Dissertation - Ningapi.ning.com/files/XK2Klt0F5AurVyM3L1MLLdZoRyH1zSXE60cyWWiznx… · I express my...

I

““DDEESSIIGGNN AANNDD PPHHYYSSIICCOO--CCHHEEMMIICCAALL CCHHAARRAACCTTEERRIIZZAATTIIOONN OOFF TTAABBLLEETT CCOONNTTAAIINNIINNGG

NNOOVVEELL AANNTTIIDDEEPPRREESSSSAANNTT DDRRUUGG UUSSIINNGG VVAARRIIOOUUSS FFOORRMMUULLAATTIIOONN TTEECCHHNNIIQQUUEESS””

Dissertation

Submitted to KLE University, Belgaum, Karnataka In partial fulfillment of the requirement for the degree of

MMMaaasssttteeerrr ooofff PPPhhhaaarrrmmmaaacccyyy IIInnn

PPPhhhaaarrrmmmaaaccceeeuuutttiiicccsss

By

Mr. RITESH A. UDHANI B.Pharm

Under the guidance of

DR. BASAVARAJ K.NANJWADE M.Pharm, Ph.D

DEPARTMENT OF PHARMACEUTICS, JN MEDICAL COLLEGE,

BELGAUM-590010, KARNATAKA, INDIA

MAY-2010

II

KKLLEE UUNNIIVVEERRSSIITTYY,, BBEELLGGAAUUMM,, KKAARRNNAATTAAKKAA

Declaration by the Candidate

II hheerreebbyy ddeeccllaarree tthhaatt tthhiiss ddiisssseerrttaattiioonn eennttiittlleedd ““DDEESSIIGGNN

AANNDD PPHHYYSSIICCOO--CCHHEEMMIICCAALL CCHHAARRAACCTTEERRIIZZAATTIIOONN OOFF TTAABBLLEETT

CCOONNTTAAIINNIINNGG NNOOVVEELL AANNTTIIDDEEPPRREESSSSAANNTT DDRRUUGG UUSSIINNGG

VVAARRIIOOUUSS FFOORRMMUULLAATTIIOONN TTEECCHHNNIIQQUUEESS”” iiss aa bboonnaaffiiddee aanndd

ggeennuuiinnee rreesseeaarrcchh wwoorrkk ccaarrrriieedd oouutt bbyy mmee uunnddeerr tthhee gguuiiddaannccee ooff

Dr. BASAVARAJ K. NANJWADE PPrrooffeessssoorr,, DDeeppaarrttmmeenntt ooff

PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm.

DDaattee::

PPllaaccee:: BBeellggaauumm..

MMrr.. RRIITTEESSHH AA.. UUDDHHAANNII BB..PPhhaarrmm DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm –– 559900 001100,, KKaarrnnaattaakkaa..

III


Certificate by the Guide

II hheerreebbyy ddeeccllaarree tthhaatt tthhiiss ddiisssseerrttaattiioonn eennttiittlleedd ““DDEESSIIGGNN

AANNDD PPHHYYSSIICCOO--CCHHEEMMIICCAALL CCHHAARRAACCTTEERRIIZZAATTIIOONN OOFF TTAABBLLEETT

CCOONNTTAAIINNIINNGG NNOOVVEELL AANNTTIIDDEEPPRREESSSSAANNTT DDRRUUGG UUSSIINNGG VVAARRIIOOUUSS

FFOORRMMUULLAATTIIOONN TTEECCHHNNIIQQUUEESS”” iiss aa bboonnaaffiiddee rreesseeaarrcchh wwoorrkk ddoonnee

bbyy MMrr.. RRIITTEESSHH AA.. UUDDHHAANNII iinn ppaarrttiiaall ffuullffiillllmmeenntt ooff tthhee

rreeqquuiirreemmeenntt ffoorr tthhee ddeeggrreeee ooff MMaasstteerr ooff PPhhaarrmmaaccyy iinn

PPhhaarrmmaacceeuuttiiccss..

DDaattee:: PPllaaccee:: BBeellggaauumm..

DDrr.. BB..KK.. NNAANNJJWWAADDEEMM..PPhhaarrmm,,PPhh.. DD PPrrooffeessssoorr,, DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm –– 559900 001100,, KKaarrnnaattaakkaa..

IV


Endorsement By The HOD, Principal/ Head of The Institution

This is to certify that the dissertation entitled ““DDEESSIIGGNN AANNDD

PPHHYYSSIICCOO--CCHHEEMMIICCAALL CCHHAARRAACCTTEERRIIZZAATTIIOONN OOFF TTAABBLLEETT

CCOONNTTAAIINNIINNGG NNOOVVEELL AANNTTIIDDEEPPRREESSSSAANNTT DDRRUUGG UUSSIINNGG

VVAARRIIOOUUSS FFOORRMMUULLAATTIIOONN TTEECCHHNNIIQQUUEESS”” is a bonafide

research work done by Mr. RITESH A. UDHANI in partial

fulfillment of the requirement for the degree of Master of

Pharmacy in Pharmaceutics, under the guidance of DDrr.. BB.. KK..

NNAANNJJWWAADDEE,, Professor, Department of Pharmaceutics, JN Medical

College, Belgaum.


DDRR.. VV.. DD.. PPAATTIILL MMDD,, DDCCHH

PPrriinncciippaall,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm –– 559900 001100,, KKaarrnnaattaakkaa..

MMRRSS.. RR.. SS.. MMAASSAARREEDDDDYY MM..PPHHAARRMM AAssssoocciiaattee PPrrooffeessssoorr && HHeeaadd,, DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm –– 559900 001100.. KKaarrnnaattaakkaa


V


Copyright Declaration by the Candidate

II hheerreebbyy ddeeccllaarree tthhaatt tthhee KKLLEE UUnniivveerrssiittyy,, BBeellggaauumm,,

KKaarrnnaattaakkaa sshhaallll hhaavvee tthhee rriigghhttss ttoo pprreesseerrvvee,, uussee aanndd

ddiisssseemmiinnaattee tthhiiss ddiisssseerrttaattiioonn//tthheessiiss iinn pprriinntt oorr eelleeccttrroonniicc ffoorrmmaatt

ffoorr aaccaaddeemmiicc//rreesseeaarrcchh ppuurrppoossee..

DDaattee::

PPllaaccee:: BBeellggaauumm..

© J.N. Medical College, KLE University, Belgaum, Karnataka

MMrr.. RRIITTEESSHH AA.. UUDDHHAANNIIBB..PPhhaarrmm DDeepptt.. ooff PPhhaarrmmaacceeuuttiiccss,, JJNN MMeeddiiccaall CCoolllleeggee,, BBeellggaauumm –– 559900 001100,, KKaarrnnaattaakkaa..

VI

AAffffeeccttiioonnaatteellyy DDeeddiiccaatteedd

TToo

MMyy BBeelloovveedd PPaarreennttss

&&

EEsstteeeemmeedd gguuiiddee

VII

Acknowledgement

It is a great pleasure for me to acknowledge all those who have contributed

towards the conception, origin and nurturing of this project.

The person whose picture comes first in my mind is that of my esteemed guide

Dr. Basavaraj K. Nanjwade, Professor, Department of Pharmaceutics, KLE University,

Belgaum, for his invaluable guidance, timely advice, kind co-operation, understanding and

constant inspiration throughout the course of the study. It is with affection and reverence

that I dedicate often beyond the call of duty; it was pleasure of working under his

guidance. No words can speak of his involvement and fatherly care.

It is a delightful moment for me, to put into words all my gratitude to my esteemed

industrial guide, Mr. Pramod Pathak, Research Associate, F & D, PTC, Zydus Cadila,

Ahmedabad, for his inestimable guidance, valuable suggestions and constant

encouragement during the course of this study. It is with affection and reverence that I

acknowledge my indebtness to him and his outstanding dedication, often far beyond the

call of duty. Apart from guiding me, his unwearing moral support and advice was of great

help.

I shall forever remain indebted to my co-guide Ms. Arti Potdar, Sr. GM and

Mr. Praful Chouhan, Dy. GM, F&D, Pharmaceutical technology center, Cadila

Healthcare Limited, Ahmedabad, allowing me to carry out M.Pharm dissertation work

within a well established organization along with their valuable guidance, keen interest,

perennial inspiration and everlasting encouragement. I would also like to thank Mr. Vinay

Upadhyay who supported me during my dissertation work.

VIII

It gives me pleasure in thanking Mr. Sunil B. Roy, Sr. VP, PTC, Zydus Cadila,

Ahmedabad for allowing me to undertake this present work. I would like to give special

thanks to Mr. Vinit Thombare, Mr. Narendra Patidar and Mr. Rahul Agarwal who

guided me during my dissertation work. Apart from guiding me, their unwearing moral

support and advice.

I give my special thanks to our respected Vice Chancellor Dr. C. K. Kokate, KLE

University and Dr. Pramod H. J. for their help and support during my study.

I would like to give the special thanks to Mr. Nishit Bhatt, Research Scientist and

Ms. Hiral Raval for supporting me from the very first day of my project in industry.

I am grateful to Dr. Hemendra Bhatt, Dr. Manish Rachchh, Dr. H.M. Tank and

Mr. Darshan Parekh for their constant moral support throughout my career.

I express my deep gratitude to Jigar Vyas, Kalpit Dalal, Abhilash Bhong, Ruchir

Shah, Ambuj Shukla, Vinod Raguvanshi, Devendra Dewangan, Basant Verma, Nikalesh

Patel, Prateek Gandhi, Bhavesh Patel and other scientist who have supported me directly

or indirectly during my project work. I am also thankful to Dhruvin, Ashish, Vijay, Ankit,

Milan, Karamsinh, Maunesh, Abhishekh, Akshita and all other colleagues who supported

me during this project.

“A Friend in need is the Friend Indeed”: I would like to give a special thank to

Jatin, Dhaval, Mac, Ayaz, Ketan and Pratin for their ever appraising support and who

helped me when I needed someone desperately.

IX

I would also like to thank one special person, Ms. Sai Susmitha, who has always

been with me on every step of mine during the course and who gave me all the support I

needed.

I am thankful to my friends who have always cared for me, Viral, Kalyani, Ankit,

Rugved, Kaushal, Vinod, Jay, Jiten, Devang, Nikunj, Dilip, Varun and all others.

I am thankful to my batchmates Vishwas, Amol, Bhushan, Rajesh, Nitin, Eshwar,

Kunal, Suhas, Chirag, Vishal, Kemy, Rucha, Anu and Kiran.

I owe my thanks to my juniors Aman, Nishant, Amit, Jagdish, Alok and Mayank

for their support and respect.

I owe my special thanks to Mr. R. M. Kolar and his family for showing care and

support and making my stay at Belgaum a comfortable one.

At this moment, I thanks with deep gratitude to my Mother, Father, brother

Sandeep, sisters Poonam, Ekta, Sheetal and Dipika and all other family members for their

moral support, constant encouragement and patience absolutely needed to complete my

entire study. It was the blessing of them that gave me courage to face the challenges and

made my path easier. I expect and request them to shower their blessings and love on me

throughout my life and for my future endeavors.

I acknowledge from the bottom of my heart to my uncle and my aunty for bearing

the pain for me and making my stay very comfortable at Ahmedabad. I will always be

indebted to their blessings.

I owe my special thanks to Mr. Sanjay Sheth and Mr. Akhil Dalal, the two people

without whom, it was impossible for me to reach at the present stage of life. It is with

affection and reverence that I acknowledge my indebtness to them.

X

I sincerely acknowledge my Jiju Mr. Parshotam Bhaktyarpuri for his continuous

help while my stay at Ahmedabad.

I sincerely acknowledge my Jiju Mr. Mukesh Thakwani for his continuous support

which was a solid pillar for my work.

I am thankful to Miss. Veena and Mr. Deepak of Sai DTP and Xerox, Belgaum,

for formatting, printing and binding of my thesis.

I firmly believe that there cannot be any gain without the pain, so at last I would

like to thank all those people who said me no, who left me on the way and those who gave

me pain; because of whom I did it myself.

Thanks to one and all………

Ritesh Udhani

XI

ABBREVIATIONS

USP : United states of pharmacopeia

HPMC : Hydroxy propyl methyl cellulose

MTC : Minimum toxic concentration

MEC : Minimum effective concentration

cGMP : Current good manufacturing practice

SUPAC : scale up post approval changes

KF : Karl Fischer

R & D : Research and Development

FDA : Food and drug administration

QC : Quality control

CNS : central nervous system

INV : Invega

PEO : Polyethylene Oxide

EC : Ethyl cellulose

PEG : Polyethylene Glycol

BHT : Butylated hydroxy Toluene

ER : Extended release

DSC : Differnetial Scanning Calorimetry

API : Active Pharmaceutical Ingredient

RH : Relative Humidity

LOD : Loss on drying

NMT : Not more than

NLT : Not less than

MCC : Microcrystalline cellulose

RPM : Rotations per minute

XII

ABSTRACT

The present work was based on “DESIGN AND PHYSICO-CHEMICAL

CHARACTERIZATION OF TABLET CONTAINING NOVEL

ANTIDEPRESSANT DRUG USING VARIOUS FORMULATION

TECHNIQUES”. 32 full factorial experiment was designed to study the effect of

Concentration of HPMC (X1) and PEO (X2) combination on the % cumulative

release after two hours (Y1), after 6 hours (Y2) and on the % cumulative release after

10 hours (Y3) in the core tablet. In vitro release profiles of all the batches were

performed with the kinetic model studies. Response surface graph were presented to

examine the effects of independent variables on the responses studied. The optimized

factorial batch was further given the functional coating to control the release. 32 x 21

factorial design was applied to study the effect of ratio of polymer:plasticizer (X1), %

coating (X2) and grade of polymer(X3). Polymer grade was used at 2 levels, whereas

other two factors at 3 levels. The final optimized batch was kept for 3 months of

stability study according to ICH guidelines and formulation was found to be stable

after 3 months of study. The optimized batch was studied for the dissolution kinetic

modeling.

KEYWORDS: Surface response graphs, 32 full factorial design, functional coating,

Anti-depressant drug, 32 x 21 factorial design

XIII

CONTENTS

SL. NO. TITLE PAGE

NO.

1. INTRODUCTION 1-36

2. OBJECTIVE OF STUDY 37-38

3. INTRODUCTION TO MATERIALS 39-69

4. REVIEW OF LITERATURE 70-79

5. MATERIAL & METHODOLOGY-1 80-100

6. RESULTS AND DISCUSSION-1 101-147

7. MATERIAL & METHODOLOGY-2 148-163

8. RESULTS AND DISCUSSION-2 164-179

9. CONCLUSION 180-181

10. SUMMARY 182-184

11. BIBLIOGRAPHY 185-195

12. ANNEXURE

XIV

LIST OF TABLES

TABLE NO. TITLE PAGE

NO.

1.1 Advantages of extended release dosage forms over conventional forms 8

1.2 Parameters for drug selection 20

1.3 Pharmacokinetic parameters for drug selection 21

1.4 Typical process of tablet 32

3.1 Drug Interactions 44

3.2 Typical viscosity values for 2% (w/v) aqueous solutions of Methocel 51

3.3 Uses of ethylcellulose 54

3.4 Summary of ethylcellulose grades, suppliers, viscosity, and particle size 56

3.5 Number of repeat units and molecular weight as a function of polymer grade for polyethylene oxide. 58

5.1 Materials Used In the Present Investigation 80

5.2 Instruments Used In Present Investigation 81

5.3 Composition of Tablet formulation 83

5.4 Effect of Carr’s Index and Hausner’s Ratio on flow property 86

5.5 Effect of Angle of repose (ф) on Flow property 86

5.6 Drug excipients compatibility study 87

5.7 Release profile fixed 89

5.8 Formula of trial batches F001 to F004 90



5.11 32 Full Factorial Design Layout 96

XV


NO.

5.12 Formula of Factorial batches 97

5.13 Formula of Trial F021 98

6.1 Result of Preformulation study of Drug 119

6.2 Result of Drug excipients compatibility study After 1 month at 40ºC±2°C / 75%RH± 5 % RH 123

6.3 Standard calibration curve of Drug in 0.1 N HCl 124

6.4 Standard calibration curve of Drug in Phosphate Buffer (pH 6.8) 125

6.5 In–Vitro Release study of Innovator 126

6.6 Result of Evaluation of powder blend of trial batches F001 to F004 127

6.7 Result of Evaluation of Tablets of trial batches F001 to F004 128

6.8 Result of In-vitro release of trial batches F001 to F004 129

6.9 Evaluation of Powder blend of trial batches F005 to F008 130

6.10 Evaluation of Tablets of trial batches F005 to F008 130


6.12 Evaluation of Powder blend of trial batches F009 to F011 132

6.13 Evaluation of Tablets of trial batches F009 to F011 132


6.15 Evaluation of powder blend of Factorial batches 135

6.16 Evaluation of tablets of Factorial batches 136

6.17 In-vitro release study of Factorial batches 137

6.18 Effect of Independent variable on dependent variable by 32 full factorial design of Sustained release matrix tablet 139

6.19 Summary of regression analysis for Extended release matrix tablet 140

XVI


NO.

6.20 Evaluation of powder blend of Reproducible batch F021 144

6.21 Evaluation of Tablets of Reproducible batch F021 144

6.22 In-vitro drug release of Reproducible batch F021 and F016 145

6.23 Data analysis by using different model 147

7.1 Dissolution time points fixed 154

7.2 Coating composition 154

7.3 32 x 21 Factorial Design Layout 156

7.4 Factorial Batches formulations 157

7.5 Processing Parameters 158

7.6 Similarity factor value and its significance 162

8.1 % drug release profile of Innovator’s product 170

8.2 Cumulative % drug release from tablets coated using 80:20 ratio of polymer:plasticizer 171






8.8 Data analysis by using different model 177

8.9 Result of Accelerated stability study 178

XVII

LIST OF FIGURES

FIGURE NO. TITLE PAGE

NO.

1.1 Drug release from hydrophilic matrix tablet 13

1.2 The fronts in a swellable HPMC matrix 17

3.1 Structure of Drug 39

3.2 Structure of HPMC 48

3.3 Structure of Ethyl cellulose 53

6.1 Thermal Analysis result of pure drug 119

6.2 Thermal Analysis result of Drug + PEO 120

6.3 Thermal Analysis result of Drug + MCC 120

6.4 Thermal Analysis result of Drug + HPMC 121

6.5 Thermal Analysis result of Drug + Stearic Acid 121

6.6 Thermal Analysis result of Drug + Mg - stearate 122

6.7 Thermal Analysis result of Mixture of Drug with other excipients

122

6.8 Calibration curve of Drug in 0.1 N HCl at 275nm 124

6.9 Calibration curve of Drug in Phosphate buffer pH 6.8 at 275nm

125

6.10 In-vitro drug release profile of Innovator’s product 126

6.11 Dissolution profile of F001 to F004 129

6.12 Dissolution Profile of f005 to foo8 131

6.13 Comparative dissolution profile of Trials F009 to F011 134

6.14 Comparative dissolution profile of Factorial batches of F012 to F020

138

XVIII

FIGURE NO. TITLE PAGE

NO.

6.15 Surface response plot of Response Y1 141



6.18 Comparative dissolution profile of Reproducible batch F021 and F016

146

8.1 Dissolution profile of tablets coated with EC 4cps using 80:20 ratio of EC: PEG

171


172


173


174


175


176

8.7 Dissolution profile of F037 after stability studies 179

Chapter -1 IInnttrroodduuccttiioonn

Department of Pharmaceutics, KLE University, Belgaum 1

1.1 Oral drug delivery systems 1.1.1 Introduction

Oral drug delivery has been known for decades as the most widely utilized route of

administration among all the routes that have been explored for the systemic delivery

of drugs via various pharmaceutical products of different dosage forms. The reasons

that the oral route achieved such popularity may be in part of its ease of

administration as well as the traditional belief that by oral administration the drug is

well absorbed as the food stuffs that are ingested daily. The development of a

pharmaceutical product for oral delivery irrespective of its physical forms (solid,

semisolid, or oral liquid dosage form) involves varying extents of optimization of

dosage form characteristics within the inherent constraints of gastrointestinal

physiology1.

Oral dosage forms are taken orally for a local effect in the mouth, throat or

gastrointestinal tract or for a systemic effect in the body after absorption from the

mouth or gastrointestinal tract. Oral dosage forms can be divided into two main

groups based on the physical state of the dosage form, solid oral dosage forms

(tablets, capsules or powders) and liquid oral dosage forms (solutions, syrups,

emulsions, and powders for suspensions)2.

1.1.2 Merits and Demerits of solid oral dosage forms

1.1.2.1 Merits

Unit dose system and Long shelf life

More Economic and Ease of administration

Tastelessness and Elegance

Patient compliance



1.1.2.2 Demerits

Posses swallowing difficulty

Onset of action is slow and depends on disintegration and dissolution

1.1.3 Merits and Demerits of liquid oral dosage forms

1.1.3.1 Merits

Onset of action is quick as compared to pills, tablets and capsules

Certain medicinal substances can only be given in liquid form such as liquid

paraffin, castor oil etc

Certain drugs are to be in suspended or diffused form to produce maximum

surface area viz., kaolin

Few drugs if taken in dry form may cause pain and irritation for e.g. potassium

bromide and aspirin.

1.1.3.2 Demerits

Dose has to be measured

May not be highly stable

May face storage and transportation hazards3

1.1.4 Types of oral drug delivery systems

Approximately 50% of the drugs in the market are available in their oral dosage forms

because of its easily administration and patient compliance; some of the oral dosage

forms are as follows.



1.1.4.1 Solid oral dosage forms

1.1.4.1.1 Powders

Powders are dry mixtures of finely divided medicinal and nonmedicinal agents

intended for internal or external use. Powders may be dispensed to a patient and used

in bulk form or as a single unit packaged form.

1.1.4.1.2 Tablets

Tablets are solid oral dosage forms containing one or more medicinal substances with

or without added pharmaceutical ingredients. Tablets may be coated for appearance,

for stability, to mask the bitter taste of the medication, or to provide controlled drug

release. Tablets are solid, flat or biconvex discs prepared by compressing a drug or

mixture of drugs with or without suitable diluents. They vary in shape and differ

greatly in size and weight depending on the amount of medicinal substances and the

intended mode of administration. Most tablets are intended to be swallowed orally.

Some however, are prepared for chewing and have a pleasant taste and feel. Other

tablets dissolve in the mouth (buccal tablets) or under the tongue (sublingual tablets),

whereas effervescent tablets are intended to be dissolved in water before taking.

1.1.4.1.3 Capsules

Hard gelatin capsules are solid dosage forms in which one or more medicinal and

inert substances are enclosed within small shells of gelatin. Capsule shells are

produced in varying size, shape, thickness, softness, and color. Hard shell capsules,

which have two telescoping parts–the body and the cap are commonly used in

extemporaneous hand filling operations as well as in small & large scale manufacture

of commercial capsules. After filling, two capsule parts are joined for tight closure.

Soft-shell gelatin capsules, which are one bodied, are formed, filled, and sealed in the

same process. Highly specialized and large-scale equipment is required, and thus soft



gelatin capsules are only prepared commercially. They are rendered soft through the

addition of a plasticizer to the capsule shell. Soft gelatin capsules may be filled with

powders, semisolids, or liquids.

1.1.4.1.4 Lozenges

Lozenges are solid preparations containing one or more medicinal agents in a

flavored, sweetened base intended to dissolve or disintegrate slowly in the mouth,

releasing medication generally for localized effects. Lozenges are prepared by

molding or compression.

1.1.4.2 Liquid oral dosage forms

1.1.4.2.1 Solutions

The USP states that “Oral solutions are liquid preparations, intended for oral

administration, that contain one or more substances with or without flavoring,

sweetening or coloring agents dissolved in water or cosolvent-water mixture.” A

solution is a homogeneous, one phase system, or product that has two or more

components.

1.1.4.2.2 Elixir

An elixir is a type of solution. Therefore, it is a homogeneous one –phase product. An

elixir has three or more components. Two of the components are water and alcohol.

An elixir is a solution since all of the components are present in one phase.

1.1.4.2.3 Syrup

Syrup is another type of solution. Like a solution or elixir, it is a homogeneous, one-

phase product. Syrups can be medicated or nonmedicated. Medicated syrups contain

three or more components. Most syrup contains a high proportion of sucrose, usually

60 to 80 % (w/v). The most commonly used syrup is syrup NF, also known as simple

syrup.



1.1.4.2.4 Suspensions

A suspension is a dispersion of insoluble drug particles (the disperse phase) in a

liquid; usually water (the dispersion medium). This is a two phase system since there

is one kind of solid particle dispersed in a continuous fluid medium. Drugs with

limited solubility, or large dose requirements, are often formulated in a suspension

dosage form.

