In vitro and
in vivo evaluation of two sustained release formulations of diltiazem HCl (Published in African journal of
pharmacy and pharmacology) Vol. 4(9): 678-694.. Impact factor 0.667. (HEC recognized)
13. Haroon Khan, Syed Umer Jan, Hashmatullah,M Farid Khan, Kamran Ahmad Khan, Asim Ur Rehman And
Abdul Wahab (2010). Effect of Lithium on The chemical status of Glutathione in whole Blood (especially in
plasma and cytosolic fraction in human) (Published in Pakistan journal of Pharmaceutical Sciences Vol. 23
(2):188-193. Impact factor 0.728. (HEC recognized)
14. Rehan Zafar Paracha, Haroon Khan, Muhammad Farid Khan, Zahid Rasul Niazi, Kamran, Ahmad Khan, Syed
Ummar Jan, Barkat Ali, Hashmat Ullah, Abdul Wahab (2010). Concentration and time dependent effect of zinc
chloride on glutathione level in aqueous medium (Published in GomaL, University, Journal of research) Vol.
26(2): 9-14. (HEC recognized)
15. Haroon Khan, Muhammad Farid Khan, Rehan Zafar Paracha, Kamran Ahmad Khan, Hashmat Ullah, Syed Umer
Jan, Zahid Rasul Niazi, Saif Ullah Mehsud and Abdul Wahab (2010). Effect of aluminum metal on the
chemical status of Glutathione in aqueous medium (Published, in GomaL, University, Journal of research) Vol.
26(1): 13-19. (HEC recognized)
16. Muhammad Farid Khan, Haroon Khan, Rehan Zafar Paracha, Hashmat Ullah, Gul Majid Khan, Usman Zafar
Parach, Saif Ullah Khan, Abdul Wahab, Kamran Ahmad Khan (2008). Effect of Silver metal on the chemical
status of Glutathione in aqueous medium (Published in GomaL, University, Journal of research) Vol. 24(2): 8-
12. (HEC recognized)
17. Haroon Khan, Muhammad Farid Khan, Naseem Ullah, Muhammad Mukhtiar, Naheed Haque, Barkat Ali, Abdul
Wahab, Arshad Farid, Kamal Shah. Effect of aluminium acetyl acetone on the chemical status of glutathione by
influential parameters in aqueous medium. (Published, in International journal of basic medical sciences and
pharmacy) Vol.1, No.1: 23-26. (HEC recognized)
18. Nauman Rahim Khan, Gul Majid Khan, Abdul Rahim Khan, Abdul Wahab, Muhammad Akhlaq, Abid Hussain
(2012). Formulation, Physical, In vitro and Ex-vivo evaluation of Diclofenic diethylamine matrix-patches
containing turpentine oil as penetration enhancer (Published in African journal of Pharmacy and Pharmacology).
Vol. 6(6):434-439. . Impact factor 0.667. (HEC recognized)
19. Abid Hussain, Gul Majid Khan, Shefaat Ullah Shah, Kifayat Ullah Shah, Nauman Rahim, Abdul Wahab and
Asim-ur-Rehman. Development of Novel Ketoprofen transdermal patch: Effect of Almond oil as penetration
enhancers on in-vitro and ex-vivo penetration of ketoprofen through rabbit skin (Published, in Pakistan journal
of pharmaceutical sciences). Vol. 25(1): 227-232. . Impact factor 0.728. (HEC recognized)
20. Abdul Wahab, Marco Favretto, Onyeagor, Gul Majid Khan, Dynnis Douroumis, Casely-Hayford, Paraskevi
Kallinteri (2012). Development of poly(glycerol adipate) nanoparticles loaded with non-steroidal anti-
inflammatory drugs (Accepted in Journal of Microencapsulation). Impact factor 1.738. (HEC recognized)
References By: A.Wahab
Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, KPK, Pakistan Page 251
21. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq, Nauman Rahim and Abid Hussain, Haroon khan, Saif
Ullah Mehsud. Preparation and evaluation of solid dispersions of Ibuprofen using Glucosamine HCl as a carrier
(Accepted in Die Pharmazie). . Impact factor 1. (HEC recognized)
22. Abid Hussain, Gul Majid Khan, Syed Umer Jan, Shefaat Ullah Shah, Kifayatullah Shah,
Muhammad Akhlaq, Nauman Rahim Khan, Asif Nawaz and Abdul Wahab (2012). Effect of
olive oil on transdermal penetration of flurbiprofen from topical gel as enhancer. (Published in
Pakistan journal of pharmaceutical sciences) Vol. 25(2): 365-369. Impact factor 0.728. (HEC
recognized)
23. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq, Nauman Rahim and Abid Hussain, Haroon khan, Saif
Ullah Mehsud. Preparation and solid state characterization and evaluation of Ketoprofen-Glucosamine HCl
solid dispersions: A novel approach (Submitted)
24. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab. To Investigate a Simple and Rapid Approach for In-Vitro
In-Vivo Evaluation of Diclofenac Sodium Controlled Release Matrices Using Albino Rabbits (Submitted)
25. Abid Hussain, Gul Majid Khan, Nauman Rahim Khan, Muhammad Akhlaq, Abdul Wahab and Asif.
Ketoprofen Transdermal Gel Development: A Novel approach to evaluate the penetration enhancement
capability of Olive oil. (submitted)
26. Formulation, Physical, In vitro and Ex-vivo evaluation of transdermal hydrogels of Diclofenic sodium
containing turpentine oil as penetration enhancer (Submitted)
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