1.1.4.2.5 Emulsion

An emulsion is a two phase system with at least three components. It is composed of

oil and water and an appropriate emulsifying agent. If water droplets are dispersed

throughout a continuous oil phase, then it is a water-in-oil emulsion. If oil droplets are

dispersed throughout a continuous water phase, it is an oil-in-water emulsion2.



1.2 Extended drug delivery systems:

1.2.1 Introduction

Extended release drug delivery systems are designed to release drug in a pre-

determined manner over an extended period of time. An extended-release dosage

form may be desirable to provide patients with a convenient dosage regimen that

allows less frequent dosing, thus enhancing compliance. Extended release dosing can

reduce peak-related side effects, maintain therapeutic concentrations throughout the

dosing period avoiding periods of insufficient therapeutic plasma concentrations

between doses, and enable a less frequent dosing regimen. Extended drug delivery

systems are beneficial especially for the patients who are not able to take the medicine

frequently specially in geriatric and mental patients2.

1.2.2 Types of extended-release products

1.2.2.1 Diffusion-controlled products

In these systems, there is a water-insoluble polymer, which controls the flow of water

and the subsequent release of dissolved drug from the dosage form. Both diffusional

and dissolution processes are involved. In `reservoir' devices, a core of drug is coated

with the polymer and, in `matrix' systems; the drug is dispensed throughout the

matrix. Cellulose derivatives are commonly used in the reservoir types, while the

matrix material may be plastic, e.g. methylacrylate-methylmethacrylate, polyvinyl

chloride, and hydrophilic polymers such as cellulose derivatives or fatty compounds

including carnauba wax.

1.2.2.2 Dissolution-controlled products

In these products, the rate of dissolution of the drug (and thereby availability for

absorption) is controlled by slowly soluble polymers or by microencapsulation. Once

the coating is dissolved, the drug becomes available for dissolution. By varying the



thicknesses of the coat and its composition, the rate of drug release can be controlled.

Some preparations contain a fraction of the total dose as an immediate-release

component to provide a pulse dose soon after administration4. The pellet dosage

forms of diffusion- or dissolution-controlled products can be encapsulated or prepared

as a tablet. These products should not be chewed as the coating may be damaged. One

of the advantages of encapsulated pelleted products is that the onset of absorption is

less sensitive to stomach emptying. The entrance of the pellets into the small intestine

(where the majority of drug absorption occurs) is usually more uniform than with

non-disintegrating extended-release tablet formulations2.

1.2.2.3 Erosion products

The release of drug from these products is controlled by the erosion rate of a carrier

matrix. The rate of release is determined by the rate of erosion. With this product,

some patients may experience a later onset of effect after the morning dose, compared

to conventional tablets. E.g.: Delayed release of the drug Levodopa.

1.2.2.4 Osmotic pump system

The rate of release of drug in these products is determined by the constant inflow of

water across a semipermeable membrane into a reservoir, which contains an osmotic

agent. The drug is either mixed with the agent is located in a reservoir. The dosage

form contains a small hole from which dissolved drug is pumped at a rate determined

by the rate of entrance of water due to osmotic pressure. The rate of release is

constant and can be controlled within tight limits yielding relatively constant blood

concentrations. The advantage of this type of product is that the constant release is

unaltered by the environment of the gastrointestinal tract and relies simply on the

passage of water into the dosage form. The rate of release can be modified by altering

the osmotic agent and the size of the hole.



1.2.2.5 Ion exchange resins

Some drugs can be bound to ion exchange resins and, when ingested, the release of

drug is determined by the ionic environment within the gastrointestinal tract4.

Table 1.1: Advantages of extended release dosage forms over conventional forms5

Advantage Explanation

Reduction in drug blood level fluctuation

Frequency reduction in dosing

Enhanced patients convenience and

compliance

Reduction in adverse side effects

Reduction in overall health care costs.

By controlling the rate of drug release, “peaks

and valleys” of drug blood levels are

eliminated.

Extended release products deliver frequently

more than a single dose of medication and

thus they may be taken less often than

conventional forms.

With less frequency of dose administration, a

patient is less apart to neglect taking a dose.

There is also greater patient and/or caregiver

convenience with dynamic and nighttime

medication administration.

Because there are fewer drug blood level

peaks outside of the drug’s therapeutic range

and into the toxic range, adverse side effects

occur less frequently.

Although the initial cost of extended-release

dosage forms may be greater than that for

conventional dosage forms, the overall cost of

treatment may be less due to enhanced

therapeutic benefit, fewer side effects, and

reduced time required of health care

personnel to dispense and administer drugs

and monitor patients.



1.2.3 Mechanisms of drug release from matrix systems

The release of drug from controlled devices is via dissolution or diffusion or a

combination of the two mechanisms.

1. Dissolution controlled systems

A drug with slow dissolution rate will demonstrate sustaining properties, since the

release of the drug will be limited by the rate of dissolution. In principle, it would

seem possible to prepare extended release products by decreasing the

dissolution rate of drugs that are highly water-soluble7. This can be done by:

Preparing an appropriate salt or derivative

Coating the drug with a slowly dissolving material – encapsulation

dissolution control

Incorporating the drug into a tablet with a slowly dissolving carrier –

matrix dissolution control (a major disadvantage is that the drug release

rate continuously decreases with time).

The dissolution process can be considered diffusion-layer-controlled, where the

rate of diffusion from the solid surface to the bulk solution through an unstirred

liquid film is the rate-determining step. The dissolution process at steady-state is

described by the Noyes-Whitney equation:

………………….. (1)

Where,

dC / dt = dissolution rate

D = the dissolution rate constant (equivalent to the diffusion coefficient

divided by the thickness of the diffusion layer D/h)



Co = saturation solubility of the solid

C = concentration of solute in the bulk solution

A = Surface area

h = Diffusion layer thickness

Equation predicts that the rate of release can be constant only if the following

parameters are held constant:

Surface area

Diffusion coefficient

Diffusion layer thickness

Concentration difference.

These parameters, however, are not easily maintained constant, especially

surface area, and this is the case for combination diffusion and dissolution

systems7.

2. Diffusion controlled systems

Diffusion systems are characterized by the release rate of a drug being

dependent on its diffusion through an inert membrane barrier6. Usually, this barrier is

an insoluble polymer. In general, two types or subclasses of diffusional systems are

recognized: reservoir devices and matrix devices7. It is very common for the

diffusion-controlled devices to exhibit a non-zero order release rate due to an

increase in diffusional resistance and a decrease in effective diffusion area as the

release proceeds8.

Diffusion in matrix devices

In this model, drug in the outside layer exposed to the bathing solution is

dissolved first and then diffuses out of the matrix. This process continues with the

interface between the bathing solution and the solid drug moving toward the



interior. It follows obviously that for this system to be diffusion controlled, the rate

of dissolution of drug particles within the matrix must be much faster than the

diffusion rate of dissolved drug leaving the matrix7. Derivation of the

mathematical model to describe this system involves the following

assumptions:

a. A pseudo-steady state is maintained during drug release;

b. The diameter of the drug particles is less than the average distance of drug

diffusion through the matrix;

c. T he diffusion coefficient of drug in the matrix remains constant (no change

occurs in the characteristics of the polymer matrix7;

d. The bathing solution provides sink conditions at all times;

e. No interaction occurs between the drug and the matrix;

f. The total amount of drug present per unit volume in the matrix is substantially

greater than the saturation solubility of the drug per unit volume in the

matrix(Excess solute is present)9

g. Only the diffusion process occurs10

In a hydrophilic matrix, there are two competing mechanisms involved in the

drug release: Fickian diffusional release and relaxation release. Diffusion is not

the only pathway by which a drug is released from the matrix; the erosion of the

matrix following polymer relaxation contributes to the overall release. The relative

contribution of each component to the total release is primarily dependent on the

properties of a given drug11.

For example, the release of a sparingly soluble drug from hydrophilic matrices

involves the simultaneous absorption of water and desorption of drug via a

swelling-controlled diffusion mechanism. As water penetrates into a glassy



polymeric matrix, the polymer swells and its glass transition temperature is

lowered. At the same time, the dissolved drug diffuses through this swollen

rubbery region into the external releasing medium12.

This type of diffusion and swelling does not generally follow a Fickian diffusion

mechanism10. The semi-empirical equation to describe drug release behavior from

hydrophilic matrix systems12:

Q = k ⋅ t n …………………(2) Where,

Q = fraction of drug released in time t,

k = rate constant incorporating characteristics of the macromolecular network

system and the drug

n = the diffusional exponent. It has been shown that the value of n is indicative of

the drug release mechanism.

For n=0.5, drug release follows a Fickian diffusion mechanism that is driven by a

chemical potential gradient. For n=1 drug release occurs via the relaxational transport

that is associated with stresses and phase transition in hydrated polymers. For

0.5<n<1 non-Fickian diffusion is often observed as a result of the

contributions from diffusion and polymer erosion10.



(Fig. 1.1: Drug release from hydrophilic matrix tablet)

Advantages of hydrophilic matrix tablets

With proper control of manufacturing process, reproducible release profiles are

possible. They variability associated with them is slightly less than that characterizing

coated release forms. Their capacity to incorporate active principles is large, which

suits them to delivery of large doses14.

Disadvantages of hydrophilic matrix tablet

For a hydrophilic sustained release matrix tablet, in which the release is mainly

controlled by erosion of the swollen polymer gel barrier at the tablet surface, the

presence of food may block the pores of the matrix and inhibit the drug release

rate13-14.

Tablet erosion : Outer layer becomes fully hydrated, eventually dissolving into the gastric fluids. Water continues to permeate toward the tablet core.

Gel layer

Ingestion of tablet

Initial wetting: Tablet surface wets and polymer begins to hydrate, forming a gel layer, initial burst release occur from the surface of the tablet.

Expansion of the gel layer: Water permeates into the tablet, increasing the thickness of the gel layer, soluble drugs diffuse through the gel layer.

Soluble drug: Is released primarily by diffusion through the gel layer.

Insoluble drug : Is released primarily through tablet erosion.



The hydrophilic polymers can be arranged into three broad categories13-14:

(A) Non-cellulose natural or semi synthetic polymer

These are products of vegetable origin and are generally used as such. Agar, alginate,

guar gum, chitosan, modified starches, are commonly used polymer.

(B) Polymers of acrylic acid

These are arranged in carbomer group and commercialized under the name of

carbopol. The major disadvantage of this type of polymer is its pH dependent gelling

characteristics.

(C) Cellulose ether

This group of semi-synthetic cellulose derivatives is the most widely used group of

polymer. Non-ionic such as Hydroxypropylmethylcellulose (HPMC) of different

viscosity grades are widely used group of polymers. Non-ionic such as HPMC of

different viscosity grades is widely used.

3. Bioerodible and combination of diffusion and dissolution systems

Strictly speaking, therapeutic systems will never be dependent on dissolution or

diffusion only. In practice, the dominant mechanism for release will overshadow

other processes enough to allow classification as either dissolution rate-limited or

diffusion-controlled release7.

As a further complication these systems can combine diffusion and dissolution of

both the drug and the matrix material. Drugs not only can diffuse out of the dosage

form, as with some previously described matrix systems, but also the matrix

itself undergoes a dissolution process. The complexity of the system arises from

the fact that as the polymer dissolves the diffusional path length for the drug may

change. This usually results in a moving boundary diffusion system. Zero-

order release is possible only if surface erosion occurs and surface area does not



change with time.

Swelling-controlled matrices exhibit a combination of both diffusion and dissolution

mechanisms. Here the drug is dispersed in the polymer, but instead of an insoluble

or non-erodible polymer, swelling of the polymer occurs. This allows for the

entrance of water, which causes dissolution of the drug and diffusion out of the

swollen matrix. In these systems the release rate is highly dependent on the polymer-

swelling rate and drug solubility. This system usually minimizes burst effects, as

rapid polymer swelling occurs before drug release7.

With regards to swellable matrix systems, different models have been proposed to

describe the diffusion, swelling and dissolution processes involved in the drug

release mechanism. However the key element of the drug release mechanism is

the forming of a gel layer around the matrix, capable of preventing matrix

disintegration and further rapid water penetration11, 15, 16.

When a matrix that contains a swellable glassy polymer comes in contact with a

solvent or swelling agent, there is an abrupt change from the glassy to the

rubbery state, which is associated with the swelling process. The individual

polymer chains, originally in the unperturbed state absorb water so that their end-to-

end distance and radius of gyration expand to a new solvated state. This is due to

the lowering of the transition temperature of the polymer (Tg), which is controlled

by the characteristic concentration of the swelling agent and depends on both

temperature and thermodynamic interactions of the polymer– water system. A

sharp distinction between the glassy and rubbery regions is observed and the matrix

increases in volume because of swelling. On a molecular basis, this phenomenon

can activate a convective drug transport, thus increasing the reproducibility of the

drug release. The result is an anomalous non-Fickian transport of the drug,



owing to the polymer-chain relaxation behind the swelling position. This, in turn,

creates osmotic stresses and convective transport effects.

The gel strength is important in the matrix performance and is controlled by the

concentration, viscosity and chemical structure of the rubbery polymer. This restricts

the suitability of the hydrophilic polymers for preparation of swellable matrices.

Polymers such as carboxymethyl cellulose, hydroxypropyl cellulose or tragacanth gum,

do not form the gel layer quickly. Consequently, they are not recommended as

excipients to be used alone in swellable matrices15, 17.

The swelling behavior of heterogeneous swellable matrices is described by front

positions, where ‘front’ indicates the position in the matrix where the physical

conditions sharply change. Three fronts are present, as shown in Figure 1.215.

The ‘swelling front’ clearly separates the rubbery region (with enough water to

lower the Tg below the experimental temperature) from the glassy region

(Where the polymer exhibits a Tg that is above the experimental temperature).

The ‘erosion front’, separates the matrix from the solvent. The gel-layer

thickness as a function of time is determined by the relative position of the

swelling and erosion moving fronts.

The ‘diffusion front’ located between the swelling and erosion fronts, and

constituting the boundary that separates solid from dissolved drug, has been

identified.

During drug release, the diffusion front position in the gel phase is dependent on

drug solubility and loading. The diffusion front movement is also related to

drug dissolution rate in the gel18.



(Fig. 1.2: the fronts in a swellable HPMC matrix) 18

Drug release is controlled by the interaction between water, polymer and drug. The

delivery kinetics depends on the drug gradient in the gel layer. Therefore, drug

concentration and thickness of the gel layer governs the drug flux. Drug

concentration in the gel depends on drug loading and solubility. Gel-layer thickness

depends on the relative contributions of solvent penetration, chain

disentanglement and mass (polymer and drug) transfer in the solvent. Initially

solvent penetration is more rapid than chain disentanglement, and a rapid build- up

of gel-layer thickness occurs. However, when the solvent penetrates slowly, owing

to an increase in the diffusional distance, little change in gel thickness is observed

since penetration and disentanglement rates are similar. Thus gel-layer thickness

dynamics in swellable matrix tablets exhibit three distinct patterns. The thickness

increases when solvent penetration is the fastest mechanism, and it remains

constant when the disentanglement and water penetration occur at a similar rate.

Finally, the gel-layer thickness decreases when the entire polymer has undergone

the glassy–rubbery transition. In conclusion, the central element of the release

mechanism is a gel-layer forming around the matrix in response to water penetration.



Phenomena that govern gel-layer formation, and consequently drug-release rate, are

water penetration, polymer swelling, drug dissolution and diffusion, and matrix

erosion. Drug release is controlled by drug diffusion through the gel layer, which can

dissolve and/or erode15, 18.

1.2.4 Biological factors influencing oral sustained-release dosage form design 19

1) Biological half-life:

Therapeutic compounds with short half-lives are excellent candidates for sustained-

release preparations, since this can reduce dosing frequency.

2) Absorption:

The absorption rate constant is an apparent rate constant, and should, in actuality, be

the release rate constant of the drug from the dosage form. If a drug is absorbed by

active transport, or transport is limited to a specific region of the intestine, sustained-

release preparations may be disadvantageous to absorptions.

3) Metabolism:

Drugs that are significantly metabolized before absorption, either in the lumen or

tissue of the intestine, can show decreased bioavailability from slower-releasing

dosage forms. Most intestinal wall enzyme systems are saturable. As the drug is

released at a slower rate to these regions, less total drug is presented to the enzymatic

process during a specific period, allowing more complete conversion of the drug to its

metabolite.



1.2.5. Physicochemical factors influencing oral sustained-release dosage form

design19

1) Dose Size:

In general, single dose of 0.5 – 1.0 g is considered maximal for a conventional dosage

form. This also holds true for sustained-release dosage forms. Another consideration

is the margin of safety involved in administration of large amounts of drug with a

narrow therapeutic range.

2) Ionization, pKa, and aqueous solubility:

Most drugs are weak acids or bases. Since the unchanged form of a drug

preferentially permeates across lipid membranes, it is important to note the

relationship between the pKa of the compound and the absorptive environment.

Delivery systems that are dependent on diffusion or dissolution will likewise be

dependent on the solubility of drug in the aqueous media. For dissolution or diffusion

sustaining forms, much of the drug will arrive in the small intestine in solid form,

meaning that the solubility of the drug may change several orders of magnitude

during its release. The lower limit for the solubility of a drug to be formulated in a

sustained release system has been reported to be 0.1 mg/ml.

3) Partition coefficient:

Compounds with a relatively high partition coefficient are predominantly lipid-

soluble and, consequently, have very low aqueous solubility. Furthermore these

compounds can usually persist in the body for long periods, because they can localize

in the lipid membranes of cells.



4) Stability:

Orally administered drugs can be subjected to both acid-base hydrolysis and

enzymatic degradation. For drugs that are unstable in the stomach, systems that

prolong delivery over the entire course of transit in the GI tract are beneficial.

Compounds that are unstable in the small intestine may demonstrate decreased

bioavailability when administered from a sustaining dosage form.

1.2.6. Drug selection for oral sustained release drug delivery systems 20

The biopharmaceutical evaluation of a drug for potential use in controlled release

drug delivery system requires knowledge on the absorption mechanism of the drug

form the G.I. tract, the general absorbability, the drug’s molecular weight, solubility

at different pH and apparent partition coefficient.

Table 1.2: Parameters for drug selection

Parameter Preferred value

Molecular weight/ size < 1000

Solubility > 0.1 mg/ml for pH 1 to pH 7.8

Apparent partition coefficient High

Absorption mechanism Diffusion

General absorbability From all GI segments

Release Should not be influenced by pH and

enzymes

The pharmacokinetic evaluation requires knowledge on a drug’s elimination half- life,

total clearance, absolute bioavailability, possible first- pass effect, and the desired

steady concentrations for peak and through.



1.2.7. Basic kinetics of controlled drug delivery 21

In order to establish a basis for discussion of the influence of drug properties and the

route of administration on controlled drug delivery, following mechanisms need a fair

mention,

Behavior of drug within its delivery systems

Behavior of the drug and its delivery system jointly in the body.

The first of the two elements basically deal with the inherent properties of drug

molecules, which influence its release from the delivery system. For conventional

systems, the rate-limiting step in drug availability is usually absorption of drug across

a biological membrane such as the gastro intestinal wall.

Table 1.3: Pharmacokinetic parameters for drug selection

Parameter Comment

Elimination half life Preferably between 0.5 and 8 h

Total clearance Should not be dose dependent

Elimination rate constant Required for design

Apparent volume of distribution

Vd

The larger Vd and MEC, the larger will be

the required dose size.

Absolute bioavailability Should be 75% or more

Intrinsic absorption rate Must be greater than release rate

Therapeutic concentration Css

av

The lower Css av and smaller Vd, the loss

among of drug required

Toxic concentration Apart the values of MTC and MEC, safer

the dosage form. Also suitable for drugs

with very short half-life.



However, in sustained/controlled release product, the release of drug from the dosage

form is the rate limiting instead; thus, drug availability is controlled by the kinetics of

drug release than absorption.

1.2.8. Factors influencing the in vivo performance of sustained release dosage

formulations 22

There are various factors that can influence the performance of a sustained release

product. The physiological, biochemical, and pharmacological factors listed below

can complicate the evaluation of the suitability of a sustained release dosage

formulation.

Physiological

Prolonged drug absorption

Variability in GI emptying and motility

Gastrointestinal blood flow

Influence of feeding on drug absorption

Pharmacokinetic/ biochemical

Dose dumping

First- pass metabolism

Variability in urinary pH; effect on drug elimination

Enzyme induction/ inhibition upon multiple dosing

Pharmacological

Changes in drug effect upon multiple dosing

Sensitization/ tolerance



1.2.9. In vitro evaluation of sustained release formulation

The data is generated in a well-designed reproducible in-vitro test such as dissolution

test. The method should be sensitive enough for discriminating any change in

formulation parameters and lot-to-lot variations. The key elements for dissolution are:

a) Reproducibility of method

b) Proper choice of media

c) Maintenance of sink conditions

d) Control of solution hydrodynamics

e) Dissolution rate as a function of pH ranging from pH 1 to 8 including several

intermediate values preferably as topographic dissolution characterization.

f) Selection of the most discriminating variables (media, pH rotation speed etc.)

as the basis for dissolution test and specification.

Ideal in-vitro method can be utilized to characterize bio-availability of the sustained

release product and can be relied upon to ensure lot-to-lot performance.



1.3 Introduction of product development

Product development usually begins when the active chemical entity has been shown

to process the necessary attributes for a commercial product. Generally product

development activities can be sub divided into formulation development and

process development.

1.3.1 Formulation development 23

Formulation development provides the basic information on the active chemical, the

formula and the impact of raw materials or excipients on the product. A typical

supportive data generated during these activities may include:

1. Preformulation profile, which includes all the basic physical or chemical

information about the chemical entity.

2. Formulation profile, which consist of physical and chemical characteristics

required for the product, drug excipients compatibility studies, and effect of

formulation on in-vitro dissolution.

3. Effect of formulation variable on the bioavailability of the product.

4. Specific test methods.

5. Key product attributes and specification

6. Optimum formulation

Formulation development should not be considered complete until all those factors

which could significantly alter the formulation have been studied. Subsequent minor

changes to the formulation, however, may be acceptable, provide they are thoroughly

tested and as shown to have no adverse effect on product characteristics. In case of

drug development process, compound tested is only one. A variety of studies must be

performed for this single drug, each designed to characterize its efficacy, safety,



selectivity or purity. Much of the data generation is driven by strict and extensive

regulatory control and in this most of the studies are interdependent.

Objective: The overall objective of a drug development process is to move product

candidate through development so that a new drug applicant (NDA) or product

license application (PLA) can be submitted as quickly as possible with best chance of

approval.

1.3.2 Pharmaceutical issues in drug development

1) Role of excipients in drug development: The bulk of final product in dosage

form such as tablet, capsule etc the speed of disintegration, rate of dissolution/ release

of drug, protection against moisture and stability during storage, as well as

compatibility are determined by the excipients. Various excipients used are adhesives,

absorbent excipients, liquid excipients, diluents, fillers, disintegrants, etc.

The general characteristics of excipients are

Must not react with drug substance

No effect on function of other excipients

Not interfere with the bioavailability of active material nor influence

dissolution of the product.

No pharmaceutical or physiological activity.

Have consistent and stable chemical and physical characteristics & properties

from batch to batch and ideally between suppliers.

Colorless and not support microbiological growth in the product.

Performance characteristics of the excipients are 24

Functionality: The control of functionality is important because many

excipients have multiple functions or sometimes there is lack of awareness in

some situations that excipients behave differently.



Rework ability: The reworking potential is defined as the ratio of areas under

the tensile strength compression profiles for re compression and for initial

compression. Often the results show that recompression reduces tablet

strength and that this reduction is more significant when the initial compaction

is carried out at high pressure.

Response and force loading rate:

Modes of deformation: Tabletting machines, which deform plastically with

little elastic recovery, should produce better quality tablets than more resilient

materials.

Effects on compression rate: Mostly strength of the tablets depend on the

speed of rotary tablet press and hence on rate of tablet compression. In

virtually all the cases, increase in tablet press speed led to a decrease in tablet

strength.

2) Dosage form design 25

A rational approach to dosage form design for any drug requires a complete

understanding of its physiochemical and biopharmaceutical properties which can have

a tremendous impact on its bioavailability and thereby on its efficacy and toxicity

profile. Properties that dictate the selection and formulation of dosage forms include:

Solubility and dissolution rate.

Partition coefficient.

Stability and/or degradation in physiologic fluids.

Susceptibility to metabolic inactivation.

Transport mechanism across biological membranes.



3) In-vitro correlation26

In vitro dissolution tests seem to be the most sensitive and reliable predictors of in

vivo availability. Invitro invivo correlations are classified as pharmacological

correlations, semi quantitative correlations and quantitative correlations.

Drug development also includes phase 1, 2 and 3 trials carried out on a particular

group of people after analogue development and screening process.

1.3.3 Process development

Process development activities begin after the formulation has been developed. The

process development should meet the following objectives:

1. Develop a suitable process to produce a product which meets all:

a. Product specifications

b. Economic constrains

c. cGMP

2. Identify the key process parameters that affect the product attributes

3. Identify in-process specification and test method

4. Identify generic and specific equipment that may required.



Product development flowchart

Solid, Dosage Forms STAGE 1

LITERATURE SEARCH

STAGE 2 ACTIVE SOURCING

STAGE 3 ACTIVE EVALUATION

Do not evaluate material While still in a R & D stage STAGE 4 Use only production activity ACTIVE PURCHASING PREFORMULATION STAGES

STAGE 5

ACTIVE TESTING

STAGE 6 INNOVATOR PRODUCT PURCHASING

Purchase a new lot Lot number every 3 mth From the smallest to the STAGE 7 Largest pack size INNOVATOR PRODUCT TESTING (in each dosage strength )

STAGE 8

BULK ACTIVE TESTING

STAGE 9 EXCIPIENT EVALUATION

Residual solvent Check STAGE 10

CONTAINER CLOSURE SYSTEM CHOICES

STAGE 11 DEVELOPMENT MANUFACTURING PROCESS EVALUATION BATCHES

STAGE 12 BULK ACTIVE PURCHASE

STAGE 13 ANALYTICAL EVALUATION



STAGE 14 Prepared full written protocol PROCESS OPTIMIZATION for PO scale up & PQ batches PO BATCH

STAGE 15

ANALYTICAL DEVELOPMENT PROCESS OPTIMIZATION

STAGE 16

SCALE – UP

STAGE 17 PROCESS

QUALIFICATION

STAGE 18 PIVOTAL BATCHES

PIVOTAL BATCH PRODUCTION

STAGE 19 BIO EQUIVALENTS BIO STUDY EVALUATION STUDY

REVIEW all raw data development STAGE 20 & lab note book . evaluate all interim ANDA PRE-SUBMISSION Report that from part of the AUDIT Product Development Report

SCOPE OF PRODUCT STAGE 21 DEVELOPMENT

ANDA SUBMISSION

STAGE 21 B PRODUCT DEVELOPMENT REPORT

Process validation STAGE 22 Signify the first THREE Process Validation & Consecutive production Statistics Process Validation Lots (same batches size and (3 commercial lots) Active lot no :)

STAGE 23 Process Revalidation after a major change

(Check SUPAC)



1.3.3.1 Process development can be divided into several stages:

1. Design

2. Ranging

3. Characterization

4. Verification

1. Design

This is the initial planning stage of process development. During this stage, technical

operation in both the manufacturing and quality-control departments should be

consulted. The practically and the reality of the manufacturing operation should be

kept in perspective.

Key documents for the technical definition of the process are the flow diagram, the

cause and effect diagram and the influence matrix.

The flow diagram provides a convenient basic on which to develop a detailed list of

variables and responses. Preliminary working documents are critical, but they should

never be “cast in stone”, since new experimental data may drastically alter them. The

final version will eventually be an essential part of the process characterization and

technical transfer documents. Regardless of the stage of formulation/process

development being considered, a detail identification of variables and response is

necessary for early program planning.

As the development program progresses, new discoveries will provide an update of

the variable and responses. It is important that current knowledge be adequately

summarized for the particular process being considered. It should be pointed out,

however that common sense and experience must be used in evaluating the variable

during process design and development.



An early transfer of the preliminary documentation to the manufacturing and quality

control department is essential, so that they can being to prepare for any new

equipment or facilities that may required.

2. Ranging

Process-ranging studies will test whether identified parameter are critical to the

product and process being developed. These studies determined the:

a. Feasibility of the design process

b. Criticality of the parameter

c. Failure limits for each of the critical variable

d. Validity of the test methods

This is usually a transition stage between the laboratory and the projected final

process.

3. Characterization

Process characterization provides a systematic examination of critical variables found

during process ranging. The objectives of these studies are:

a) Confirm key process control variables and quality their effect on product

attributes.

b) Establish product conditions for each unit operation.

c) Determine in process operating limits to guarantee acceptable finished product

and yield.

d) A carefully planned and coordinate experimental program is essential in order

to achieve these objectives.

4. Verification

Prior to a process being scale-up and transferred to production, verification is

required.



This ensures that it behave as designed under simulated production conditions and

determines its reproducibility. Key elements of the process-verification runs should be

evaluated using well-designed in-process sampling procedure. These should be

focused on potentially critical unit operations. Validated in-process and final product

analytical procedures should always be used. Sufficient replicate batches should be

produced to determine between and within-batch variations.

The typical process verification analysis of a tableted product includes:

Table 1.4: Typical process of tablet

Unit Operation Analysis

Pre-blending Blend uniformity, Dry-mix, Water content

by KF apparatus

Granulation None required

Sizing Granules size distribution, Milled

Granules-Water content by KF apparatus.

Blending Blend uniformity, Flow properties

Potency/assay

Tabletting Average weight

Hardness

Thickness

Disintegration

Dissolution

Friability

The transfer procedure that is followed in order to pass the documented knowledge

and experience gained during development and commercialization to an appropriate,

responsible and authorized party. Technology transfer embodies both the transfer of

documented and demonstrated technology, to the satisfaction of all parties and any

and all applicable regulatory bodies.



1.3.4 Technology transfer subdivided into two units

I. Sending unit

II. Receiving unit

1.3.4.1 Advantages

i. The transfer of technology from R & D (sending unit) to manufacturing

(Receiving unit) is the first key steps to getting a high quality product to the

market place.

ii. The transfers of the process technology from the R & D bench to large scale

manufacturing present some unique challenges.

iii. It also useful to make a timeframe of the process for that particular product.

iv. Hold time studies is useful for the planning of the product with other batches.

1.3.4.2 Objectives

The objective of the technology transfer guide in two-fold.

1. To describe the appropriate information set that needs to be complied to

support the transfer of the information and provide regulatory filing

documents.

2. To provide guidance on effective approaches for ensuring this information is

available at “print of use” where guidance on specific topic already exists this

will be referred.

The technology transfer guide is planning in such a way that technology transfer

performed in accordance with the recommendations in this guide will be the

regulatory authorities.



1.3.5 Process optimization

In the environment of increasing international competition where counters with lower

production cost luckily catch up technologically, new thinking is required in order to

meeting the competition is to focus on maximizing the utilization of exiting

technology. This means much more than just investing in new equipment.

The ability to optimize or improve a process is dependent upon the ability to control

the process. The ability to control the process is dependent upon the access to reliable

and valid management. A successful industrial organization thus entails a strategic

approach encompassing the whole chain.

1) Need for optimization

In an environment of increasing competition where countries with lower production

cost, quickly catch up technologically, new thinking is required in order to meet the

competition. Efficient organization and leadership is more difficult to copy than

technology. A successful way of meeting the increasing competition can thus be to

focus the effort on adapting the organization for maximal utilization of existing

technology and faster than competitors, being able to continuously introduce and

make use of new technology.

2) Optimization technology

There are two type optimization problems. They are:

1.Constrained optimization

Constrains are those restricted placed on the system due to physical limitation.

(Ex: Economic consideration)

2.Unconstrained optimization



In unconstrained optimization problems there are no restriction (such as tablet

hardness and disintegration).

An additional complication in pharmacy is that formulations are not usually simple

system. They often contain many ingredients and variables, which may interact with

one another to produce unexpected.

1.3.6 Scale up & technology transfer consideration

Scale up means increase the batch size; it acts a link between the formulation research

development and production. The pilot plant and its staff play a critical role in

technology evolution scale-up and transfer activity of new products. These activities

being early in the development cycle and include technical aspects of process

development and scale-up, organization and responsibility of technology transfer

team, documentation of transfer process, and obtain preparation for an FDA pre-

approval inspection. A properly design and operated pilot plant enhance the collection

of scientific data necessary to support internal transfer activities as well as regulatory

submission and FDA pre-approval inspection.

Four key technical aspects must be addressed during scale-up in the pilot plant.

I. Identification and control of critical component and formulation variables early

in the development.

II. Pilot plant equipment that simulates as closely as possible equipment used at

the manufacturing site.

III. Identification of critical process parameter and operating ranges with pilot plant

equipment through the use of engineering and regret ion models.

IV. Collection of product and process data to adequately characterized each unit

operation.



The success of any program is highly dependent on the effectiveness of the

communication presiding its implementation. Therefore, the preparation and

distribution of a complete document summarizing the raw material and equipment

requirements, manufacturing and packing process, process validation protocol, QC

processor, safe handling processor as well as a detail plan of action out limiting

expected result and time framer must be distributes prior to scale-up experiences. The

three main considerations to be address during an effective technology transfer of

plan. The person involved and process steps. Once prepared, the plan must be

communicated to the involved part in research, at the corporate level and at the

production site. The facility design plan a critical role in addressing each of their

technical aspects, however scientific and pilot plant staff involved in manufacturing

operations within the pilot facility also play a key role in ensuring smooth and timely

transfer of process technology to the manufacturing site. In the part, the transfer of

formulation and, manufacturing technology was sometimes discretely processed from

development staff with little interaction. Today, however, it is commonly recognize

the interaction of these groups at an early development stage is critical in obtaining an

efficient and successful transfer. Scientific and pilot plants staff a key role in

demonstrating new product manufacturing techniques to produce personal in the pilot

plant environment. A team orientation approach to the manufacture of pilot or large

scale batches in the pilot plant will allow key production site personnel to view and

comment on the process and make a specific recommendation for improvement based

on the knowledge of the manufacturing site.

Chapter -2 OObbjjeeccttiivvee ooff SSttuuddyy


2.1. Aim of the present work:

Depression is the most common affective disorder and affects as many as 1 in 4

people in their teen years. It is an extremely common psychiatric condition, about

which a variety of neurochemical theories exist and for which a corresponding variety

of different types of drug is used in treatment ‘Major’ depression is a severe and

widespread psychiatric disorder which is on way to becoming a killer disease

worldwide.

There is no single cause for depression. Many factors play a role including genetics,

environment, life events, medical conditions, and the way people react to things that

happen in their lives. Depression involves the brain’s delicate chemistry –

specifically, it involves chemicals called neurotransmitters. These chemicals send

messages between nerve cells in the brain. Certain neurotransmitters regulate mood,

and if they run low, people become depressed, anxious, and stressed. Stress also

affects the balance of neurotransmitters and lead to depression.

Anti depressants are the classes of drugs which can elevate mood in depressive

illness. Almost all anti-depressants affect mono-aminergic transmission in the brain.

There are various classes of anti-depressant drugs available viz.,

1. Reversible Inhibitors of MAO-A

2. Tricyclic Antidepressants

3. Selective serotonin reuptake inhibitors

4. Atypical antidepressants.

But all the drugs in above mentioned classes have various side-effects such as

sedation, hypotension, cardiac arrhythmias, seizure precipitation, enzyme inhibitory

Chapter -2 OObbjjeeccttiivvee ooff SSttuuddyy


action, dose related CNS toxicity, renal diabetes insipidus, loss of libido and failure or

orgasm.

Hence, there is a need for the development of a formulation containing new anti-

depressant drug belonging to any of the above class which will help to overcome

above mentioned side-effects.

2.2. Objectives of the present study:

1. Preparation and characterization of novel anti-depressant tablet.

2. To study the various formulation variables that ultimately affects the drug release.

3. Selection and optimization of polymer concentration, that has pronounced effect

on tablet properties and drug release profile of the formulations.

4. To maintain the plasma concentration of drug within the therapeutic window.

5. To increase the patient’s compliance.

Chapter -3 IInnttrroodduuccttiioonn ttoo DDrruugg


3.1 INTRODUCTION TO DRUG27

3.1.1 Structural Formula

Figure 3.1: Structure of Drug

CAS No. 144598-75-4

3.1.2 Description

The drug is a psychotropic agent belonging to the chemical class of benzisoxazole

derivatives. It consists of the racemic mixture. The chemical name is (±)-3-[2-[4-(6-

fluoro-1, 2benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2

methyl-4Hpyrido[1,2-a]pyrimidin-4-one.

3.1.3 Physical and chemical properties

Chemical Formula : C23H27FN4O3

Molecular weight : 426.49 gm/mole

pKa1 : 8.2

pKa2 : 2.6

Melting Point : 189 - 2030 C

Wave Length : 275 nm

Optical Rotation : No specific rotation



Color : White to pale yellow

Log P : 2.39

Solubility - : Drug is sparingly soluble in 0.1N HCl and methylene chloride

practically insoluble in water, 0.1N NaOH, and hexane; and

slightly soluble in N,N-dimethylformamide.

3.1.4 Pharmacology

3.1.4.1 Mechanism of Action

Drug is the major active metabolite of risperidone. The mechanism of action of drug,

as with other drugs having efficacy as antidepressant, mood stabilizer and in

schizophrenia, is unknown, but it has been proposed that the drug's therapeutic

activity is mediated through a combination of central dopamine Type 2 (D2) and

serotonin Type 2 (5HT2A) receptor antagonism. Drug also has antagonist effect at α1

and α2 adrenergic receptors and at H1 histamine receptors.

3.1.4.2 Pharmacodynamics

Drug is a centrally active dopamine Type 2 (D2) antagonist and with predominant

serotonin Type 2 (5HT2A) activity. It is also active as an antagonist at α1 and α2

adrenergic receptors and H1 histaminergic receptors, which may explain some of the

other effects of the drug. It has no affinity for cholinergic muscarinic or β1- and β2-

adrenergic receptors. The pharmacological activity of the (+)- and (-)- drug

enantiomers is qualitatively and quantitatively similar.

3.1.4.3 Pharmacokinetics

Following a single dose, the plasma concentrations of paliperidone gradually rise to

reach peak plasma concentration (Cmax) approximately 24 hours after dosing. The

pharmacokinetics of drug following oral administration are dose-proportional within



the available dose range. The terminal elimination half-life of drug is approximately

23 hours. Steady-state concentrations of drug are attained within 4-5 days of dosing

with INV in most subjects. The mean steady-state peak:trough ratio for an INV dose

of 9 mg was 1.7 with a range of 1.2-3.1.

Absorption and Distribution

The absolute oral bioavailability of drug following INVEGA® administration is 28%.

Administration of a 12 mg drug extended-release tablet to healthy ambulatory

subjects with a standard high-fat/high-caloric meal gave mean Cmax and AUC values

of drug that were increased by 60% and 54%, respectively, compared with

administration under fasting conditions. Clinical trials establishing the safety and

efficacy of INV were carried out in subjects without regard to the timing of meals.

While INV can be taken without regard to food, the presence of food at the time of

INV administration may increase exposure to drug.

Based on a population analysis, the apparent volume of distribution of drug is 487 L.

The plasma protein binding of racemic drug is 74%.

Metabolism and Excretion

Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the

metabolism of drug, in vivo results indicate that these isozymes play a limited role in

the overall elimination of drug. One week following administration of a single oral

dose of 1 mg immediate-release 14C-paliperidone to 5 healthy volunteers, 59% (range

51% - 67%) of the dose was excreted unchanged into urine, 32% (26% - 41%) of the

dose was recovered as metabolites, and 6% - 12% of the dose was not recovered.

Approximately 80% of the administered radioactivity was recovered in urine and 11%

in the feces. Four primary metabolic pathways have been identified in vivo, none of



which could be shown to account for more than 10% of the dose: dealkylation,

hydroxylation, dehydrogenation, and benzisoxazole scission.

Population pharmacokinetic analyses found no difference in exposure or clearance of

paliperidone between extensive metabolizers and poor metabolizers of CYP2D6

substrates.

3.1.5 Indications

Extended release tablets are indicated for acute and maintenance treatment of bipolar

disorder, schizophrenia, as an adjunct to mood stabilizers.

3.1.6 Contraindications

Pregnancy Patients with dementia related psychosis.

Severe renal or hepatic impairment.

Patients with serious cardiac or gastrointestinal disorders.

Patients with orthostatic hypotension.

Hypersensitivity to drug.

Children under 2 years of age.

3.1.7 Precautions

Concerns related to adverse effects:

• Gastrointestinal symptoms: Dosage reduction is recommended in

patients who develop gastrointestinal symptoms (anorexia, diarrhea,

nausea, vomiting) related to drug therapy.

• Weakness: Dosage reduction is recommended in patients who develop

weakness related to drug therapy.



Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with mild-to-

moderate cardiac disease.

• Hepatic impairment: No dosage adjustment is required in patients with

mild to moderate hepatic impairment

• Renal impairment: Dosing must be individualized according to the

patient's renal function status

• Diabetic Condition: Use with caution in patients with high blood sugar

conditions as the drug may infrequently make blood sugar level rise,

causing or worsening diabetes.

Special populations:

• Pregnancy: Should be used only when clearly needed.

• Nursing: Breast-feeding while using this drug is not recommended.

• Safety and effectiveness of INV in patients < 18 years of age have not

been established

• INV (drug) is not approved for the treatment of dementia-related

psychosis



3.1.8 Drug Interactions

Table 3.1: Drug Interactions Sr. No. Drug Interaction

1 Bupropion Increased risk of seizure with this combination

2 Isoniazid Increased risk of seizure with this combination

3 Theophylline Increased risk of seizure with this combination

4 Phenothiazines Increased risk of seizure with this combination

5 Antihistamines Cause drowsiness

6 Anti-seizure drugs Cause drowsiness

7 Lovastatin Irregular heartbeat

8 Pravastatin Irregular heartbeat

9 Rosuvastatin Irregular heartbeat

10 Simvastatin Irregular heartbeat

11 Prazosin Synergistic action

3.1.9 Side Effects

Increased mortality in elderly patients with dementia-related psychosis

Cerebrovascular adverse events, including stroke, in elderly patients with

dementia-related psychosis

Tardive dyskinesia

Hyperglycemia and diabetes mellitus

Hyperprolactinemia

Potential for Gastrointestinal Obstruction

Potential for cognitive and motor impairment

Increased sensitivity in patients with Parkinson's disease or those with

dementia with Lewy bodies

Diseases or conditions that could affect metabolism or hemodynamic

responses



3.1.10 Dosage and administration

The recommended dose of INV (drug) Extended-Release Tablets for the treatment of

bipolar depression is 6 mg once daily, administered in the morning. Initial dose

titration is not required. Although it has not been systematically established that doses

above 6 mg have additional benefit, there was a general trend for greater effects with

higher doses. This must be weighed against the dose-related increase in adverse

reactions. Thus, some patients may benefit from higher doses, up to 12 mg/day, and

for some patients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6

mg/day should be made only after clinical reassessment and generally should occur at

intervals of more than 5 days. When dose increases are indicated, increments of 3

mg/day are recommended. The maximum recommended dose is 12 mg/day.

Children:

The safety and effectiveness in this age group have not been established.

Elderly:

Because elderly patients may have diminished renal function, dose adjustments may

be required according to their renal function status. In general, recommended dosing

for elderly patients with normal renal function is the same as for younger adult

patients with normal renal function. For patients with moderate to severe renal

impairment (creatinine clearance 10 mL/min to < 50 mL/min), the maximum

recommended dose of INV is 3 mg once daily

Reduced hepatic function:

For patients with mild to moderate hepatic impairment, (Child-Pugh Classification A

and B), no dose adjustment is recommended.



Reduced renal function:

Dosing must be individualized according to the patient's renal function status. For

patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80

mL/min), the recommended initial dose of INV is 3 mg once daily. The dose may

then be increased to a maximum of 6 mg once daily based on clinical response and

tolerability. For patients with moderate to severe renal impairment (creatinine

clearance ≥ 10 mL/min to < 50 mL/min), the recommended initial dose of INV is 1.5

mg once daily, which may be increased to a maximum of 3 mg once daily after

clinical reassessment.

Chapter -3 IInnttrroodduuccttiioonn ttoo PPoollyymmeerrss


3.2.1 Hydroxypropylmethylcellulose

1. Nonproprietary Names

BP: Hypromellose

JP: Hydroxypropylmethylcellulose

PhEur: Hypromellosum

USP: Hypromellose

2. Chemical Name and CAS Registry Number

Cellulose hydroxypropyl methyl ether [9004-65-3]

3. Empirical Formula and Molecular Weight

The PhEur 2005 describes hypromellose as a partly O-methylated and O-(2-

hydroxypropylated) cellulose. It is available in several grades that vary in viscosity

and extent of substitution. Grades may be distinguished by appending a number

indicative of the apparent viscosity, in mPa s, of a 2% w/w aqueous solution at 20°C.

Hypromellose defined in the USP 28 specifies the substitution type by appending a

four-digit number to the nonproprietary name: e.g., hypromellose 1828. The first two

digits refer to the approximate percentage content of the methoxy group (OCH3). The

second two digits refer to the approximate percentage content of the hydroxypropoxy

group (OCH2CH(OH)CH3), calculated on a dried basis. It contains methoxy and

hydroxypropoxy groups conforming to the limits for the types of hypromellose stated

in Table I. Molecular weight is approximately 10 000–1 500 000. The JP 2001

includes three separate monographs for hypromellose: hydroxypropylmethylcellulose

2208, 2906, and 2910, respectively.



4. Structural Formula

where R is H, CH3, or CH3CH(OH)CH2

(Fig. 3.2: Structure of HPMC)

5. Functional Category

Coating agent

Film-former

Rate-controlling polymer for sustained release

Stabilizing agent

Suspending agent

Tablet binder

Viscosity-increasing agent.

6. Applications in Pharmaceutical Formulation or Technology

Hypromellose is widely used in oral, ophthalmic and topical pharmaceutical

formulations. In oral products, hypromellose is primarily used as a tablet binder, in

film-coating, and as a matrix for use in extended-release tablet formulations.

Concentrations between 2% and 5% w/w may be used as a binder in either wet- or

dry-granulation processes. High-viscosity grades may be used to retard the release of

drugs from a matrix at levels of 10–80% w/w in tablets and capsules28-39.

Depending upon the viscosity grade, concentrations of 2–20% w/w are used for film-

forming solutions to film-coat tablets. Lower-viscosity grades are used in aqueous

film-coating solutions, while higher-viscosity grades are used with organic solvents.



Examples of film-coating materials that are commercially available include AcryCoat

C, Spectracel, and Pharmacoat.

Hypromellose is also used as a suspending and thickening agent in topical

formulations. Compared with methylcellulose, hypromellose produces aqueous

solutions of greater clarity, with fewer undispersed fibers present, and is therefore

preferred in formulations for ophthalmic use. Hypromellose at concentrations between

0.45–1.0% w/w may be added as a thickening agent to vehicles for eye drops and

artificial tear solutions.

Hypromellose is also used as an emulsifier, suspending agent, and stabilizing agent in

topical gels and ointments. As a protective colloid, it can prevent droplets and

particles from coalescing or agglomerating, thus inhibiting the formation of

sediments.

In addition, hypromellose is used in the manufacture of capsules, as an adhesive in

plastic bandages, and as a wetting agent for hard contact lenses. It is also widely used

in cosmetics and food products.

7. Description & Typical Properties

Hypromellose is an odorless and tasteless, white or creamy-white fibrous or granular

powder.

Acidity/alkalinity: pH = 5.5–8.0 for a 1% w/w aqueous solution.

Ash: 1.5–3.0%, depending upon the grade and viscosity.

Autoignition temperature: 360°C

Density (bulk): 0.341 g/cm3

Density (tapped): 0.557 g/cm3

Density (true): 1.326 g/cm3



Melting point: browns at 190–200°C; chars at 225–230°C. Glass transition

temperature is 170–180°C.

Moisture content: hypromellose absorbs moisture from the atmosphere; the

amount of water absorbed depends upon the initial moisture content and the

temperature and relative humidity of the surrounding air.

Solubility: soluble in cold water, forming a viscous colloidal solution; practically

insoluble in chloroform, ethanol (95%), and ether, but soluble in mixtures of

ethanol and dichloromethane, mixtures of methanol and dichloromethane, and

mixtures of water and alcohol. Certain grades of hypromellose are soluble in

aqueous acetone solutions, mixtures of dichloromethane and propan-2-ol, and other

organic solvents.

Specific gravity: 1.26

Viscosity (dynamic): a wide range of viscosity types are commercially available.

Aqueous solutions are most commonly prepared, although hypromellose may also

be dissolved in aqueous alcohols such as ethanol and propan-2-ol provided the

alcohol content is less than 50% w/w. Dichloromethane and ethanol mixtures may

also be used to prepare viscous hypromellose solutions. Solutions prepared using

organic solvents tend to be more viscous; increasing concentration also produces

more viscous solutions.

To prepare an aqueous solution, it is recommended that hypromellose is dispersed and

thoroughly hydrated in about 20–30% of the required amount of water. The water

should be vigorously stirred and heated to 80–90°C, then the remaining hypromellose

should be added. Sufficient cold water should then be added to produce the required

volume.



When a water-miscible organic solvent such as ethanol (95%), glycol, or mixtures of

ethanol and dichloromethane are used, the hypromellose should first be dispersed into

the organic solvent, at a ratio of 5–8 parts of solvent to 1 part of hypromellose. Cold

water is then added to produce the required volume

Typical viscosity values for 2% (w/v) aqueous solutions of Methocel (Dow

Chemical Co.). Viscosities measured at 20°C.

8. Stability and Storage Conditions

Hypromellose powder is a stable material, although it is hygroscopic after drying.

Solutions are stable at pH 3–11. Increasing temperature reduces the viscosity of

Table 3.2: Typical viscosity values for 2% (w/v) aqueous solutions of Methocel

Methocel product USP 28 designation Nominal viscosity (mPa s)

Methocel K100 Premium 2208 100

Methocel K4M Premium 2208 4000

Methocel K15M Premium 2208 15 000

Methocel K100M Premium 2208 100 000

Methocel E4M Premium 2910 4000

Methocel F50 Premium 2906 50

Methocel E10M Premium 2906 10 000

Methocel E3 Premium LV 2906 3





Metolose 60SH 2910 50, 4000, 10 000

Metolose 65SH 2906 50, 400, 1500, 4000

Metolose 90SH 2208 100, 400, 4000, 15 000



solutions. Hypromellose undergoes a reversible sol–gel transformation upon heating

and cooling, respectively. The gel point is 50–90°C, depending upon the grade and

concentration of material40.

Aqueous solutions are comparatively enzyme-resistant, providing good viscosity

stability during long-term storage. However, aqueous solutions are liable to microbial

spoilage and should be preserved with an antimicrobial preservative: when

hypromellose is used as a viscosity-increasing agent in ophthalmic solutions,

benzalkonium chloride is commonly used as the preservative. Aqueous solutions may

also be sterilized by autoclaving; the coagulated polymer must be redispersed on

cooling by shaking.

Hypromellose powder should be stored in a well-closed container, in a cool, dry

place.

9. Incompatibilities

Hypromellose is incompatible with some oxidizing agents. Since it is nonionic,

hypromellose will not complex with metallic salts or ionic organics to form insoluble

precipitates.



3.2.2 Ethyl Cellulose


BP: Ethylcellulose

PhEur: Ethylcellulosum

USPNF: Ethylcellulose

2. Synonyms

Aquacoat ECD; Aqualon; E462; Ethocel; Surelease.


Cellulose ethyl ether [9004-57-3]


Ethylcellulose with complete ethoxyl substitution (DS = 3) is

C12H23O6(C12H22O5)nC12H23O5 where n can vary to provide a wide variety of

molecular weights. Ethylcellulose, an ethyl ether of cellulose, is a long-chain polymer

of β-anhydroglucose units joined together by acetal linkages.


(Fig. 3.3: Structure of Ethyl cellulose)


Coating agent; flavoring fixative; tablet binder; tablet filler; viscosity-increasing

agent.




Ethylcellulose is widely used in oral and topical pharmaceutical formulations; see in

table 3.3. The main use of ethylcellulose in oral formulations is as a hydrophobic

coating agent for tablets and granules44-46. Ethylcellulose coatings are used to modify

the release of a drug,47, 48 to mask an unpleasant taste, or to improve the stability of a

formulation; for example, where granules are coated with ethylcellulose to inhibit

oxidation. Modified-release tablet formulations may also be produced using

ethylcellulose as a matrix former49- 51.

Ethylcellulose, dissolved in an organic solvent or solvent mixture, can be used on its

own to produce water-insoluble films. Higher-viscosity ethylcellulose grades tend to

produce stronger and more durable films. Ethylcellulose films may be modified to

alter their solubility, by the addition of hypromellose or a plasticizer; An aqueous

polymer dispersion (or latex) of ethylcellulose such as Aquacoat ECD (FMC

Biopolymer) or Surelease (Colorcon) may also be used to produce ethylcellulose

films without the need for organic solvents.

.

Drug release through ethylcellulose-coated dosage forms can be controlled by

diffusion through the film coating. This can be a slow process unless a large surface

area (e.g. pellets or granules compared with tablets) is utilized. In those instances,

aqueous ethylcellulose dispersions are generally used to coat granules or pellets.

Ethylcellulose-coated beads and granules have also demonstrated the ability to absorb

Table 3.3: Uses of ethylcellulose Use Concentration (%)

Microencapsulation 10.0–20.0

Sustained-release tablet coating 3.0–20.0

Tablet coating 1.0–3.0

Tablet granulation 1.0–3.0



pressure and hence protect the coating from fracture during compression. High-

viscosity grades of ethylcellulose are used in drug microencapsulation52.

Release of a drug from an ethylcellulose microcapsule is a function of the

microcapsule wall thickness and surface area.

In tablet formulations, ethyl cellulose may additionally be employed as a binder, the

ethyl cellulose being blended dry or wet-granulated with a solvent such as ethanol

(95%). Ethylcellulose produces hard tablets with low friability, although they may

demonstrate poor dissolution.

Ethylcellulose has also been used as an agent for delivering therapeutic agents from

oral (e.g. dental) appliances.

In topical formulations, ethylcellulose is used as a thickening agent in creams, lotions,

or gels, provided an appropriate solvent is used. Ethylcellulose has been studied as a

stabilizer for emulsions. Ethylcellulose is additionally used in cosmetics and food

products53.

8. Description

Ethylcellulose is a tasteless, free-flowing, white to light tan-colored powder.

9. Typical Properties


Glass transition temperature: 129–133°C 54

Moisture content: Ethylcellulose absorbs very little water from humid air or during

immersion, and that small amount evaporates readily55.

Solubility: Ethylcellulose is practically insoluble in glycerin, propylene glycol, and

water. Ethylcellulose that contains less than 46.5% of ethoxyl groups is freely soluble

in chloroform, methyl acetate, and tetrahydrofuran, and in mixtures of aromatic

hydrocarbons with ethanol (95%). Ethylcellulose that contains not less than 46.5% of



ethoxyl groups is freely soluble in chloroform, ethanol (95%), ethyl acetate, methanol,

and toluene.

Specific gravity: 1.12–1.15 g/cm3

Viscosity: The viscosity of ethylcellulose is measured typically at 25°C using 5% w/v

ethylcellulose dissolved in a solvent blend of 80% toluene : 20% ethanol (w/w).

Grades of ethylcellulose with various viscosities are commercially available; (table

1.2). They may be used to produce 5% w/v solutions in organic solvent blends with

viscosities nominally ranging from 7 to 100 mPa s (7–100 cp). Specific ethylcellulose

grades, or blends of different grades, may be used to obtain solutions of a desired

viscosity. Solutions of higher viscosity tend to be composed of longer polymer chains

and produce strong and durable films.

Table 3.4: Summary of ethylcellulose grades, suppliers, viscosity, and particle size

Grade Supplier Solution viscosity (mPa s)

Mean particle size (µm)

Ethocel Std 4 Premium Dow Chemical 3.0–5.5 — N-7 Aqualon 5.6–8.0 — Ethocel Std 7FP Premium Dow Chemical 6.0–8.0 5.0–15.0 Ethocel Std 7 Premium Dow Chemical 6.0–8.0 310.0 T-10 Aqualon 8.0–11.0 — N-10 Aqualon 8.0–11.0 — Ethocel Std 10FP Premium Dow Chemical 9.0–11.0 3.0–15.0 Ethocel Std 10P Premium Dow Chemical 9.0–11.0 375.0 N-14 Aqualon 12.0–16.0 — Ethocel Std 20P Premium Dow Chemical 18.0–22.0 — N-22 Aqualon 18.0–24.0 — Ethocel Std 45P Premium Dow Chemical 41.0–49.0 — N-50 Aqualon 40.0–52.0 — N-100 Aqualon 80.0–105.0 — Ethocel Std 100FP Premium Dow Chemical 90.0–110.0 30.0–60.0 Ethocel Std 100P Premium Dow Chemical 90.0–110.0 465.0

The viscosity of an ethylcellulose solution increases with an increase in ethylcellulose

concentration; e.g. the viscosity of a 5% w/v solution of Ethocel Standard 4 Premium

is 4 mPa s (4 cP) and of a 25% w/v solution of the same ethylcellulose grade is

850 mPa s (850 cP). Solutions with a lower viscosity may be obtained by



incorporating a higher percentage (30–40%) of a low-molecular-weight aliphatic

alcohol such as ethanol, butanol, propan-2-ol, or n-butanol with toluene. The viscosity

of such solutions depends almost entirely on the alcohol content and is independent of

toluene.

In addition, nonpharmaceutical grades of ethylcellulose that differ in their ethoxyl

content and degree of polymerization are available.


Ethylcellulose is a stable, slightly hygroscopic material. It is chemically resistant to

alkalis, both dilute and concentrated, and to salt solutions, although it is more

sensitive to acidic materials than are cellulose esters.

Ethylcellulose is subject to oxidative degradation in the presence of sunlight or UV

light at elevated temperatures. This may be prevented by the use of antioxidant and

chemical additives that absorb light in the 230–340 nm range.

Ethylcellulose should be stored at a temperature not exceeding 32°C (90°F) in a dry

area away from all sources of heat. It should not be stored next to peroxides or other

oxidizing agents.


Incompatible with paraffin wax and microcrystalline wax.



3.2.3 Polyethylene Oxide


USPNF: Polyethylene oxide

2. Synonyms

Polyox; polyoxirane; polyoxyethylene


Polyethylene oxide [25322-68-3]


Table 3.5: Number of repeat units and molecular weight as a function of polymer grade for polyethylene oxide.

Polyox grade Approximate number of repeating units

Approximate molecular weight

WSR N-10 2 275 100 000 WSR N-80 4 500 200 000 WSR N-750 6 800 300 000 WSR N-3000 9 100 400 000 WSR 205 14 000 600 000 WSR 1105 20 000 900 000 WSR N-12K 23 000 1 000 000 WSR N-60K 45 000 2 000 000 WSR 301 90 000 4 000 000 WSR Coagulant 114 000 5 000 000 WSR 303 159 000 7 000 000


The USPNF 23 describes polyethylene oxide as a nonionic homopolymer of ethylene

oxide, represented by the formula (CH2CH2O)n, where n represents the average

number of oxyethylene groups. It may contain up to 3% of silicon dioxide.


Mucoadhesive; tablet binder; thickening agent.




Polyethylene oxide can be used as a tablet binder at concentrations of 5–85%. The

higher molecular weight grades provide delayed drug release via the hydrophilic

matrix approach.

The relationship between swelling capacity and molecular weight is a good guide

when selecting products for use in immediate- or sustained-release matrix

formulations.

Polyethylene oxide has been shown to be an excellent mucoadhesive polymer56. Low

levels of polyethylene oxide are effective thickeners, although alcohol is usually

added to water based formulations to provide improved viscosity stability.

8. Description

White to off-white, free-flowing powder. Slight ammoniacal odor.

9. Typical Properties

Angle of repose: 340


Melting point: 65–700C

Moisture content: <1%

Solubility: Polyethylene oxide is soluble in water and a number of common organic

solvents such as acetonitrile, chloroform, and methylene chloride. It is insoluble in

aliphatic hydrocarbons, ethylene glycol, and most alcohols57.


Store in tightly sealed containers in a cool, dry place. Avoid exposure to high

temperatures since this can result in reduction in viscosity.

Chapter -3 IInnttrroodduuccttiioonn ttoo EExxcciippiieennttss


3.3.1 Magnesium stearate58

1. Non- proprietary Name:

NF: Magnesium Stearate

BP: Magnesium Stearate

2. Synonyms:

Metallic stearic, Magnesium salt.

3. Functional category:

Tablet and capsule lubricant

4. Chemical Names:

Octadecanoic acid; Magnesium salt; magnesium Stearate.

5. Structurla Formula:

6. Emperical Formula:

C36H70MgO4

7. Molecular Weight:

591.3

8. Description:

It is a fine, white, precipitated, or milled, impalpabale powder of low bulk density,

having a faint characteristic odour and taste. The powder is greasy to touch and

readily adheres to the skin.



9. Typical properties:

Solubility

Practically insoluble in ethanol, ethanol(95%), ether and water, slightly soluble in

benzene and warm ethanol(95%)

Stability and storage conditions:

Stable, non-self polymerizable. Store in a cool, dry place in a well closed container.

Incompatibilities:

Incompatible with strong acids, alkalies, iron salts and with strong oxidizing material.

10. Applications in Pharmaceuticals Formulation or Technology:

Tablet and capsule lubricant, glidant and antiadherent in the concentration range of

0.25-2.0%.



3.3.2 Povidone58

1. Nonproprietary Names:

BP: Povidone

JP: Povidone

PhEur: Povidonum

USP: Povidone

2. Synonyms:

Kollidon; Plasdone

3. Chemical Name:

1-Ethenyl-2-pyrrolidinone homopolymer

4. Empirical Formula:

(C6H9NO) n

5. Molecular Weight:

50, 000

6. Structural Formula:

7. Functional Category:

Disintegrant; dissolution aid; suspending agent; tablet binder

8. Description:

Povidone occurs as a fine, white to creamy-white colored, odorless or almost

odorless, hygroscopic powder. Povidones with K-values equal to or lower than 30 are

manufactured by Spray-drying and occur as spheres.



9. Method of Manufacture:

Povidone is manufactured by the Reppe process. Acetylene and formaldehyde are

reacted in the presence of a highly active copper acetylide catalyst to form butynediol,

which is hydrogenated to butanediol and then cyclodehydrogenated to form

butyrolactone. Pyrrolidone is produced by reacting butyrolactone with ammonia. This

is followed by a vinylation reaction in which pyrrolidone and acetylene are reacted

under pressure. The monomer, vinylpyrrolidone, is then polymerized in the presence

of a combination of catalysts to produce povidone.

10. Typical Properties:

Density: 1.180 g/cm 3

Melting point: Softens at 150°C.

Solubility: Freely soluble in acids, chloroform, ethanol (95%), ketones, methanol, and

water; practically insoluble in ether, hydrocarbons, and mineral oil.

11. Incompatibilities:

Povidone is compatible in solution with a wide range of inorganic salts, natural and

synthetic resins, and other chemicals. It forms molecular adducts in solution with

sulfathiazole, sodium salicylate, salicylic acid, phenobarbital, tannin, and other

compounds.

12. Stability and Storage Conditions:

Povidone darkens to some extent on heating at 150°C, with a reduction in aqueous

solubility. It is stable to a short cycle of heat exposure around 110–130°C; steam

sterilization of an aqueous solution does not alter its properties. Aqueous solutions are

susceptible to mold growth and consequently require the addition of suitable



preservatives. Povidone may be stored under ordinary conditions without undergoing

decomposition or degradation. However, since the powder is hygroscopic, it should be

stored in an airtight container in a cool, dry place.

13. Application in Pharmaceutical Formulation and Technology:

Although povidone is used in a variety of pharmaceutical formulations, it is primarily

used in solid-dosage forms. In tableting, povidone solutions are used as binders in

wet-granulation processes. Povidone is also added to powder blends in the dry form

and granulated in situ by the addition of water, alcohol, or hydroalcoholic solutions.

Povidone is used as a solubilizer in oral and parenteral formulations and has been

shown to enhance dissolution of poorly soluble drugs from solid-dosage forms.

Povidone solutions may also be used as coating agents.



3.3.3 Stearic acid58


BP: Stearic acid

JP: Stearic acid

PhEur: Acidum stearicum

USPNF: Stearic acid

2. Synonyms

Cetylacetic acid; Crodacid; E570; Edenor; Emersol; Hystrene; Industrene; Kortacid

1895; Pearl Steric; Pristerene; stereophonic acid; Tegostearic.


Octadecanoic acid [57-11-4]

4. Empirical Formula C18H36O2 5. Molecular Weight

284.47 (for pure material)


7. Functional Category Emulsifying agent; solubilizing agent; tablet and capsule lubricant. 8. Description

Stearic acid is a hard, white or faintly yellow-colored, somewhat glossy, crystalline

solid or a white or yellowish white powder. It has a slight odor and taste suggesting

tallow.



9. Typical properties :

Saponification value: 200–220

Solubility: freely soluble in benzene, carbon tetrachloride, chloroform, and ether;

soluble in ethanol (95%), hexane, and propylene glycol; practically insoluble in water.


Stearic acid is a stable material; an antioxidant may also be added to it; see Section

13. The bulk material should be stored in a well-closed container in a cool, dry place.


Stearic acid is incompatible with most metal hydroxides and may be incompatible

with oxidizing agents. Insoluble stearates are formed with many metals; ointment

bases made with stearic acid may show evidence of drying out or lumpiness due to

such a reaction when compounded with zinc or calcium salts. A number of differential

scanning calorimetry studies have investigated the compatibility of stearic acid with

drugs. Although such laboratory studies have suggested incompatibilities, e.g. with

naproxen, they may not necessarily be applicable to formulated products. Stearic acid

has been reported to cause pitting in the film coating of tablets coated using an

aqueous film-coating technique; the pitting was found to be a function of the melting

point of the stearic acid.

12. Applications in Pharmaceutical Formulation or Technology:

Stearic acid is widely used in oral and topical pharmaceutical formulations. It is

mainly used in oral formulations as a tablet and capsule lubricant, although it may

also be used as a binderor in combination with shellac as a tablet coating. It has also

been suggested that stearic acid may be used as a sustained-release drug carrier.



In topical formulations, stearic acid is used as an emulsifying and solubilizing agent.

When partially neutralized with alkalis or triethanolamine, stearic acid is used in the

preparation of creams.

Stearic acid is also widely used in cosmetics and food products.



3.3.4 Microcrystalline Cellulose58

1. Synonyms:

Avicel, cellulose gel, crystalline cellulose, E460, Emocel, Fibrocel, Tabulose,

Vivacel.

2. Chemical Name and CAS Registry Number:

Cellulose [9004-34-6]

3. Empirical Formula and Molecular Weight:

(C6H10O5)n 36 000

4. Structural Formula:

5. Functional Category:

Tablet and Capsule diluent, suspending agent, adsorbent, tablet disintegrant.

6. Applications:

As a diluent in tablets (wet granulation and direct compression) and capsule

formulation. In addition to its use as a diluent, it also has some lubricant and

disintegrant property.

7. Description:

White-colored, odorless, tasteless crystalline powder composed of porous particles.

Available in different particle size grades which have different properties and

applications.



8. Solubility:

Slightly soluble in 5 % w/v NaOH solution, practically insoluble in water, dilute acids

and most organic solvents.

9. Stability:

It is a stable, though hygroscopic material.

10. Storage conditions:

The bulk material should be stored in a well-closed container in a cool, dry, place.

11. Incompatibilities:

Incompatible with strong oxidizing agents.

12. Safety:

It is generally regarded as a nontoxic and nonirritant material.

Chapter -4 RReevviieeww ooff LLiitteerraattuurree


4.1 Review of Work Done using HPMC

Khanvilkar et al59 investigated the effects of three factors: 1. use of a mixture of two

different grades of hydroxypropyl methylcellulose (HPMC), 2. apparent viscosity, and

3. tablet hardness on drug release profiles of extended-release matrix tablets. They

used 23 full factorial design to study various combinations of the three factors using

eight experiments conducted in a randomized order. They reported that dissolution

rates were independent of tablet hardness for all formulations within the range of 3.3

– 6 Kp. Although significantly shorter lag times were observed for the tablets

formulated with low- and high-viscosity HPMC mixtures in comparison to those

containing a single grade of HPMC. They have concluded that lot-to-lot variability in

apparent viscosity of HPMC should not be a concern in achieving similar dissolution

profiles. Results also indicated that an HPMC mixture of two viscosity grades could

be substituted for another HPMC grade if the apparent viscosity was comparable.

They also concluded that the drug release from an HPMC matrix tablet prepared by

dry blend and direct compression approach was independent of tablet hardness, and

depend mostly on the viscosity of the gel layer formed.

Suvarna et al60 had formulated ranitidine hydrochloride sustained release tablets with

three different viscosity grades of HPMC viz. K 100M, K 15M and K4M, as release

retardants. Drug and matrix materials were blended for direct compression and

granulated using absolute ethanol for wet granulation. For all the three polymers, it

was observed that as the polymer concentration was increased, drug release was

retarded for longer period of time and percentage as well was more irrespective of

granulation method used. However, drug:polymer ratio and other excipients was kept

constant. The granulation method had a significant effect on the dissolution profile.

The dissolution rate was higher for wet granulated tablets as compared to direct



compression. By wet granulation, drug:polymer ratio of 3:2.5 showed t90 and t50 of

12.5 hr and 3.7 hour respectively. There was greater release retardation in initial

period with direct compression method as compared to wet granulation method.

Higher viscosity grades of polymer retarded the drug release for a longer period of

time for both the methods. In conclusion, direct compression method resulted in

prolonged and consistent drug release with reduced processing steps at lower polymer

concentration, as compared to wet granulation process for preparation of controlled

release ranitidine hydrochloride tablets.

Ayhan et al61 studied the effect of formulation variables on release profile of

diclofenac sodium from hydroxypropylmethyl cellulose and chitosan matrix tables.

Diclofenac sodium tablets were prepared by wet granulation and direct compression

method and different ratios of HPMC and chitosan were used. They reported that 20%

HPMC contained sustained release formulation with direct (dry) compression method

was the optimum formulation due to its better targeting profile in terms of release.

This formulation exhibited the best-fitted formulation into the zero order kinetics.

However, in developing sustained release formulations containing diclofenac sodium,

it has been shown that chitosan provided a better result in preparation of sustained

release formulation prepared by wet granulation method. In addition, better results

have been seen with 15%, 20%, and 25% chitosan in these formulations.

Yaw-Bin Huang et al62 had formulated the pH-dependent release of nicardipine

hydrochloride extended release tablets. Simultaneously combination two hydrophilic

polymers: Hydroxypropylmethylcellulose and sodium alginate as retardant and avicel

as additive were used to formulate tablets. The constrained mixture experimental

design and the response surface methodology (RSM) and multiple response

optimizations utilizing the polynomial equation were used to search for the optimal



formulation. The combination effect of HPMC and sodium alginate was the most

influencing factor on the drug release from extended-release matrix tablets. The

release kinetic of drug from HPMC matrix tablets with alginate followed the zero-

order release pattern. The mechanism of drug release from extended-release matrix

tablets was dependent on the added amount of alginate.

Shoufeng et al63 illustrated statistical experimental design and data analysis using

response surface methodology. A central composite Box-Wilson design for the

controlled release of calcium was used with three formulation variables like HPMC

loading, citric acid loading and magnesium stearate loading. Sustained release

delivery of calcium with increased bioavailability was achieved.

Kavanagh et al64 checked the effect of dissolution medium variables, such as

medium composition, ionic strength and agitation rate, on the swelling and erosion of

Hypromellose (hydroxypropylmethylcellulose, HPMC) matrices of different

molecular weights. Swelling and erosion of HPMC polymers were determined by

measuring the wet and subsequent dry weights of matrices. The extent of swelling

increased with increasing molecular weight, and decreased with increasing agitation

rate. The erosion rate was seen to increase with decrease in polymer molecular

weight, with a decrease in ionic strength and with increasing agitation rate.

Farouk et al65 developed a programmable controlled release drug delivery system.

The device in the form of a non-digestible oral capsule was designed to utilize an

automatically operated geometric obstruction that kept the device floating. Different

viscosity grades of HPMC were employed as model eroding matrices. Zero-order

release could be maintained for periods ranging between 5 to 20 days before the

geometric obstruction was triggered off. The rate of drug release was dependant on

the nature, viscosity and ratio of polymer employed.



Siepmann et al66 had developed mathematical model to predict the release kinetics of

water-soluble drugs from HPMC matrices. The effects of the dimensions and aspect

ratio (radius:height) of the tablets on the drug release rate were evaluated. Drug

release rates were overestimated at the beginning and underestimated at the end of the

process. It has been conclude that the mathematical model generated was capable of

predicting the drug release kinetics from hydrophilic polymer matrices of various

shapes and sizes, in different release media, and for different drugs. It can thus be

used to calculate the required aspect ratio and dimensions of new controlled drug

delivery systems to achieve desired release profiles, hence facilitating the

development of new products. The effect of the initial matrix radius on release was

found to be more pronounced than the effect of the initial thickness.

Fua et al67 studied the effect of physicochemical properties of drug and polymer

concentration on drug release from HPMC matrices. They conclude that the release of

ranitidine hydrochloride, diltiazem hydrochloride, isoniazid, ribavirin, theophyline,

tinidazole, propylthiouracil, and sulfamethoxazole from HPMC matrices having

different HPMC concentration (16.5–55% w/w) follow the power law. Increasing

HPMC concentration decreased kinetic constant in Peppas’ equation, so decreased

release rate of a drug from HPMC matrices. The benefit of the novel model was to

predict Mt/M∞ values of the drug from formulation and its physicochemical

properties. The model was applicable to the HPMC matrices of different polymer

levels and different drugs including soluble drugs and slightly soluble drugs.

Gubbins et al68 reported that the inclusion of casein modified the release of

diclofenac from hydroxypropylmethycellulose (HPMC, Methocel grades K100LV

and K15M) based matrices. The presence of casein in diclofenac sodium - K100LV

matrices increased the drug release rate and rendered the release profile more linear.



Incorporation of sodium caseinate in HPMC-drug system retarded the disintegrating

tendency by enhancing the initial gel forming ability of these systems. They also

conclude that the presence of casein decreased the extent of medium uptake (swelling)

of the matrices and accelerated the rate of erosion, while not altering the dissolution

medium infiltration rate.

Williams et al69 have investigated the influence of Hydroxypropyl methylcellulose

(HPMC) molecular weight on pharmacokinetic and pharmacodynamic parameters of

controlled release formulations containing alprazolam. They used HPMC K4MP or

HPMC K100LVP in formulation. They have reported that the tablet formulations

containing either HPMC K4MP or HPMC K100LVP had similar dissolution profiles,

and the dissolution profiles did not change through 6 months at 40oC/75% RH or 12

months at 25oC/65% relative humidity. They also reported that the area under the

plasma concentration-time curve, time to peak concentration and peak plasma

concentration were not significantly different between the two tablet formulations

investigated in either the fed or fasted states. They also conclude that types and

concentrations of HPMC could not influence in vitro or in vivo performance of

controlled release tablets containing lipophilic alprazolam.

Wan et al70 was studied the action of hydroxypropylmethylcellulose (HPMC) on

aqueous penetration into matrices containing HPMC of varying viscosity and

concentration. They reported that incorporation of HPMC into matrices improved

wetting and enhanced water uptake into the matrices. As the molecular weight and

concentration of HPMC increase the water uptake by system was greater. They

concluded that the action of HPMC on aqueous uptake was depended on the

molecular weight of HPMC.



Tahara et al71 have studied the mechanisms of sustained release from tablet matrices

prepared with hydroxypropyl methylcellulose (HPMC) 2910. The two important

parameters for the release of drug from tablet matrices are the infiltration rate of

medium into the matrix, and the erosion rate of the matrix system. They reported that

the infiltration rate of medium into the matrix could be controlled by changing the

interspace volume of the matrix by the use of higher levels of materials such as

lactose, which could quickly rinse out of matrix system. The larger interspace

volumes produced by the higher ratio resulted in more rapid release of the drug. They

also reported that the viscosity of HPMC polymers was related to the molecular

weight and had a large influence on the erosion rate of matrix tablet. Use of a low

viscous grade HPMC polymer was desirable for poorly water soluble drugs because

the release rate of poorly soluble drug can be controlled by the rate of tablet erosion.

The tablet erosion rate can also be adjusted by the choice of HPMC polymer viscosity

or by mixing HPMC of different viscosity grades.

Vazquez et al72 used hydroxypropylmethylcellulose {Methocel K100LV (an HPMC

with nominal viscosity of 100 cP) and Methocel K100M (HPMC with nominal

viscosity of 100000 cP)} mixtures as gelling agents in matrix tablets for hydrosoluble

drugs and to investigate relationship between gelling agent viscosity and the kinetics

of drug release from such tablets. Atenolol tablets were formulated with 40% or 80%

gelling agent (i.e. K100LV, K100M or one of the K100LV:K100M mixtures). From

Higuchi's model and the equation of Korsmeyer, drug release was found to be

diffusion limited. They reported that a negative relationship was observed between the

Higuchi constant for each tablet type and the apparent viscosity of the corresponding

gelling agent in aqueous dispersion.



Sarvanan et al73 have formulated the hydroxypropyl methylcellulose based

cephalexin extended release tablet, which could release the drug for six hours in

predetermined rate. Cephalexin extended release tablets were prepared by changing

various physical and chemical parameters (hardness and granulation), in order to get

required theoretical release profile. They reported that a higher amount of HPMC in

tablet composition resulted in reduced drug release. Addition of MCCP resulted in

faster drug release. Tablets prepared by dry granulation released the drug slowly than

the same prepared with a wet granulation technique. Addition of wetting agent in the

tablets prepared with dry granulation technique showed slower release. An increase in

tablet hardness resulted in faster drug release. They also studied the effect of storage

on in vitro release and physicochemical properties for successful batch. Results were

found to be within acceptable limit.

Bravo et al74 have formulated the uncoated HPMC matrix tablets and evaluated the

relationship and influence of different content levels of microcrystalline cellulose

(MCC), starch and lactose in order to achieve a zero-order release of diclofenac

sodium. They reported that release of diclofenac sodium was influenced by the

presence of MCC and by the different concentrations of starch and lactose. Drug

release kinetics from these formulations corresponded best to the zero-order kinetics.

Compared to conventional tablets, release of the model drug from these HPMC matrix

tablets was prolonged. As a result, an oral controlled release dosage form to avoid the

gastrointestinal adverse effects was achieved.

María Elena et al75 have formulated matrix tablets of metronidazole with

hydroxypropyl methylcellulose prepared by granulation with water. They studied on

the influence of the HPMC viscosity grade and particle size on the release profile of

metronidazole. They evaluated the release profile of metronidazole at viscosity grades



of 15, 860, 5000, 20 000 and 30 000 cps and at particle sizes of 163, 213, 335 and 505

µm. They observed a linear relationship between the release rate and the cube of the

diameter of the HPMC particles. An increasing burst effect occurred with increasing

viscosity grades and increasing particle sizes of HPMC.

Sharma et al76 have used Methocel K15M as a bioadhesive polymer. They evaluated

its adhesion and bioadhesion characteristics by shear stress measurement and

detachment force measurement methods, respectively. They have reported the

maximum adhesion was found between pH 5 and pH 6 and maximum adhesion

strength was found in the duodenal portion of the intestine. They also reported that the

release of chlorpheniramine maleate (1:1 and 1:1.5) and with diclofenac sodium (1:1,

1:1.2, and 1:14) followed initial first-order release behavior and then zero-order

release behavior.



4.2. Review of Work Done using PEO

Yang et al77 developed a mathematical model to describe the transport phenomena of

a water-soluble small molecular drug (caffeine) from highly swellable and dissoluble

polyethylene oxide (PEO) cylindrical tablets. It was found Drug release from PEO

matrices involves two mechanisms, diffusion through swelling polymer and release

via polymer dissolution. Thus the swelling and dissolution behaviors of tablets made

of pure polymer play important roles in the overall drug release process. It is found

that swelling is the dominant factor in drug release kinetics for higher molecular

weight of PEO (Mw=8x106) while both swelling and dissolution are important to

caffeine release for lower molecular weight PEO (Mw=4x106).

Zelko et al78 studied the effect of storage and active ingredient properties on the drug

release profile of poly(ethylene oxide) matrix tablets. Study suggests that both the

hydration properties of the active ingredient and the molecular weight of the polymer

influence the effect of physical ageing of poly(ethyle oxide) on the drug release of

matrix tablets.

Lambov et al79 performed the study of Verapamil hydrochloride release from

compressed hydrophilic Polyox-Wsr tablets. It was found that mol. wt. of polymer

affects significantly the drug release – the higher the mol. wt., the smaller the amount

of the drug released. The main factors determining release rate were found to be mol.

wt. of polymer in the matrix and drug conc. (to a lesser extent).

Petrovic et al80 conducted the water uptake and polymer dissolution studies of pure

PEO matrices. Diffusion coefficient of water was found to be D1=3442×10−5 cm2/s

and concentration dependent constant β1 was 0.74. Dissolution rate constant Kdiss,

polymers mass loss rate normalized to the actual surface of the system, was found to

be 1.84×10−6 g/cm2s. From the study it was found that developing mathematical



models which give complex insight into drug release is crucial for adequate

characterization of sustained release dosage forms. It enables elucidation of the

precise drug release mechanism and prediction of behavior of different drug loadings

of matrices.

Conte et al81 compared the performance of PEO and HPMC polymers when

employed in the Geomatrix® technology, a versatile, well-known method to achieve

extended release of drugs at a constant rate. Four core formulations were prepared,

containing a soluble drug (diltiazem) and, alternatively, PEO or HPMC of two

different viscosity grades. Dissolution tests performed on the four different core

formulations showed that the diltiazem release rate from the two matrices containing

HPMC is slower compared to the release rate of PEO matrices. HPMCs tablets

showed a slow and continuous volume increase, up to four-fold (Methocel K4M) or

six-fold (Methocel K100M) the volume of the dry tablet, after 20 h in distilled water.

On the other hand, tablets made of pure PEOs swelled rapidly (up to six-fold or two-

fold in the case of Polyox WSR 303 or Polyox NF-60K tablets, respectively, after 8

h), but these polymers formed a weaker gel, which tend to be eroded much more

quickly and the tablet volume decreases progressively. It was concluded that HPMC

controls the release rate better as compared to PEO.

Chapter -5 MMaatteerriiaallss && MMeetthhooddoollooggyy--11


Table 5.1: Materials Used In the Present Investigation:

Sr. No. Name of materials Name of company

1 Drug Zydus Cadila Ltd., Ahmedabad.

2 Hydroxy Propyl Methyl

Cellulose S. D. Fine Chemicals Ltd., Mumbai, India

3 Polyethylene Oxide Colorcon India Ltd, Goa.

4 Polyvinyl Pyrrolidone (PVP-

K30)

S. D. Fine Chemicals Ltd., Mumbai,

India.

5 Microcrystalline cellulose S.D. Fine Chem. Ltd, Mumbai, India.

6 Butyrated Hydroxy Toluene

(BHT) S.D. Fine Chem. Ltd, Mumbai, India.

7 Stearic acid S.D. Fine Chem. Ltd, Mumbai, India.

8 Magnesium Stearate S.D. Fine Chem. Ltd, Mumbai, India.

9 Ethyl Cellulose Colorcon India Ltd, Goa.

10 Polyethylene Glycol S.D. Fine Chem. Ltd, Mumbai, India.

11 Isopropyl Alcohol Finar Chemicals Ltd., Ahmedabad

12 Dichloromethane Finar Chemicals Ltd., Ahmedabad

13 Hydrochloride acid Finar Chemicals Ltd., Ahmedabad

14 Sodium Hydroxide S.D. Fine Chem. Ltd, Mumbai, India.

15 Potassium Dihydrogen

Orthophosphate S.D. Fine Chem. Ltd, Mumbai, India.



Table 5.2: Instruments Used In Present Investigation:

Sr. No. Instrument Company

1 Sartorious Electronic

Balance Model CP 224 S, Labtronic

2 Tablet machine Rimek minipress-11 MT, Karnavati

Engineearing Ltd. , Ahmedabad, India

3 pH meter Systronics µ pH system 361, Ahmedabad,

India

4 UV Spectrometer UV-1700 Double beam Spectrophotometer,

Shimadzu (Kyoto, Japan.)

5 Dissolution tester Dissolution Test Apparatus-TDT-06T

(Electrolab, Mumbai, India

6 Disintegration tester Disintegration test apparatus, Electrolab,

Mumbai, India.

7 Roche Friabilator Camp-bell Electronics, Mumbai, India

8 Hardness Tester Validated dial type, Model: 1101, Shivani

Scientific Industries Pvt. Ltd., Mumbai

9 Differential Scanning

Calorimeter Shimadzu 60 with TDA trend line software

10 Coating Machine Avon engineering works

11 Moisture Analyzer Mettler Toledo, Switzerland.



5. Formulation and Development

5.1 Characterization of Drug:

1. Description: White to yellow powder.

2. Identification:

By Infrared Spectroscopy: The Infra Red absorption spectrum of the finely

ground sample in KBr dispersion compressed into a disc should exhibit maxima

only at the same wavelengths as that of a similar preparation of working standard.

By HPLC: The retention time of the principal peak in the sample preparation for

assay should corresponds with the retention time of the principal peak in the

standard preparation for assay82.

3. Related Substances :

Unknown Impurities: 0.08%w/w (Not more than 0.3%)

Total Impurities: 0.21% (Not more than 1.0%)

4. Assay on Anhydrous bases: 99.7% (98% - 102%w/w)

5. Loss of Drying: 0.03% (Not more than 0.5%)

6. Heavy Metals: Not more than 0.002% w/w

7. Sulphated ash: Not more than 0.2% w/w

8. Heavy Metals: Not more than 0.002% w/w

9. Melting Point: 189-203°C



5.2 Selection and justification of Excipients28

Diluents: In view of the low or medium dose of drug, it is essential to add bulking

agents or diluents to increase the weight of the tablet. Microcrystalline Cellulose

(Avicel) was selected as diluent. Microcrystalline cellulose gives better flowability;

hence it was used as diluent in this ER preparation.

Matrix-forming Polymers: HPMC which is most widely used matrix-forming

polymer because of its excellent compatibility, multifunctional property and cost

effective. It is available in different grades depending upon its viscosity. Detail

specification was given in table 3.2. PEO is the polymer used on the wide

concentration scale as a tablet binder and thickening agent. It is available in different

grades depending upon number of repeating units.

Lubricants: Magnesium Stearate and Stearic acid are widely used as lubricating

agent.

Table 5.3: Composition of Tablet formulation

Ingredients Qty. per tablet Function Drug 1.5 mg Drug

Hydroxypropylmethylcellulose * Polymer

Polyethylene Oxide * Polymer

Microcrystalline Cellulose * Diluent

Polyvinyl Pyrolidone 5 % Binder

BHT * Antioxidant

Stearic Acid * Lubricant

Magnesium Stearate * Lubricant

Iron Oxide Red 1 mg Color

Total 130 mg

* Quantity in mg for one tablet as per formula



5.3 Preformulation Study83-87

Preformulation can be defined as investigation of physical and chemical properties of

drug substance alone and when combined with excipients.

Preformulation studies are the first step in the rational development of dosage form of

a drug substance. The objectives of preformulation studies are to develop a portfolio

of information about the drug substance, so that this information is useful to develop

formulation.

Preformulation investigations are designed to identify those physicochemical

properties and excipients that may influence the formulation design, method of

manufacture, and pharmacokinetic-biopharmaceutical properties of the resulting

product. Followings studies performed for in the preformulation study.

5.3.1 Description

White to off-white colored crystalline powder.

5.3.2 Solubility:

Solubility of drug was checked in different solvents such as water, 0.1 N HCl,

Methanol and buffers such as pH 4.5 Acetate buffer and pH 6.8 Acetate buffer.

5.3.3 Bulk Density:

a) Loose Bulk Density: Weighed accurately 5 g of drug (M), which was previously

passed through 20 # sieve and was transferred in 50 ml graduated cylinder. Powder

was carefully leveled without compacting, and read the unsettled apparent volume

(V0). Apparent bulk density in gm/ml was calculated by the following formula:

Bulk density = Weight of powder / Bulk volume …………….. (3)



b) Tapped bulk density: Weighed accurately 5 g of drug, which was previously

passed through 20 # sieve was transferred in 50 ml graduated cylinder. Then the

cylinder containing the sample was mechanically tapped by raising the cylinder and

allowing it to drop under its own weight using mechanically tapped density tester that

provides a fixed drop of 14± 2 mm at a nominal rate of 300 drops per minute.

Cylinder was tapped for 500 times initially and then measured the tapped volume (V1)

to the nearest graduated units, taping was repeated for an additional 750 times and

tapped volume (V2) was measured to the nearest graduated units. If the difference

between the two volumes is less than 2% then final the volume (V2) should be taken.

Calculate the tapped bulk density in gm/ml by the following formula:

Tapped Density = Weight of powder / Tapped volume ………….. (4)

5.3.4 Carr’s Index

The Compressibility Index of the powder blend was determined by Carr’s

compressibility index. It is a simple test to evaluate the BD and TD of a powder and

the rate at which it packed down. The formula for Carr’s Index is as below:

Carr’s Index (%) = [(TD-BD) x100]/TD ………….. (5)

5.3.5 Hausner’s Ratio

The Hausner’s ratio is a number that is correlated to the flowability of a powder or

granular material.

Hausner’s Ratio = TD / BD ……………. (6)



Table 5.4: Effect of Carr’s Index and Hausner’s Ratio on flow property

Carr’s Index (%) Flow Character Hausner’s Ratio

< 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

>38 Very, very poor >1.60

5.3.6 Angle of repose

The angle of repose of API powder was determined by the funnel method. The

accurately weighed powder blend was taken in the funnel. The height of the funnel

was adjusted in such a way the tip of the funnel just touched the apex of the powder

blend. The powder blend was allowed to flow through the funnel freely on to the

surface. The diameter of the powder cone was measured and angle of repose was

calculated using the following equation.

tan = h/r …………….(7)

Where, h and r are the height and radius of the powder cone respectively.

Table 5.5: Effect of Angle of repose (ф) on Flow property

Angle of Repose (Ф) Type of Flow

< 20 Excellent

20-30 Good

30-34 Passable

>35 Very poor



5.3.7 Drug excipients compatibility study88

API and excipients were been thoroughly mixed in predetermined ratio given in

below table and passed through the 40# sieve. The blend was to be filled in

transparent glass vials and were closed with gray colored rubber stoppers and further

sealed with aluminum seal and charged in to stress condition at above condition.

Similarly API was also kept at all condition as for the samples. Samples were

withdrawn for analysis within two day of sampling date as per the compatibility study

plan. Physical observation was done at every week up to 1 month and DSC studies

were carried out to determine the compatibility of excipients with the drug.

Table 5.6: Drug excipients compatibility study

Drug + Excipient Ratio

25ºCº±2°C /

60%RH± 5 %

RH

40ºC±2°C /

75%RH± 5 %

RH

Drug 1 4 Weeks 4 Weeks

Drug: PEO 1:1 4 Weeks 4 Weeks

Drug : MCC 1:1 4 Weeks 4 Weeks

Drug : HPMC 1:1 4 Weeks 4 Weeks

Drug: Stearic Acid 1:0.25 4 Weeks 4 Weeks

Drug : Mg Stearate 1:0.25 4 Weeks 4 Weeks

Drug+ HPMC+ PEO+ MCC+

PVP+ Mg. Stearate+ Stearic

Acid

Proportional

Mixture 4 Weeks 4 Weeks



5.4 Analytical Method Development Calibration curve of Drug:

Calibration curve for Drug was taken in 0.1 N HCl and Phosphate buffer (pH 6.8)

Preparation of Reagents:

(i) 0.1 N Hydrochloric acid (pH = 1.2):89

8.5 ml of concentrated Hydrochloric acid was taken and added to 1000 ml of

water and measured the pH of solution.

(ii) 6.8 pH Phosphate buffer solution:

Weighed 27.22g of monobasic potassium phosphate and diluted up to 1000 ml

to get stock solution of monobasic potassium phosphate. Weighed 8g Sodium

hydroxide and diluted up to 1000ml to get 0.2M sodium hydroxide solution.

Then 50 ml of the monobasic potassium phosphate solution was taken from

stock solution in a 200-mL volumetric flask, 22.4 ml of sodium hydroxide

solution was added from stock solution of 0.2M sodium hydroxide solution,

and then water was added to make final volume.

(iii)Standard (Stock) solution:

Drug (10 mg) was dissolved in a 100 ml of buffer solution to obtain 100g/ml

stock solution. 0.3 ml of stock solution was diluted to 10 ml with buffer

solution to get 3g/ml solution. Then 0.6, 0.9, 1.2, 1.5, 1.8 ml solution was

taken from stock solution and diluted with buffer solution to get 6, 9, 12, 15,

18 g/ml concentration solution. Absorbance of each solution was measured at

275 nm using Shimadzu UV-1700 UV/Vis double beam spectrophotometer

and Dissolution Medium as reference standard. The standard curve was

generated for the entire range from 3 to18 mcg/ml.



5.5 API Equivalent Dose Calculation

Assay & LOD Compensation:

The dose was adjusted by compensating the LOD and assay of the API using the

following formula.

Drug Required = API Calculated * 100 * 100/ Assay * (100 – LOD)

5.6 In–Vitro Release study of Innovator and Targeted Release profile

Dissolution parameter:

Medium: 0.1N Hydrochloric acid, pH 6.8 Phosphate buffer solution

Volume: 900ml

Apparatus: USP-II (Paddle)

RPM: 50 rpm

Time point: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hrs.

Temperature: 37°C ± 0.5°C

5.7 In–Vitro Release study profile fixed

Table 5.7: Release profile fixed

Time (hrs) % drug release

2 hrs NMT 10 %

8 hrs 25-60 %

14 hrs NLT 70 %



5.8 Formulation of Preliminary Trials: 5.8.1 Trial batches with HPMC

5.8.1.1 Formula

Method of Preparation of ER Tablet

Method: ER Tablets were prepared by direct compression technique.

Sifting: Drug was passed through 40# sieve. HPMC was passed through 30# sieve.

All the other ingredients were passed through 40 # sieve accept Mg Stearate and Iron

Oxide Red. Mg Stearate was passed through 60# sieve and Iron oxide red was passed

through 100#.

Mixing & Lubrication: Drug & MCC were mixed in double cone blender for 10min.

at 18 RPM. Add polymer into above mixture and again mix for 10min. at 18 RPM.

Add Mg Stearate and Stearic Acid into above mixture and mixed it for 3min. at 18

RPM. Add Iron oxide red into above mixture and mixed for 3min. at 18 RPM.

Table 5.8: Formula of trial batches F001 to F004

Trial F001 F002 F003 F004

Ingredients %w/w %w/w %w/w %w/w

Drug 1.15% 1.15% 1.15% 1.15%

HPMC 25% 30% 35% 40%

MCC 67.04% 62.04% 57.04% 52.04%

PVP 5 % 5 % 5 % 5 %

BHT 0.05% 0.05 0.05 0.05

Stearic Acid 0.5 % 0.5 % 0.5 % 0.5 %

Magnesium Stearate 0.5 % 0.5 % 0.5 % 0.5 %

Iron oxide Red 0.76% 0.76% 0.76% 0.76%

Total 100.00 100.00 100.00 100.00

Tablet Weight 130.0 mg 130.0 mg 130.0 mg 130.0 mg



Compression: The prepared blend was compressed (8/32 diameter (6.35mm), flat

punches) using 8 station tablet compression machine (Cadmach, Ahmedabad, India).

Evaluation of Powder blend89

1. Blend Uniformity:

An accurately weighed amount of powdered drug blend (150 mg) was extracted with

0.1N HCl and the solution was filtered through 0.45-µ membrane. The absorbance

was measured at 275 nm after suitable dilution.

Other Evaluation parameters of powder blend were done as per the section 5.3.

Evaluation of Tablets

1. Appearance

Twenty tablets of each formulation were taken to check any discoloration or surface

ruffness in the tablet formulation.

2. Weight variation test

To study weight variation twenty tablets of the formulation were weighed using a

Mettler Toledo electronic balance and the test was performed according to the official

method.

3. Hardness

The hardness of five tablets was determined using the Benchsavertm Series type

hardness tester and the average values were calculated.

4. Thickness

The Thickness of the tablets was determined by using Digital vernier calipers. Five

tablets were used, and average values were calculated.



5. Friability

The friability of twenty tablets was measured by Roche friabilator for 4min at 25rpm

for 100 revolutions. Accurately weighed twenty tablets were placed into Roche

friabrilator for 100 revolutions than dedusted and weighed again.

100%0

0

W

WWFriability

6. Content Uniformity test

3 tablets from each formulation batches were extracted with 0.1 N HCl for 12 hrs and

the solution was filtered through 0.45-µ membrane. The absorbance was measured at

275 nm after suitable dilution.

7. In-Vitro Release study

Drug release studies were carried out using a USP type -II dissolution rate test

apparatus (Apparatus 2, 50 rpm, 37 °C) for 2 hr in 0.1 M HCl (900 ml) as the average

gastric emptying time is about 2 hr. Then the dissolution medium was replaced with

pH-6.8 phosphate buffer (900 ml) and tested for drug release up to complete drug

release. At the end of the time period 10 ml of the samples were taken and analyzed

for Drug content. A 10 ml Volume of fresh and filtered dissolution medium was

added to make the Volume after each sample withdrawal. Sample was analyzed using

UV spectrophotometer at 275 nm.



5.8.2 Trials with Polyethylene Oxide

5.8.2.1 Formula

Method of preparation of tablet was as per the section 5.8.1.

Evaluation of Powder blend

Evaluation parameters of powder blend were done as per the section 5.8.1.


Evaluation parameters of tablets were done as per the section 5.8.1.


Trial F005 F006 F007 F008

Ingredients %w/w %w/w %w/w %w/w

Drug 1.15% 1.15% 1.15% 1.15%

PEO 25% 30% 35% 40%

MCC 67.04% 62.04% 57.04% 52.04%

PVP 5 % 5 % 5 % 5 %

BHT 0.05% 0.05 0.05 0.05

Stearic Acid 0.5 % 0.5 % 0.5 % 0.5 %

Magnesium Stearate 0.5 % 0.5 % 0.5 % 0.5 %

Iron oxide Red 0.76% 0.76% 0.76% 0.76%

Total 100.00 100.00 100.00 100.00

Tablet Weight 130.0 mg 130.0 mg 130.0 mg 130.0 mg



5.8.3 Trials with combination of HPMC and PEO

5.8.3.1 Formula

Method of preparation of tablet was as per the section 5.8.1.






Trial F009 F010 F011

Ingredients %w/w %w/w %w/w

Drug 1.15% 1.15% 1.15%

HPMC 25% 25% 30%

PEO 20% 25% 25%

MCC 47.04% 42.04% 37.04%

PVP 5 % 5 % 5 %

BHT 0.05% 0.05 0.05

Stearic Acid 0.5 % 0.5 % 0.5 %

Magnesium Stearate 0.5 % 0.5 % 0.5 %

Iron oxide Red 0.76% 0.76% 0.76%

Total 100.00 100.00 100.00

Tablet Weight 130.0 mg 130.0 mg 130.0 mg



5.9 Formulation and Optimization of Sustained release matrix tablets

by using 32 full factorial designs90-92

It is desirable to develop an acceptable pharmaceutical formulation in shortest

possible time using minimum number of man-hours and raw materials. Traditionally

pharmaceutical formulations after developed by changing one variable at a time

approach. The method is time consuming in nature and requires a lot of imaginative

efforts. Moreover, it may be difficult to develop an ideal formulation using this

classical technique since the joint effects of independent variables are not considered.

It is therefore very essential to understand the complexity of pharmaceutical

formulations by using established statistical tools such as factorial design. In addition

to the art of formulation, the technique of factorial design is an effective method of

indicating the relative significance of a number of variables and their interactions.

A statistical model incorporating interactive and polynomial terms was used to

evaluate the responses. The number of experiments required for these studies is

dependent on the number of independent variables selected. The response (Yi) is

measured for each trial.

2222

2111211222110 XbXbXXbXbXbbY ……… (7)

Where Y is the dependent variable,

b0 is the arithmetic mean response of the nine runs and

bi is the estimated coefficient for the factor Xi.

The main effects (X1 and X2) represent the average result of changing one factor at a

time from its low to high value. The interaction terms (X1X2) show how the response

changes when two factors are simultaneously changed.



A 32 randomized full factorial design was utilized in the present study. In this design

two factors were evaluated, each at three levels, and experimental trials were carried

out at all nine possible combinations. The design layout and coded value of

independent factor is shown in table 5.22 respectively. The factors were selected

based on preliminary study. The concentration of HPMC (X1) and concentration of

PEO (X2) were selected as independent variables. The % drug release at 2, 6 and 8th

hours were Q2, Q6 and Q8 respectively selected as dependent variables.

32 full factorial design layout of Sustained release matrix tablet

Table 5.11: 32 Full Factorial Design Layout

Batch No. Independent variables

X1 X2

F012 -1 -1

F013 -1 0

F014 -1 1

F015 0 -1

F016 0 0

F017 0 1

F018 1 -1

F019 1 0

F020 1 1

Concentration of Independent variable

Level Concentration of HPMC Concentration of PEO

-1 30% 30 %

0 35 % 35 %

1 40 % 40 %



5.9.1 Formulation of Factorial batches

5.9.1.1 Formula

Table 5.12: Formula of Factorial batches

Trial F012 F013 F014 F015 F016 F017 F018 F019 F020

Ingredients % % % % % % % % %

Drug 1.15 1.15 1.15 1.15 1.15 1.15 1.15 1.15 1.15

HPMC 30 30 30 35 35 35 40 40 40

PEO 30 35 40 30 35 40 30 35 40

MCC 32.04 27.04 22.04 27.04 22.04 17.04 22.04 17.04 12.04

PVP 5 5 5 5 5 5 5 5 5

BHT 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05

Stearic Acid 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

Magnesium

Stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

Iron oxide

Red 0.76 0.76 0.76 0.76 0.76 0.76 0.76 0.76 0.76

Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

Tablet

Weight

(mg)

130 130 130 130 130 130 130 130 130

Method of Preparation of ER Tablet





through 100#.













5.9.2 Reproducible batch of optimized batch with larger batch size

5.9.2.1 Formula

Table 5.13: Formula of Trial F021 Trial F021 Batch Size 10000 tablets

Strategy Take reproducible batch of

optimized F016 which contains 35%HPMC and 35% PEO

Ingredients Qty / tab (mg) %w/w

Drug 1.504 1.157% HPMC 45.5 35% PEO 45.5 35% MCC 28.65 22.04% PVP 6.5 5 % BHT 0.07 0.05% Stearic Acid 0.65 0.5 % Magnesium Stearate 0.65 0.5 % Iron oxide Red 1 0.76% Total 130.00 100.00



Method of Preparation of ER Matrix tablet





through 100#.













5.10 Drug release kinetic analysis by using different release model

of Extended release matrix tablet93-94

To know the mechanism of drug release from these formulations, the data were

treated according to first-order, zero order, Higuchis’s, Korsmeyer and Hixon-

Crowell’s model.

Chapter -6 RReessuullttss && DDiissccuussssiioonn--11


6.1 Preformulation Studies 6.1.1 Solubility:

Freely soluble in water, 0.1N HCl and pH 4.5 Acetate buffer.

Freely Soluble in methanol.

Soluble in pH 6.8 Acetate buffer.

6.1.2 Other preformulational parameters:

The preformulational parameters of pure drug such as Angle of repose, Loose bulk

density, Tapped bulk density, Carr’s compressibility index and Hausner’s Ratio of

pure drug are shown in Table 6.1. From the Results of Preformulation studies of the

API, It was concluded that drug has poor flow property and compressibility property.

So, to improve the flow and compressibility property, it was beneficial to use the

directly compressible grade components in the formulation of tablet.

6.1.3 Drug excipients compatibility study

Compatibility studies of pure drug with polymers and other excipients were carried

out prior to the preparation of tablets. DSC spectra of pure drug, and that of with

polymers and other ingredients were obtained, which are shown in Figure 6.1 to 6.7.

The results of DSC study shown that there is no change in drug’s melting peak after

the preparation of tablet. So we can conclude that drug and other excipients are

compatible which each other. It shows that there was no significant change in the

chemical integrity of the drug. The results of compatibility study are shown in Table

6.2.



6.2 Analytical Method Development

Table 6.3 shows the absorption reading of standard drug solution containing 3 –

18µg/ml of drug in pH 1.2 at the maximum wavelength of 275 nm.

Figure 6.8 shows the standard calibration curve for pure drug in pH 1.2 with slope,

intercept and regression co-efficient. The calculations of drug contents and in-vitro

drug release study are based on this standard curve.

Table 6.4 shows the absorption reading of standard drug solution containing 3 –

18µg/ml of drug in pH 6.8 phosphate buffer at the maximum wavelength of 275 nm.

Figure 6.9 shows the standard calibration curve for pure drug in pH 6.8 phosphate

buffer with slope, intercept and regression co-efficient. The calculations of drug

contents and in-vitro drug release study are based on this standard curve.

6.3 API Equivalent Dose Calculation

Drug Required = API Calculated * 100 * 100/ Assay * (100 – LOD)

= 1.50 * 100 * 100/ 99.9 * 99.87

= 1.504 mg

6.4 In–Vitro Release study of Innovator

The Innovator’s tablets were subjected for in vitro dissolution studies using

dissolution test apparatus USP XXIII. The dissolution medium used was pH 1.2 for

initial 2 hrs as average gastric emptying time of stomach is 2 hrs and rest was carried

out in pH 6.8 phosphate buffer solution to study the release of drug. The samples were

withdrawn at different intervals of time and analyzed at 275nm using UV

Spectrophotometer. Cumulative percentage drug release was calculated on the basis

of average amount of drug present in the dissolution chamber. The results obtained in



the in-vitro drug release study are tabulated in Table 6.5. The cumulative percentage

of drug released as a function of time for all the formulations are shown in Figure

6.10. From the in-vitro drug release profile data of Innovator’s product, three time

points were fixed for the generic product’s dissolution to match the release profile

with Innovator.

6.5 Formulation of Preliminary Trials

6.5.1 Trials with HPMC:


Bulk density and tapped density

Loose bulk density (LBD) and tapped bulk density (TBD) of the powder blends of all

the batches are shown in Table 6.6. The loose bulk density and tapped bulk density of

all the batches were varied from 0.431 to 0.468 gm/cm3 and 0.504 to 0.534 gm/cm3.

Carr’s consolidation index

The results of Carr’s consolidation index or compressibility index of all the trial

batches with HPMC ranged from 11.83% to 15.28%. Results of Carr’s consolidation

index are shown in Table 6.6. Results clearly showed that flowability of all the

batches is good and also the blend has good compressibility as per the Table 5.4.

Hausner’s Ratio

The Hausner’s ratio of all the batches prepared with HPMC ranged from 1.13 to 1.18.

Results are tabulated in Table 6.6. The results obtained indicated that all the powder

blends had good flow property.



Angle of repose

The data obtained for angle of repose for all the batches prepared by using HPMC are

tabulated in Table 6.6. The values were found to be in the range of 23.31 to 25.14. All

the formulations showed the Carr’s consolidation index between 14 to 20 and angle of

repose less than 30 which reveals good to fair inherent flow property of the powder

blend.

Blend Uniformity

The results of blend uniformity of all the powder blends were found to be ranging

from 98.32% to 99.21%. The results are tabulated in Table 6.6. The results showed

that the drug was uniformly mixed and distributed throughout the powder blend in all

the formulation powder blends.


Appearance

Formulations prepared were randomly picked from each batch examined under lens

for shape and in presence of light for color. Tablets showed standard concave surfaces

with circular shape. Tablets were red in color.

Weight variation test

The weight variation for all the formulations is shown in Table 6.7. All the tablets

passed the weight variation test, i.e., average percentage weight variation was found

within the pharmacopoeial limits of ±7.5%.

Hardness

Hardness or crushing strength of the tablets of all the batches was found to be ranging

from 6.5 to 8.0 kP. The mean hardness test results are tabulated in Table 6.7. The low

standard deviation values indicated that the hardness of all the formulations was



almost uniform and the tablets possess good mechanical strength with sufficient

hardness.

Thickness

The results of thickness for tablets are shown in Table 6.7. The mean thickness of

tablets (n=3) prepared using HPMC polymer was found be ranging from 3.45 – 3.51

mm.

Friability

Friability values of all the batches were in the range of 0.048 % to 0.062 %. The

obtained results were found to be well within the approved range (<1%) in all the

designed formulations. That indicated tablets possess good mechanical strength.

Friability results of all the batches are tabulated in Table 6.7.

Content Uniformity test

Drug content uniformity was performed for all the formulations. Three replicates of

each test were carried out and the average value of all the formulations was

calculated. Drug content uniformity in the formulations was found to be 99.7% to

102.3%. The results are tabulated in Table 6.7.

In-Vitro Release study

All the formulations prepared were subjected for in vitro dissolution studies using

dissolution test apparatus USP XXIII. The results of in-vitro dissolution study of trial

batches F001 to F004 which was taken using single polymer HPMC is shown in the

Table 6.8 and comparative dissolution profile was shown in Figure. 6.11. The results

of in-vitro dissolution study of trial batches F001 and F002 which were taken with

HPMC showed the faster drug release as compared to the targeted drug release.

Formulation F001 and F002 failed to generate sustained release of drug upto 12 hr



and drug was completely release at 8 hrs. So, to retard the drug release next trial

batches F003 and F004 were taken with higher percentage of HPMC (35%) and

HPMC (40%). As the percentage of polymer increased, the release of drug from tablet

was decreased. This may be due to structural reorganization of hydrophilic HPMC

polymer. Increase in concentration of HPMC may result in increase in the tortuosity

or gel strength of the polymer. Further study was carried out by increasing the

viscosity of HPMC. In the present study, HPMC was used as a hydrophilic matrixing

agent because it forms a strong viscous gel on contact with aqueous media, which

may be useful in controlled delivery of highly water-soluble drugs.

From the above result, it was concluded that by using single polymer like HPMC,

release profile was not desirable. So, further study was planned by using some release

retardant polymer like Polyethylene Oxide in different concentration.



6.5.2 Trials with PEO


Bulk density and tapped density

Loose bulk density (LBD) and tapped bulk density (TBD) of the powder blends of all

the batches from F005 to F008 are shown in Table 6.9. The loose bulk density and

tapped bulk density of all the batches were varied from 0.419 to 0.489 gm/cm3 and

0.502 to 0.564 gm/cm3.

Carr’s consolidation index

The results of Carr’s consolidation index or compressibility index of all the trial

batches with PEO ranged from 12.59% to 16.80%. Results of Carr’s consolidation

index are shown in Table 6.9. Results clearly showed that flowability of all the

batches is good and also the blend has good compressibility as per the Table 5.4.

Hausner’s Ratio

The Hausner’s ratio of all the batches prepared with PEO ranged from 1.14 to 1.20.

Results are tabulated in Table 6.9. The results obtained indicated that all the powder

blends had good flow property.

Angle of repose

The data obtained for angle of repose for all the batches prepared by using HPMC are

tabulated in Table 6.9. The values were found to be in the range of 22.14 to 24.84. All

the formulations showed the Carr’s consolidation index between 14 to 20 and angle of

repose less than 30 which reveals good to fair inherent flow property of the powder

blend.



Blend Uniformity

The results of blend uniformity of all the powder blends were found to be ranging

from 97.85% to 101.2%. The results are tabulated in Table 6.9. The results showed

that the drug was uniformly mixed and distributed throughout the powder blend in all

the formulation powder blends.


Appearance

Formulations prepared were randomly picked from each batch examined under lens

for shape and in presence of light for color. Tablets showed standard concave surfaces

with circular shape. Tablets were red in color.

Weight variation test

The weight variation for all the formulations is shown in Table 6.10. All the tablets

passed the weight variation test, i.e., average percentage weight variation was found

within the pharmacopoeial limits of ±7.5%.

Hardness

Hardness or crushing strength of the tablets of all the batches was found to be ranging

from 6.5 to 8.0 kP. The mean hardness test results are tabulated in Table 6.10. The

low standard deviation values indicated that the hardness of all the formulations was

almost uniform and the tablets possess good mechanical strength with sufficient

hardness.

Thickness

The results of thickness for tablets are shown in Table 6.10. The mean thickness of

tablets (n=3) prepared using PEO polymer was found be ranging from 3.46 to 3.50

mm.



Friability

Friability values of all the batches were in the range of 0.072 % to 0.084 %. The

obtained results were found to be well within the approved range (<1%) in all the

designed formulations. That indicated tablets possess good mechanical strength.

Friability results of all the batches are tabulated in Table 6.10.

Content Uniformity test

Drug content uniformity was performed for all the formulations. Three replicates of

each test were carried out and the average value of all the formulations was

calculated. Drug content uniformity in the formulations was found to be 98.4% to

99.6%. The results are tabulated in Table 6.10.


The results of in-vitro dissolution study of trial batches F005 to F008 which was taken

using single polymer PEO is shown in the Table 6.11 and comparative dissolution

profile was shown in Figure 6.12. In further formulation development process, trial

batches F005 and F006 were modified by incorporation of retarding polymer PEO

25% and 30% respectively and showed the faster drug release than targeted drug

release at all the time points and the drug was completely released from the matrix

within 12h. The tablets from F005 and F006 released 79.24% and 68.10% of the drug

at 2h, respectively (Figure 6.12). As the concentration of retarding polymer PEO

increases the drug release was decreased but not up to the desired mark. In addition 3

to 12h, the tablets slowly released the drug, and at the end of 12h the drug release was

99.97% and 99.89% from F006 and F007 respectively.

The trial batches F007 and F008 were taken using 35% and 40% of retarding

polymer. The in-vitro release study in formulation F007 showed the 66.93% drug



release in 2h that is comparable with targeted release profile. Furthermore, from 3 to

12h the drug release was sustained from the tablets and 99.45% drug was released at

the end of 12h from the matrix. The F008 batch shown 55.54% drug release in initial

2h and 98.12 % drug was released at end of 12 hr.

The results with release retardant polymer PEO indicate that the formulations still

need modification to get desired release profile. Based on this study, it was proposed

to use the combination of both water soluble matrix forming polymer HPMC and

PEO in proper concentration.



6.5.3 Trials with HPMC and PEO Evaluation of Powder blend

The powder blends of different formulations were evaluated for angle of repose, LBD,

TBD, compressibility index, and drug content and the results are shown in Table 6.12.

The results of angle of repose and compressibility index ranged from 21.58 to 23.39

and 13.19 to 14.89 respectively. The results of Hausner’s ratio and blend uniformity

ranged from1.15 to 1.18 and 97.85 to 99.87. The results of angle of repose (<30)

indicate good flow properties of the powder. The Carr’s index was also lower than 15

which also supported for good flow property.


All the tablet formulations showed acceptable pharmacotechnical properties and

complied with the in-house specifications for weight variation, drug content (98.3 to

99.6%), hardness (6-8 kP), and friability (0.011 to 0.061%). Result of evaluation

parameters are shown in Table 6.13.


Trial batches formulated using combination of HPMC and PEO were evaluated for

dissolution study (Table 6.14). Trial F009 shown 56.97 % initial 2h release and at the

end of 12h 98.51 % drug was released. It is known that higher viscosity grade

polymer HPMC hydrates at faster rate and therefore, it is capable of forming gel

structure quick than a low viscosity grade PEO polymer. So, in further trials the

concentration of HPMC and PEO was varied to check the effect on drug release when

two polymers are used in combination. Trial F010 shown 46.33% initial drug release

at 2h, and at the end of 12h the drug release was 91.58%. In F010 batch prepared with

higher concentration of HPMC and PEO, it shown 47.29% initial release at 2h and at



the end of 12h the drug release was found to be 89.97. Graphs are shown in Figure

6.13.

Hydrophilic matrix of HPMC and PEO in combination sustained the drug release

effectively for more than 12 hours. From the above result, it was concluded that the

combination of HPMC and PEO can be successfully utilized to create core tablet

formulation and then control the release further with polymeric functional coating. On

the basis of the preliminary trials in the present investigation a 32 full factorial design

was applied to study the effect of independent variables, i.e. concentration of HPMC

(X1) and concentration of PEO (X2) on dependent variables like %drug release Q2, Q6

and Q10.



6.6 Formulation and Optimization of Extended release matrix

tablets by using 32 full factorial designs


Factorial batches taken by using 32 full factorial designs of Sustained release matrix

tablets (Table 5.12). The powder blends of different formulations were evaluated for

angle of repose, LBD, TBD, compressibility index, and drug content; the results of

which are shown in Table 6.15.

The results of angle of repose and compressibility index ranged from 19.80 to 25.10

and 11.39 to 15.22 respectively. The results of Hausner’s ratio and blend uniformity

ranged from 1.13 to 1.18 and 97.64 to 100.32%. The results of angle of repose (<30)

indicate good flow properties of the powder. It was further supported by lower

compressibility index value that was less than 15.5%.


The tablet formulations were evaluated for different parameter like hardness,

friability, assay, weight variation (Table 6.16). Hardness of the prepared tablets was

found in range of 6-8 kP. All the tablet formulations showed acceptable

pharmacotechnical properties and complied with the in-house specifications for

weight variation, drug content, hardness, and friability. The size and surface area were

kept constant by adding required quantity of MCC as a diluent, as it is well known

fact that the drug release is also dependent on the size and surface area of matrix

tablets.


The drug release profiles were characterized by an initial burst effect Q2 i.e. initial 30-

35% drug release required in 2 hrs (Figure 6.14). The biphasic release is often



observed from hydrophilic matrix systems. As the release rate limiting polymer like

HPMC changes from a glassy state to rubbery state, a gel structure is formed around

the tablet matrix, which considerably decreases the release rate of drug since the drug

has to diffuse through this gel barrier into bulk phase. The strength of the gel depends

on the chemical structure and molecular size of the polymer. It is known that higher

viscosity grade polymer hydrates at faster and therefore, it is capable of forming gel

structure quickly than a low viscosity grade polymer. The drug release is significantly

dependent on the proportion and type of the polymer used. PEO was responsible for

initial burst effect and HPMC was used to sustained drug release. Factorial batches

formulated using combination of HPMC and PEO were evaluated for dissolution

study (Table 6.17).

6.6.1 Effect of Independent variable on dependent variable by 32 full factorial

design of extended release matrix tablet

The factorial batches were prepared by using independent variable concentration of

HPMC (X1) and PEO (X2) and check its effect on dependent variable like Q2, Q6, and

Q10.

The values of dependent variables are shown in Table 6.18.

Factorial batches of sustained release matrix tablets were evaluated for the in-vitro

drug release and by regression analysis of it, the effect of the individual polymer and

combination of the polymers studied. The summary of regression analysis for

Sustained release matrix tablet shown in Table 6.19.

The result of regression analysis showed that all the co-efficient bear a different sign,

which indicate that both the polymers shows different effect on the release of drug.

Drug release at 2nd hr (Q2) gives correlation co-efficient 0.9585. The P value for

variable X1 and X2 were 0.0087 and 0.2594 respectively (P<0.05), it indicate that X1



variable shown significant effect on drug release whereas X2 variable does not show

significant effect on drug release and combination co-efficient was positive but the P

value was not less than 0.05, which indicates that combination of independent

variable not showed significant effect at 2nd h release.

Q2 = 45.733 – 4.133X1 – 0.933X2 + 0.175X1X2 + 6.30X12 + 0.70X2

2 ……… (9)

Drug release at 6h (Q6) has less linearity compared to Q2 with correlation co-efficient

0.9113. The P value for variable X1 and X2 were 0.024 and 0.239 (P<0.05), it indicate

that variable X1 has significant effect on the drug release at 6h; whereas X2 fails to

show any significant effect even after 6h. and the combination co-efficient was

negative but the P value was not less than 0.05 so, we say that the combination of

independent variable was not give the significant effect at 6h release. The co-efficient

of X1 and X2 were negative indicate that when concentration of both the variable

increase than drug release was decrease.

Q6 = 65.644 – 5.45X1 – 1.833X2 – 0.05X1X2 + 7.316X12 + 0.416X2

2 …………. (10)

Drug release at 10h (Q10) has the P value for variable X1, X2 and X1X2 were 0.040,

0.24, 0.973 respectively, it indicate that variable X1 has significant effect; whereas

variable X2 does not show significant effect and also the combination of variable fails

to show significant effect on drug release at 10h. The co-efficient of X1 and X2 were

negative indicate that when concentration of both the variable increase than drug

release was decrease.

Q10 = 84.322 – 3.86X1 – 1.633X2 + 0.05X1X2 + 7.233X12 + 1.733X2

2 ……… (11)

The Q2, Q6, and Q10 for all the batches F012 to F020 varied from 39.9 % to 52.4%,

57.3% to 74.6%, and 76.8% to 91.6% with correlation coefficient as 0.9585, 0.9113

and 0.9059 respectively.



The dissolution profile of all the formulation batches prepared by using 32 factorial

designs was compared with the desired level fixed. None of the factorial batches gave

the release profile as targeted; however on varying the concentration of HPMC and

PEO in various levels, it was found that batch F016 and F017 showed the least release

profile and also the release is sustained as the polymer concentration increases, but

after reaching certain level, there is no effect on release of drug and so batch F016 in

which HPMC and PEO are used at 35% concentration level was selected as optimized

batch and selected for the further process.

Reduced model equation for Q2, Q6, and Q10 showed the value of variable which has

effect on drug release and P value less than 0.05.

Q2 = 45.733 – 4.133X1 – 0.933X2 + 6.30X12 ……………… (12)

Q6 = 65.644 – 5.45X1 – 1.833X2 + 7.31X12 ………….……. (13)

Q10 = 84.322 – 3.86X1 – 1.633X2 + 0.5X1X2 ……...……… (14)

The present 32 full factorial design conclude that combination of HPMC and PEO can

be used to formulate extended release matrix tablet, however it could not sustained the

release upto the desired level in present study. From the factorial design; finally

obtained optimized batch was F016 which was prepared by using combination of 35%

HPMC and 35% PEO.

The response surface plots were plotted against X variable, Y variable and Z variable.

X variable taken as concentration of HPMC, Y variable taken as concentration of

PEO and Z variable considered as drug release at 2nd, 6th and 10th hour. The surface

response plots of drug release at 2nd, 6th and 10th hour are shown in Figure. 6.15, 6.16

and 6.17 respectively.



6.6.2 Reproducible batch of optimized batch with larger batch size


The powder blend of batch F021 was evaluated for angle of repose, LBD, TBD,

compressibility index, and drug content (Table 6.20).

The result of angle of repose and compressibility index was found 21.41 and 12.55

respectively. The result of Hausner’s ratio and blend uniformity was 1.14 and 99.16%.

The results of angle of repose (<30) indicate good flow properties of the powder. This

was further supported by lower compressibility index value that was less than 15.0%.


The formulations were evaluated for different parameter like hardness, friability,

assay, weight variation (Table 6.21).

Hardness of the prepared tablets was 6-8 kP. All the tablet formulations showed

acceptable pharmacotechnical properties and complied with the in-house

specifications for weight variation, drug content, hardness, and friability.

In-Vitro Drug release

Prepared optimized batch of large scale was evaluated for dissolution study (Table

6.22).

Drug release of F021 was comparable with F016 drug release. No significant change

was observed compared to optimized batch. Comparative dissolution profile is shown

in Figure 6.18.




of Extended release matrix tablet:

To know the mechanism of drug release from these formulations, the data were

treated according to first-order (log cumulative percentage of drug remaining vs time),

Higuchi’s15 (cumulative percentage of drug released vs square root of time),

Korsmeyer et al’s16 (log cumulative percentage of drug released vs log time), Hixon-

Crowell’s (cube root of % drug retained vs time) equations along with zero order

(cumulative amount of drug released vs time) pattern the results shown in Table 6.23.

The in vitro release profiles of drug from the optimized formulation could be best

expressed by Higuchi’s equation, as the plots showed high linearity (R2 = 0.980,

Table 6.23). To confirm the diffusion mechanism, the data were fit into Korsmeyer-

Peppas’s equation. The formulations F021 showed good linearity (R2: 0.963), with

slope (n) value 0.369, indicating that diffusion is the dominant mechanism of drug

release with these formulations. This n value, however, appears to indicate a coupling

of diffusion and erosion mechanisms so called anomalous diffusion. The relative

complexity of this formulation and its components may indicate that the drug release

is controlled by more than one process.

From the result, it was concluded that the batch taken with 35% HPMC and 35% PEO

had good reproducibility. Reproducible batch F021 was selected for further study.

The drug release followed Higuchi’s model with diffusion following Fickian

behavior; also n value indicated a coupling of diffusion and erosion mechanisms so

called anomalous diffusion. As the release profile of core matrix tablet could not

match the required drug release profile, it was decided to further control the release of

drug by functional coating with EC as a polymer using PEG as plasticizer to match

the initial time point of release.



Table 6.1: Result of Preformulation study of Drug

Drug Angle of Repose

()

Loose Bulk Density (g/ml)

Tapped Bulk Density (g/ml)

Carr’s Index (%)

Hausner’s Ratio

Drug 27.34 0.375 0.516 27.32 1.37

1) Drug

100.00 200.00Temp [C]

-30.00

-20.00

-10.00

0.00

mWDSC

197.56 C

Thermal Analysis Result

(Fig. 6.1 Thermal Analysis result of pure drug)



2) Drug + PEO

100.00 200.00 300.00Temp [C]

-30.00

-20.00

-10.00

0.00

mWDSC

189.91 C

224.95 C


(Fig. 6.2 Thermal Analysis result of Drug + PEO)

3) Drug + MCC (Avicel pH102)

(Fig. 6.3 Thermal Analysis result of Drug + MCC)



4) Drug + HPMC

(Fig. 6.4 Thermal Analysis result of Drug + HPMC) 5) Drug + Stearic Acid

(Fig. 6.5 Thermal Analysis result of Drug + Stearic Acid)



6) Drug + Mg- Stearate

(Fig. 6.6 Thermal Analysis result of Drug + Mg - stearate) 7) Drug+ PEO+ MCC+ HPMC+ Stearic Acid+ Mg- Stearate

100.00 200.00 300.00Temp [C]

-15.00

-10.00

-5.00

0.00

mWDSC

102.69 C

127.07 C

195.81 C

289.88 C


(Fig. 6.7 Thermal Analysis result of Mixture of Drug with other excipients)

Chapter -6 RR

ee ss uu ll tt ss && DDii ss cc uu ss ss ii oo nn -- 11

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ent of Pharmaceutics, K

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niversity, Belgaum 123 Table 6.2: Result of Drug excipients compatibility study After 1 month at 40ºC±2°C / 75%RH± 5 % RH

Drug + Excipient Initial Observation After 1 month at 40ºC±2°C / 75%RH± 5

% RH

Drug A white to offwhite powder Compatible

Drug: PEO A white to offwhite powder Compatible

Drug : MCC A white to offwhite powder Compatible

Drug : HPMC A white to offwhite powder Compatible

Drug : Stearic Acid A white to offwhite powder Compatible

Drug : Mg Stearate A white to offwhite powder Compatible

Drug + All Excipients A white to offwhite powder Compatible



Table 6.3 Standard calibration curve of Drug in 0.1 N HCl

Sr. No. Concentration

(g/ml)

Absorbance Average

Absorbance 1 2 3

1

2

3

4

5

6

7

0

3

6

9

12

15

18

0

0.149

0.309

0.405

0.536

0.673

0.817

0

0.129

0.243

0.378

0.501

0.632

0.748

0

0.162

0.271

0.397

0.543

0.685

0.820

0

0.146

0.274

0.393

0.526

0.663

0.795

Y = 0.0437 x + 0.0063

Correlation Co-efficient =0.9996

(Fig. 6.8: Calibration curve of Drug in 0.1 N HCl at 275nm)



Table 6.4 Standard calibration curve of Drug in Phosphate Buffer (pH 6.8)

Sr.

No. Concentration

(g/ml)

Absorbance Average

Absorbance 1 2 3

1

2

3

4

5

6

7

0

3

6

9

12

15

18

0

0.147

0.283

0.406

0.554

0.681

0.804

0

0.140

0.266

0.394

0.528

0.658

0.784

0

0.139

0.275

0.411

0.560

0.678

0.810

0

0.142

0.274

0.403

0.547

0.672

0.799

Y = 0.0444x + 0.0056

Correlation Co-efficient =0.9997

(Fig. 6.9: Calibration curve of Drug in Phosphate buffer pH 6.8 at 275nm)



Table 6.5: In–Vitro Release study of Innovator

Dissolution 0.1 HCl, 6.8 pH PBS 900ml,

USP - II (Paddle) Apparatus, 50 RPM Time (hrs.) Innovator % Drug Release

0 0 2 0 4 3.6 6 8.9 8 16.3

10 26.3 12 37.2 14 49.2 16 59.8 18 74.3 20 86.9 22 94.3 24 102.7

(Fig. 6.10: In-vitro drug release profile of Innovator’s product)



Table 6.6: Result of Evaluation of powder blend of trial batches F001 to F004

Powder blend

Angle of Repose

()

Loose Bulk

Density (g/ml)

Tapped Bulk

Density (g/ml)

Carr’s Index (%)

Hausner’s Ratio

Blend Uniformity

(%)

F001 24.69 0.462 0.524 11.83 1.13 99.21

F002 23.31 0.438 0.517 15.28 1.18 98.32

F003 24.31 0.431 0.504 14.48 1.17 99.12

F004 25.14 0.459 0.534 14.04 1.16 98.87



Table 6.7: Result of Evaluation of Tablets of trial batches F001 to F004

Trial

batches

Hardness

(kP)

Thickness

(mm)

Friability

(%)

Avg. Wt.

(mg)

Assay

(%)

F001 7-8 3.5 0.062 131.04 102.3

F002 7-8 3.45 0.052 130.74 99.7

F003 6.5-8 3.47 0.048 130.18 100.3

F004 7-8 3.51 0.049 130.19 101.1



Fig. 6.11: Dissolution profile of F001-F004

Table 6.8: Result of In-vitro release of trial batches F001 to F004

0.1 HCl, 900ml, USP - II (Paddle) Apparatus, 50 RPM

Time (hrs.)

%CDR %CDR %CDR %CDR

F001 F002 F003 F004

0 0 0 0 0

1 53.41 48.55 39.22 38.13

2 59.08 56.97 46.07 45.69

4 68.1 66.93 53.03 54.24

6 76.62 74.89 64.99 61.84

8 89.6 86.32 74.3 70.05

10 97.51 90.53 80.29 77.06

12 99.79 98.51 87.62 86.58



Table 6.9: Evaluation of Powder blend of trial batches F005 to F008

Powder

blend

Angle

of

Repose

()

Loose

Bulk

Density

(g/ml)

Tapped

Bulk

Density

(g/ml)

Carr’s

Index

(%)

Hausner’s

Ratio

Blend

Uniformity

(%)

F005 23.47 0.479 0.548 12.59 1.14 98.68

F006 22.14 0.489 0.564 13.30 1.15 99.87

F007 24.84 0.426 0.512 16.80 1.20 97.85

F008 23.87 0.419 0.502 15.53 1.20 101.2

Table 6.10: Evaluation of Tablets of trial batches F005 to F008

Trial batches Hardness (kP)

Thickness (mm)

Friability (%)

Avg. Wt. (mg)

Assay (%)

F005 7-8 3.48 0.082 131.04 99.3

F006 7-8 3.47 0.072 130.87 99.6

F007 6.5-8 3.46 0.084 130.83 98.4

F008 7-8 3.50 0.072 130.94 99.1



(Fig. 6.12: Dissolution profile of F005-F008)



Time (hrs.)

%CDR %CDR %CDR %CDR

F005 F006 F007 F008

0 0 0 0 0 1 61.09 59.08 56.97 46.33 2 79.24 68.10 66.93 55.54

4 89.84 76.62 74.89 64.02

6 96.05 89.60 86.32 73.72

8 99.14 97.51 90.53 82.53

10 99.58 99.79 98.51 91.58

12 99.97 99.89 99.45 98.12



Table 6.12: Evaluation of Powder blend of trial batches F009 to F011

Powder

blend

Angle

of

Repose

()

Loose

Bulk

Density

(g/ml)

Tapped

Bulk

Density

(g/ml)

Carr’s

Index

(%)

Hausner’s

Ratio

Blend

Uniformity

(%)

F009 22.19 0.441 0.508 13.19 1.15 98.68

F010 23.39 0.452 0.526 14.07 1.16 99.87

F011 21.58 0.440 0.517 14.89 1.18 97.85

Table 6.13: Evaluation of Tablets of trial batches F009 to F011

Trial

batches

Hardness

(kP)

Thickness

(mm)

Friability

(%)

Avg. Wt.

(mg)

Assay

(%)

F009 7-8 3.52 0.061 350.7 99.3

F010 7-8 3.51 0.057 350.3 99.6

F011 6.5-8 3.49 0.011 351.1 98.9





Time

(hrs.)

%CDR %CDR %CDR

F009 F010 F011

0 0 0 0

1 48.55 38.58 37.85

2 56.97 46.33 47.29

4 66.93 55.54 56.07

6 74.89 64.02 62.75

8 86.32 73.72 71.22

10 90.53 82.53 80.62

12 98.51 91.58 89.97



Fig. 6.13: Comparative dissolution profile of Trials F009 to F011



Table 6.15: Evaluation of powder blend of Factorial batches

Powder

blend

Angle

of

Repose

()

Loose

Bulk

Density

(g/ml)

Tapped

Bulk

Density

(g/ml)

Carr’s

Index

(%)

Hausner’s

Ratio

Blend

Uniformity

(%)

F012 21.56 0.404 0.473 15.22 1.18 99.85

F013 23.14 0.452 0.512 14.06 1.16 100.32

F014 25.10 0.429 0.504 14.88 1.17 98.45

F015 24.38 0.464 0.528 12.12 1.14 97.89

F016 22.90 0.420 0.489 14.11 1.16 98.46

F017 22.15 0.451 0.512 11.39 1.13 99.34

F018 19.80 0.437 0.515 15.15 1.18 97.64

F019 20.35 0.449 0.521 13.82 1.16 98.59

F020 20.82 0.447 0.511 12.52 1.14 99.25

Chapter -6 RR


Departm


LE U

niversity, Belgaum 136 Table 6.16: Evaluation of tablets of Factorial batches

Factorial Batches Hardness

(kP)

Thickness

(mm) Friability (%)

Avg. Wt.

(mg) Assay (%)

F012 7-8 3.48 0.045 130.2 99.8

F013 7-9 3.51 0.104 130.5 100.2

F014 6.5-8 3.49 0.128 130.3 100.1

F015 7-8 3.50 0.059 130.0 98.8

F016 7-8 3.51 0.002 130.5 98.7

F017 7-9 3.52 0.029 130.2 99.3

F018 7-9 3.50 0.019 130.3 99.4

F019 7-8 3.49 0.019 130.5 98.4

F020 7-8 3.50 0.052 130.2 99.3

Chapter -6 RR


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niversity, Belgaum 137

Table 6.17: In-vitro release study of Factorial batches

0.1 HCl, pH 6.8 PBS 900ml, USP - II (Paddle) Apparatus, 50 RPM

Time (hrs) %CDR

F012 F013 F014 F015 F016 F017 F018 F019 F020

0 0 0 0 0 0 0 0 0 0

1 44.5 43.6 43.5 38.5 34.6 34.2 37.6 37.3 36.2

2 52.4 51.9 51.6 44.6 40.1 39.9 43.7 43.8 43.6

4 65.2 66.2 65.1 56.5 49.6 48.6 53.9 53.7 53.2

6 73.5 74.6 72.5 66.4 58.6 57.3 63.1 62.9 61.9

8 82.6 81.9 81.2 76.1 67.6 67.3 72.8 72.9 72.4

10 91.6 89.6 90.6 84.8 76.9 76.8 83.2 83 82.4

12 99.8 98.9 98.4 92.9 88.2 86.9 92.8 91.9 90.9

Chapter -6 RR


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(Fig. 6.14: Comparative dissolution profile of Factorial batches of F012 to F020)



Table 6.18: Effect of Independent variable on dependent variable by 32 full

factorial design of Sustained release matrix tablet

Batch No. Independent variable Dependent variable

X1 X2 Q2 Q6 Q10

F012 -1 -1 52.4 73.5 91.6

F013 -1 0 51.9 74.6 89.6

F014 -1 +1 51.6 72.5 90.6

F015 0 -1 44.6 66.4 84.8

F016 0 0 40.1 58.6 76.9

F017 0 +1 39.9 57.3 76.8

F018 +1 -1 43.7 63.1 83.2

F019 +1 0 43.8 62.9 83

F020 +1 +1 43.6 61.9 82.4

Independent

Variables

Real Value

Low (-1) Medium (0) High (+1)

HPMC (X1) 30 % 35 % 40 %

PEO (X2) 30 % 35 % 40 %

Chapter -6 RR


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Table 6.19: Summary of regression analysis for Extended release matrix tablet

Coefficients b0 b1 b2 b12 b11 b22 R2

Q2 45.733 -4.133 -0.933 0.175 6.300 0.700 0.9585

Q6 65.644 -5.450 -1.883 -0.05 7.316 0.416 0.9113

Q10 84.322 -3.866 -1.633 0.05 7.233 1.733 0.9059

Chapter -6 RR


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Design-Expert® SoftwareQ2

Design points above predicted valueDesign points below predicted value52.4

39.9

X1 = A: HPMCX2 = B: PEO

30.00 32.00

34.00 36.00

38.00 40.00

30.00 32.00

34.00 36.00

38.00 40.00

35

40

45

50

55

Q2

A: HPMC B: PEO

(Fig. 6.15: Surface response plot of Response Y1)

Chapter -6 RR


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57.3


30.00 32.00

34.00 36.00

38.00 40.00

30.00 32.00

34.00 36.00

38.00 40.00

55

60

65

70

75

80

Q6

A: HPMC B: PEO


Chapter -6 RR


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76.8


30.00 32.00

34.00 36.00

38.00 40.00

30.00 32.00

34.00 36.00

38.00 40.00

75

80

85

90

95

Q10

A: HPMC B: PEO




Table 6.20: Evaluation of powder blend of Reproducible batch F021

Angle

of

Repose

()

Loose

Bulk

Density

(g/ml)

Tapped

Bulk

Density

(g/ml)

Carr’s

Index

(%)

Hausner’s

Ratio

Blend

Uniformity (%)

21.41 0.439 0.496 12.55 1.14 99.16

Table 6.21: Evaluation of Tablets of Reproducible batch F021

Optimized

Batch

Hardness

(kP)

Thickness

(mm)

Friability

(%)

Avg. Wt.

(mg) Assay (%)

F021 7-9 3.5 0.024 130.5 99.7



Table 6.22: In-vitro drug release of Reproducible batch F021 and F016

Time (hrs.) % Drug Release(F021) % Drug Release(F016)

0 0.0 0

1 34.9 34.6

2 41.2 40.1

4 50.1 49.6

6 59.3 58.6

8 68.6 67.6

10 77.2 76.9

12 89.1 88.2



(Fig. 6.18: Comparative dissolution profile of Reproducible batch F021 and

F016)

Chapter -6 RR


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Table 6.23: Data analysis by using different model

Model Zero order First order Higuchi Korsemeyer-

Peppas

Hixon-

Crowell

Linearity (R2) 0.888 0.945 0.980 0.963 0.954

Slope (n) 5.96 -0.06 23.283 0.369 0.164

Intercept (c) 19.866 1.954 4.44 1.329 0.249



7.1. Aim of the present work

The selected matrix tablet formulation was further coated with rate controlling

polymer to retard the initial time point release so as to match the time points selected

to match with the Innovator’s release profile. Ethyl cellulose was selected as the

polymer and PEG was added as the plasticizer. 3 grades of Ethyl cellulose (i.e., low

viscosity, medium viscosity and high viscosity) were chosen for coating. Coating

parameters were kept fixed and coating variables were changed on trial and error

method. The aim of this study was to further reduce the release rate of selected matrix

formulation with Ethyl Cellulose coating by utilizing 32 x 21 factorial design to the

desired level.

7.2. Coating Process Variables

The processing variable parameters for coating can be divided into two groups:

(1) Independent variables and (2) Dependent variables

7.2.1 Independent Variables

Independent Variables can be considered to have a direct effect on the quality of the

coated materials. These are:

Inlet air Temperature

Spray Atomizing pressure

Blower Speed

Spray Rate

The objective must be to obtain a satisfactorily coated material with minimum coating

time. This means the spray rate optimizing the spray rate with the other three

parameters. It is difficult to reproduce exactly conditions for each experimental run

due to variation in such in-house systems as steam supply and compressed air.



7.2.2. Dependent Variables

Data can also obtain from those dependent variables which result from the value of

the setting for independent variables. These are:

Dew point of exhaust air

Outlet air temperature

Bed temperature

Coat quality

Detailed consideration of processing variables:

7.2.2.1 Inlet Air Temperature:

The temperature of the inlet air is a processing factor related to both the evaporative

process and to polymer characteristics. In the evaporative sense, the higher the

temperature, the better. The limitation comes in by virtue of polymer properties. In

particular, polymeric dispersions requiring a coalescent mechanism for film formation

will have a low glass transition temperature, which is accomplished by the addition of

plasticizers to the polymer dispersion. The temperature of the incoming air will thus

be limited to the optimal temperature for film formation. Temperature is the prime

consideration in the processing of pharmaceutical polymers. Every polymer has a

distinct set of characteristics that are influenced by temperature or a change in

temperature. The effect of temperature is far reaching, often affecting the mechanical,

physical, and chemical properties of a polymer. The degree of effect will be related to

the polymer properties and the range of temperatures experienced.

The most common and obvious effects are changes in mechanical properties at key

temperatures. The mechanical changes are a physical result of imparting more

mobility to the polymer. These can be subtle effects at points where side groups in the

chain free up, or a more abrupt change when the main chains become mobile. In



amorphous polymers, the glass transition temperature, Tg, is the temperature at which

a polymer undergoes a change from a glassy to a rubbery elastomer or flexible plastic.

This transition can cause an abrupt change in mechanical properties.

Temperature not only is important in its mechanical effects on the polymer, but also

plays a role in both the physical cohesion and coalescence of colloidal particles and

the adhesion of the polymeric film to the product substrate. As the temperature

increases, the cohesive strength of the polymer and adhesivity of the film to the

substrate increases.

For aqueous polymeric dispersions, higher temperatures will increase the rate of water

evaporation, thus increasing the cohesive force between polymer particles that leads

to coalescence. It stands to reason that if the temperature is too high that this would be

an adverse effect in coating operations, causing droplet spray drying, incomplete

coalescence, and increased porosity to the film, as well as sticking or adhesion of

product during the coating process.

Temperatures may also impact product performance in augmenting a chemical or

physical interaction between the polymer and other substances, including the active

ingredient in the substrate, or with other film components. In addition, temperature

may have an indirect effect on a polymeric film by volatizing vital additives from the

film, such as plasticizers.

7.2.2.2 Outlet Air Temperature

Outlet air temperature is almost always monitored to give information on the

evaporative process taking place. Nozzle occlusions and changes in fluidization

dynamics can often be detected through changes in this temperature. In an air

suspension process, product bed temperature is also monitored because it is the most

sensitive indicator of process changes other than visual monitoring. The product



temperature reflects the balance between liquid application and water evaporation. If

this temperature is too high or too low, the coating microstructure can be adversely

affected.

7.2.2.3 Spray Rate:

The spray rate at which the polymer solution or dispersion is applied to a solid

substrate is a very important processing factor. Aqueous film coating requires the

uniform application of a polymeric film to the substrate surface, and a well-controlled

evaporation of water from that surface. The equipment design plays a key role in the

success of this process

7.2.2.4 Atomizing Spray Pressure:

Atomization is the process whereby a liquid is broken up into spray droplets.

Atomized droplets hitting the substrate during film coating should be in such a state

that they spread evenly over the surface and form the smooth continuous film of even

thickness. It is very critical parameter in the fluid bed coating process because it

directly affects the droplet size of the coating solution sprayed. The droplet size of the

liquid spray is determined by the atomizing air pressure delivered to the nozzle. The

mean droplets diameter in atomized nozzle configuration is also a function of the

liquid spray volume (air atomization volume ratio). While atomizing air pressure is a

commonly used representation for changing droplet size, the volume ratio can be

mathematically correlated to mean droplet diameter. This allows for scaling up of this

process variable when changing equipment sizes. In order for uniform, precise, and

thin film formation to occur on the substrate surface, the polymer solution or

dispersion must contact all surfaces evenly and evaporate quickly. Consistent droplet

size will result in a more even coating thickness, which, in turn, means that complete



cover of the material to be coated is obtained with less coating material. Using less

coating materials reduces both the coating time and quantity of heat required as less

solvent to evaporate. The efficiency of the coating process is therefore very dependent

upon the degree of atomization of the spray. The best way for this to be accomplished

is by breaking the liquid into small droplets, with the use of two-fluid atomizers,

hydraulic nozzles, or ultrasonic nozzles for aqueous solution & airless pump for the

nonaqueous coating solution. Higher the atomization pressure, finer the droplet size.

Very small droplets may dry before contacting the substrate, a phenomenon termed

spray drying. Large droplets will overwhelm the evaporative capacity of the system

causing overwetting. This may lead to agglomeration or loss of fluidization in fluid

bed coaters. As a result, it is desirable to control droplet diameter to optimize this

important factor. Droplet size in turn also affects the coat quality.

7.2.2.5 Blower Speed:

Blower speed is the key parameter in fluid bed coating process because proper

fluidization of bed is the function of the blower speed. Other important function of the

blowing air is to enhance the drying of coated materials. And the proper air flow rate

is most important for the successful operation of the process. Since a variety of

particles of differing size, shape and density are encountered; the precise calculation

of the required air flow rate is difficult. Since the bed of material to be coated is

considered to be truly suspended, the pressure drop across the bed must at least

approximate the weight of the bed. Lower the blower speed lesser the pressure drop,

which cause failure or insufficient bed lifting, hence improper fluidization and more

incidence of the agglomeration. Too high blower speed causes increase in air velocity

and does not yield a concomitant increase in the pressure drop. An increase in air

velocity does increase bed expansion, and ultimately at higher velocities pneumatic



transport occurs. Due to higher pneumatic transport, results in non uniform coating

and less coating efficiency.

7.2.2.6 The Dew Point of the Air:

The dew point of the air must be considered because this air is usually drawn from the

outside environment before it is HEPA filtered, heated, and passed through the

equipment. The amount of moisture in the air may vary significantly from season to

season, and even from day to day. Because air has a given capacity to hold water at a

particular temperature, changes in the dew point of the incoming air will affect the

evaporative efficiency of that air.

The most obvious solution to eliminating this processing factor is to dehumidify the

air. Another solution is to monitor the dew point of the air and adjust other variables

to compensate. This would require a process validation study that would establish

ranges of each variable and the relationship between them.

However, optimization of the process variables will required the dynamic study to

optimization each parameter because each parameter is inter related with the other

parameter. Also it is depend on the instrument configuration. So it is necessary to

determine whether the instrument configuration is designed according to the standard

or not.

7.3. In-vitro drug release profile of Innovator's product:










UV spectrophotometer at 275 nm. The results of dissolution are shown in Table 8.1.

7.4. Selection of dissolution time points:

From the above data, 3 time points were selected for % drug release to be fixed in

final formulation product.

Table 7.1: Dissolution time points fixed


2 hrs NMT 10 %

8 hrs 25-60 %

14 hrs NLT 70 %

7.5. Preparation of Coating solution:

A 5% w/v solution of Ethyl Cellulose in Isopropyl Alcohol: Dichloro Methane was

used as a membrane provider. Polyethylene Glycol was used as a plasticizer.

Table 7.2: Coating composition

Ingredients Quantity

Ethyl Cellulose

PEG

Isopropyl Alcohol

Dichloro Methane

Q.S.

Q.S.

80 %

20 %



1. Weighed quantity of PEG was dissolved in DCM.

2. Ethyl Cellulose was dissolved in IPA kept on constant stirring.

3. DCM solution was added to solution in step 2 and the final solution was kept

on constant stirring till solution becomes clear and transparent.

7.6 Factorial Design Experiments95

Factorial designs are the designs of choice for simultaneous determination of the

effects of several factors and their interactions.[12] Extended release tablets were

prepared based on 32 × 21 factorial design. The independent variables are ratios of

polymer:plasticizer (a), % Coating (b) and grade of polymer (c).

On the other hand, the drug released after 2 hrs, after 8 hrs, after 14 hrs and %RSD

are response parameters as the dependent variables. The independent variables and

their levels are shown in Table 7.3. The statistical evaluation of the results was carried

out by analysis of variance (ANOVA) using a commercially available statistical

program (SPSS 10.0).



Table 7.3: 32 x 21 Factorial Design Layout

Batch

No.

Independent variables

X1 X2 X3

F022 -1 -1 -1

F023 -1 -1 0

F024 -1 0 -1

F025 -1 0 0

F026 -1 1 -1

F027 -1 1 0

F028 0 -1 -1

F029 0 -1 0

F030 0 0 -1

F031 0 0 0

F032 0 1 -1

F033 0 1 0

F034 +1 -1 -1

F035 +1 -1 0

F036 +1 0 -1

F037 +1 0 0

F038 +1 1 -1

F039 +1 1 0

Concentration of Independent variable

Level Ratio of EC : PEG % Coating Grade of EC

-1 80 : 20 8 4 cps

0 70 : 30 10 10 cps

1 60 : 40 12 -



7.6.1 Formulation of Factorial batches

7.6.1.1 Formula

Table 7.4: Factorial Batches formulations

Formulation EC : PEG ratio % Coating Grade of EC

F022 80 : 20 8 4

F023 80 : 20 8 10

F024 80 : 20 10 4

F025 80 : 20 10 10

F026 80 : 20 12 4

F027 80 : 20 12 10

F028 70 : 30 8 4

F029 70 : 30 8 10

F030 70 : 30 10 4

F031 70 : 30 10 10

F032 70 : 30 12 4

F033 70 : 30 12 10

F034 60 : 40 8 4

F035 60 : 40 8 10

F036 60 : 40 10 4

F037 60 : 40 10 10

F038 60 : 40 12 4

F039 60 : 40 12 10



7.6.2 Processing Parameters:

Table 7.5: Processing Parameters

PARAMETER VALUE

Inlet Temperature 40-450C

Exhaust Temperature 30-350C

Bed Temperature 35-400C

Pan RPM 10

Spray RPM 6-7-8

Atomization 1.75kg/cm2

The tablets were warmed to 40 2oC before applying coating solution. The tablets

were weighed after warming and then coating was done till desired % coating is done.

% weigh gain = (Wt-Wo/ Wo) x 100

Where, Wt = weight of tablet after coating

Wo = weight of tablet before coating












UV spectrophotometer at 275 nm.


of Extended release matrix tablet93-94

Drug release kinetics can be analyzed by various mathematical models, which are

applied considering the amounts of drug released from 0 to 24 hour. Following

equations presents the models tested. Depending on these estimations, suitable

mathematical models to describe the dissolution profiles were determined. The

following plots were made: cumulative % drug release versus time (zero-order kinetic

model); log cumulative % drug remaining versus time (first-order kinetic model);

cumulative % drug release versus square root of time (Higuchi model); cube root of

drug % remaining in matrix versus time (Hixson–Crowell cuberoot law)

Zero order kinetic

Drug dissolution from pharmaceutical dosage forms that do not disaggregate and

release the drug slowly (assuming that area does not change and no equilibrium

conditions. are obtained) can be represented by the following equation:

Q1 = Q0 +K0t

Where Q is the amount of drug dissolved in time t, Q is the initial amount of drug in

the solution (most times, Q 50) and K is the zero order release constant.



First order kinetics:

The application of this model to drug dissolution studies was first proposed by

Gibaldi and Feldman (1967) and later by Wagner (1969). This model has been also

used to describe absorption and/or elimination of some drugs, although it is difficult

to conceptualise this mechanism in a theoretical basis. The following relation can also

express this model:

ln Qt =lnQ0 –k1t

Where Qt is the amount of drug released in time t, Q0 is the initial amount of drug in

the solution and K is the first order release constant. In this way a graphic of the

decimal logarithm of the released amount of drug versus time will be linear. The

pharmaceutical dosage forms following this dissolution profile, such as those

containing water-soluble drugs in porous matrices (Mulye and Turco, 1995), release

the drug in a way that is proportional to the amount of drug remaining in its interior,

in such way, that the amount of drug released by unit of time diminish.

Higuchi model

Higuchi (1961, 1963) developed several theoretical models to study the release of

water soluble and low soluble drugs incorporated in semi-solid and/or solid.

Mathematical expressions were obtained for drug particles dispersed in a uniform

matrix behaving as the diffusion media. In a general way it is possible to resume the

Higuchi model to the following exprssion

Qt = KH t 1/2

Where Qt is amount of drug released in time t and KH is release rate constants.

Higuchi describes drug release as a diffusion process based in the Fick’s law, square

root time dependent. This relation can be used to describe the drug dissolution from

several types



of modified release pharmaceutical dosage forms, as in the case of some transdermal

systems (Costa et al., 1996) and matrix tablets with water soluble drugs.

Hixon crowell model

Hixson and Crowell (1931) recognizing that the particle regular area is proportional to

the cubic root of its volume derived an equation that can be described in the following

manner:

W0 1/3 – Wt1/3 = Ks t

where W is the initial amount of drug in the pharmaceutical dosage form, W is the

remaining amount of drug in the pharmaceutical dosage form at time t and K is a

constant incorporating the surface– volume relation. This expression applies to

pharmaceutical dosage form such as tablets, where the dissolution occurs in planes

that are parallel to the drug surface if the tablet dimensions diminish proportionally, in

such a manner that the initial geometrical form keeps constant all the time. This

model has been used to describe the release profile keeping in mind the diminishing

surface of the drug particles during the dissolution.

Korsmeyer–Peppas model

Korsmeyer et al. (1983) developed a simple, semiempirical model, relating

exponentially the drug release to the elapsed time (t). An equation that can be

described in the following manner:

Mt / M∞ = atn

where a is a constant incorporating structural and geometric characteristics of the drug

dosage form, n is the release exponent, indicative of the drug release mechanism, and

the function of t is M /M (fractional release of drug). Peppas (1985) used this n value

in order to characterize different release mechanisms, concluding for values for a slab,



of n =0.5 for Fick diffusion and higher values of n, between 0.5 and 1.0, or n=1.0, for

mass transfer following a non-Fickian model.

7.8 Comparison of dissolution profiles by statistical analysis96

The similarity factor (f2) was defined by CDER, FDA and EMEA as the “logarithmic

reciprocal square root transformation of one plus the mean squared difference in

percent dissolved between the test and the reference products”. Moore and Flanner

give the model independent mathematical approach for calculating a similarity factor

f2 for comparison between dissolution profiles of different samples. The similarity

factor (f2) given by SUPAC guidelines for modified release dosage form was used as

a basis to compare dissolution profile. The dissolution profiles of products were

compared using f2. The similarity factor is calculated by following formula, 13

10011logX50 X

5.02

12

n

tttt TRwnf

Where, n is the number of dissolution time points

Rt – The reference profile at the time point t

Tt - The test profile at the same point.

Table 7.6: Similarity factor value and its significance

Similarity factor (f2) Significance

< 50 Test and reference profiles are dissimilar

50 – 100 Test and reference release profiles are similar

100 Test and reference release profiles are identical

> 100 The equation yields a negative value



A value of 100% for the similarity factor suggests that the test and reference profiles

are identical. Values between 50 and 100 indicate that the dissolution profiles are

similar whilst smaller values imply an increase in dissimilarity between release

profiles.14

7.9 Accelerated Stability study97

Optimized batch F037 was packed in blister pack (PVDC – Alu blister packing), and

was placed for stability study at 40˚C/75% RH for 3 months. Sample was collected at

every 1 month interval and evaluated for dissolution in 0.1N HCl, USP- II paddle

apparatus, 50rpm. f2 value was applied to stability study to show the effect of storage

on in-vitro drug release of formulation.



8.1 In–Vitro Release study of Innovator

The Innovator’s tablets were subjected for in vitro dissolution studies using

dissolution test apparatus USP XXIII. The dissolution medium used was pH 1.2 for

initial 2 hrs as average gastric emptying time of stomach is 2 hrs and rest was carried

out in pH 6.8 phosphate buffer solution to study the release of drug. The samples were

withdrawn at different intervals of time and analyzed at 275nm using UV

Spectrophotometer. Cumulative percentage drug release was calculated on the basis

of average amount of drug present in the dissolution chamber. The results obtained in

the in-vitro drug release study are tabulated in Table 8.1. The cumulative percentage

of drug released as a function of time for all the formulations are shown in Figure

6.10. From the in-vitro drug release profile data of Innovator’s product, three time

points were fixed for the generic product’s dissolution to match the release profile

with Innovator.

8.2 Formulation of Factorial batches

8.2.1 Coating with EC 4 cps

8.2.1.1 Cumulative % drug release profile of tablets coated using 80:20 ratio of

polymer:plasticizer



batches F022, F024 and F026 which were coated using polymer:plasticizer ratio of

80:20 is shown in the Table 8.2 and comparative dissolution profile was shown in

Figure 8.1. Formulation F022, F024 and F026 which were coated for 8%, 10% and

12% respectively showed 24, 23 and 21% drug release after initial time point of 2 hrs,

54, 54 and 56% drug release after 8 hrs and 73, 72and 68% drug release after 14 hrs.



However, % RSD for all the time points was found to be much higher than accepted

level. This may be due to uneven coating on tablet surface or may be because of

uneven distribution of polymer as the polymer concentration is much higher i.e.,

80:20 ratio of polymer:plasticizer. Further study was carried out by increasing the

level of plasticizer and ratio of polymer:plasticizer was taken as 70:30. So the study

was further continued to optimize the ratio of polymer:plasticzer and % coating to

bring the level of %RSD in acceptable range and to achieve drug release in desired

range.


polymer:plasticizer








However, % RSD for all the time points decreased as compared to the above

formulations where tablets were coated with 80:20 ratio of polymer:plasticizer, but

still found to be much higher than accepted level. This may again be due to uneven

coating on tablet surface or may be because of uneven distribution of polymer as the

polymer concentration is much higher i.e., 70:30 ratio of polymer:plasticizer. Further

study was carried out by increasing the level of plasticizer and ratio of

polymer:plasticizer was taken as 60:40. So the study was further continued to



optimize the ratio of polymer:plasticzer and % coating to bring the level of %RSD in

acceptable range and to achieve drug release in desired range.


polymer:plasticizer








% RSD for all the time points decreased as compared to all the above formulations

where tablets were coated with 80:20 ratio and 70:30 ratio of polymer:plasticizer, and

was found to be in the accepted level. But from the dissolution study; none of the

formulations could control the initial time point release. Further study was carried out

by changing the grade of polymer to EC 10 cps. So the study was further continued to

optimize the ratio of polymer:plasticzer and % coating to bring the drug release in the

desired level after selected time points.

8.2.2 Coating with EC 10 cps


polymer:plasticizer








12% respectively showed 0.3, 0 and 0% drug release after initial time point of 2 hrs,

21.6, 5.9 and 0% drug release after 8 hrs and 42.8, 14.6 and 19.5% drug release after

14 hrs. However, % RSD for all the time points was found to be much higher than

accepted level. Also, the drug release does not fit in the desired fixed level. Hence,

further study was decided to perform using 70:30 ratio of polymer:plasticizer using

EC 10 cps.


polymer:plasticizer

The results of in-vitro dissolution study of trial batches F029, F031 and F033 which

were coated using polymer:plasticizer ratio of 70:30 is shown in the Table 8.6 and

comparative dissolution profile was shown in Figure 8.5. Formulation F029, F031 and

F033 which were coated for 8%, 10% and 12% respectively showed 1.6, 0.9 and 0.5%

drug release after initial time point of 2 hrs, 23.6, 18.6 and 16.8% drug release after 8

hrs and 48.5, 41.5 and 40.5% drug release after 14 hrs. However, the drug release

does not fit in the desired fixed level. Also, the % RSD level was found to decrease to

the accepted range as the level of polymer decreases and as % coating on tablets

increases. Hence, further study was decided to perform using 60:40 ratio of

polymer:plasticizer using EC 10 cps.


polymer:plasticizer

The results of in-vitro dissolution study of trial batches F035, F037 and F039 which

were coated using polymer:plasticizer ratio of 60:40 is shown in the Table 8.7 and



comparative dissolution profile was shown in Figure 8.6. Formulation F029, F031 and

F033 which were coated for 8%, 10% and 12% respectively showed 10.3, 7.8 and

5.7% drug release after initial time point of 2 hrs, 53.7, 54.8 and 54% drug release

after 8 hrs and 78.9, 76.6 and 75.9% drug release after 14 hrs. From the in-vitro drug

release data of the tablets coated with EC 10 cps using polymer:plasticizer ratio of

60:40, it was found that formulations F037 and F039 shows the release as per our

required range and also the % RSD was well in the accepted range. From the above

two formulations, formulation F037 was selected to proceed further with stability

studies as the drug release after 20 hrs of dissolution study was found to be 95.8% in

case of F037, whereas; it was just 89.2% in case of F039.

8.3 Drug release kinetic analysis by using different release model of

Extended release matrix tablet

To know the mechanism of drug release from the best formulations, the data were

treated according to first-order (log cumulative percentage of drug remaining vs time),

Higuchi’s15 (cumulative percentage of drug released vs square root of time),

Korsmeyer et al’s16 (log cumulative percentage of drug released vs log time), Hixon-

Crowell’s (cube root of % drug retained vs time) equations along with zero order

(cumulative amount of drug released vs time) pattern the results shown in Table 8.8.

The in vitro release profiles of drug from the best formulation could be best expressed

by zero order, as the plots showed high linearity (R2 = 0.966, Table 5.33). To confirm

the mechanism of release, data were fit to other model equations. The formulation

could be best described by Hixon-Crowell’s equation, as the plot showed high

linearity (R2: 0.987).



8.4 Accelerated Stability study

The result of accelerated stability study showed that there was no change in the

formulation after 3 months. In-vitro drug release study show that after 1, 2 and 3

month, f2 value obtained was 77.35, 84.94and 73.17 respectively. The drug release

through out 24 hours obtained within range of targeted release profile. The related

substance results showed that individual maximum impurity below 0.5% and total

maximum impurity below 1.0%. After 3 month accelerated stability study the assay

result was stable. The results are shown in Table 8.9 and dissolution plots are shown

in Figure 8.7.



8.1: % drug release profile of Innovator’s product

Table 8.1: % drug release profile of Innovator’s

product


0 0

2 0

4 3.6

6 8.9

8 16.3

10 26.3

12 37.2

14 49.2

16 59.8

18 74.3

20 86.9

22 94.3

24 102.7



Table 8.2: Cumulative % drug release from tablets coated using 80:20 ratio of polymer:plasticizer

Time (Hr) F022 % RSD F024 % RSD F026 % RSD

0 0 0 0 0 0 0

2 24 121.3 23 117 21 76.2

8 54 42.3 54 37.6 56 31.9

14 73 26 72 20.3 68 23.8

20 94 16.9 89 15.6 85 13.9

(Figure 8.1: Dissolution profile of tablets coated with EC 4cps using 80:20 ratio

of EC: PEG)

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

% d

rug

rele

ase

Time (hrs)

F022

F024

F026





0 0 0 0 0 0 0

2 29 76.2 28 48.6 27 37.4

8 54 13.9 58 14.8 52 19.1

14 81 11.2 79 7 76 15.6

20 95 5.9 93 5.9 91 9.6


of EC: PEG)

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

% d

rug

rele

ase

Time (hrs)

F028

F030

F032





0 0 0 0 0 0 0

2 34 14.9 32 18.1 31 10.7

8 65 12.6 61 11.3 56 3.8

14 89 4.8 85 3.2 83 2.2

20 96 2.9 93 1.6 93 1.3


of EC: PEG)

0

20

40

60

80

100

120

0 5 10 15 20 25

% d

rug

rele

ase

Time (hrs)

F034

F036

F038





0 0 0 0 0 0 0

2 0.3 162.5 0 0 0 0

8 21.6 28.5 5.9 79.5 0 0

14 42.8 17.1 14.6 21.9 19.5 29.6

20 59.9 11.3 44.5 14.3 60.5 13.5

(Figure8.4: Dissolution profile of tablets coated with EC 10cps using 80:20 ratio

of EC: PEG)

-10

0

10

20

30

40

50

60

70

0 5 10 15 20 25

% d

rug

rele

ase

Time (hrs)

F023

F025

F027





0 0 0 0 0 0 0

2 1.6 60.7 0.9 28.5 0.5 22

8 23.6 19.8 18.6 17.1 16.8 12.6

14 48.5 8.2 41.5 9.8 40.5 7.3

20 67.7 7.6 56.8 7.1 55.9 3.6


of EC: PEG)

-10

0

10

20

30

40

50

60

70

80

0 5 10 15 20 25

% d

rug

rele

ase

Time(hrs)

F029

F031

F033





0 0 0 0 0 0 0

2 10.3 9.7 7.8 11.9 5.7 12.6

8 53.7 3.9 54.8 1.6 54 5.4

14 78.9 0.6 76.6 5.1 75.9 1

20 96.5 0.7 95.8 3.4 89.2 1.3


of EC: PEG)

-20

0

20

40

60

80

100

120

0 5 10 15 20 25

% d

rug

rele

ase

Time(hrs)

F035

F037

F039



Table 8.8: Data analysis by using different model

Model Zero

order

First

order Higuchi

Korsemeyer-

Peppas

Hixon-

Crowell

Linearity (R2) 0.966 0.938 0.954 0.967 0.987

Slope (n) 4.96 -0.06 22.79 1.11 0.149

Intercept (c) 3.30 2.10 -9.79 0.43 -0.115



Table 8.9: Result of Accelerated stability study

Pack PVDC – Alu Blister

Condition 40˚C/75%RH

Batch No. F037

In – Vitro Drug Release

Time (hrs.) Initial 1 month 2 month 3 month

0 0 0 0 0

2 7.8 7.3 6.8 8.5

8 54.8 55.3 54.2 57.2

14 76.6 77.9 73.9 78.6

20 95.8 96.1 92.9 98.3

f2 value 78.87 77.35 84.94 73.17

Related Substances

Individual Maximum

Impurity 0.26 0.33 0.32 0.28

Total Impurity 0.46 0.52 0.57 0.55

Assay

% Potency 99.7 99.2 99.4 98.9



(Figure 8.7: Dissolution profile of F037 after stability studies)

0

20

40

60

80

100

120

0 5 10 15 20 25

% C

DR

Time (hrs)

Initial

1 month

2 month

3 month

Chapter -9 CCoonncclluussiioonn


CONCLUSION:

1. The aim of Present work was to prepare extended release tablets of novel anti

depressant drug.

2. HPMC and PEO were selected to control the release of drug from the matrix

system.

3. Preliminary trials were done to optimize the level of HPMC and PEO to form the

matrix tablet.

4. 32 full factorial design was applied to obtain a validated ratio of polymers which

can control the release rate and polymer concentrations were taken as factors

(HPMC was kept as X1 and PEO was kept as X2).

5. The batches were formulated and checked for all the related parameters. Drug

release after 2 hrs (Y1), release after 6 hrs (Y2) and drug release after 10 hrs (Y3)

were taken as dependant variables.

6. Surface plots were performed to validate the batches.

7. The drug release followed Anomalous Fickian diffusion; which indiacates a

coupling of diffusion and erosion mechanism.

8. Optimized matrix tablet formulation was further coated with Ethyl Cellulose using

PEG as a plasticizer in different ratios and for different weight gain to control the

release upto the desired level.

9. 32 x 21 factorial design was applied to obtain a validated ratio of

polymer:plasticizer, % coating and also grade of Ethyl cellulose to be used to

control the release keeping %RSD in the limit (Ratio of Polymer:Plasticizer as

X1, % coating as X2 and grade of Ethyl Cellulose as X3).

Chapter -9 CCoonncclluussiioonn


10. The batches were formulated and checked for all the related parameters and

release obtained for each formulation was compared with the levels fixed keeping

a watch on %RSD.

11. Final batch F037 was selected for accelerated stability study and kinetic modeling

for drug release.

12. The drug release followed by zero order with diffusion mechanism.

13. The formulation was stable after 3 months of stability study.

Chapter -10 SSuummmmaarryy


Summary:

Depression is the most common affective disorder and affects as many as 1 in 4

people in their teen years. Anti depressants are the classes of drugs which can elevate

mood in depressive illness. But all Anti depressant drugs have various side-effects

such as sedation, hypotension, cardiac arrhythmias, seizure precipitation, enzyme

inhibitory action, dose related CNS toxicity, renal diabetes insipidus, loss of libido

and failure or orgasm. Hence, there is a need for the development of a formulation

containing new anti-depressant drug. By preparing extended release formulation of

the drug dosage frequency can be reduced, optimized and controlled therapy can be

achieved and also it has better patient compliance.

Preliminary trials of matrix tablet:

Attempts were made for preparation of matrix tablet by HPMC which is most widely

used matrix-forming polymer because of its compatibility, multifunctional property

and low cost and also by PEO which provides delayed drug release via the

hydrophilic matrix approach. Combination of HPMC and PEO was also used for

preparation of matrix tablet. Results of Preformulation studies of the drug indicated

that, it had poor flow property and compressibility property. To improve the flow and

compressibility property, it was beneficial to use the directly compressible grade

components in the formulation of tablet. Results of DSC study shown that there is no

change in drug’s melting peak after the preparation of tablet.

The preliminary trials were taken by using single polymer HPMC and PEO. The

results of PEO indicate that the drug release obtained was faster than the required

drug release. By using HPMC initial slower drug release and than after faster drug

release was obtained. Hydrophilic matrix of HPMC and PEO in combination,



sustained the drug release effectively for 12h. The result indicated that the

combination of HPMC and PEO can be successfully utilized to create matrix tablet,

but the targeted release profile was not achieved even with the combination.

Preliminary trials of Coating with Ethyl cellulose:

The optimized matrix tablet formulation was then coated with Ethyl Cellulose

polymer using PEG as plasticizer. Different ratios of Polymer:Plasticizer (viz., 80:20,

70:30 and 60:40) were evaluated to achieve the desired release profile. Tablets were

coated for different % weight gain and evaluated for release profile. Two different

grades of Ethyl Cellulose were used for same ratios and % weight gain to obtain the

desired release profile.

The results indicated that ratio of polymer:plasticizer and % weight gain had

significant effect on %RSD in release profile. Ethyl cellulose 4 cps failed to control

the release in desired level and Ethyl cellulose 10 cps successfully controlled the

release for 24 hrs and the release profile obtained was similar to the targeted release

profile.

6.2 Formulation and Optimization of Sustained release matrix tablets by using

32 full factorial designs

On the basis of the preliminary trials in the present study a 32 full factorial design was

employed to study the effect of independent variables, i.e. concentration of HPMC

(X1) and concentration of PEO (X2) on dependent variables like % drug release Q2, Q6

and Q10. Drug release is also dependent on the size of matrix tablets so, size and

surface area was kept constant. The strength of the gel depends on the chemical

structure and molecular size of the polymer. It is known that higher viscosity grade

polymer HPMC hydrates at faster rate and therefore, it is capable of forming gel



structure than a low viscosity grade PEO polymer. The co-efficients of X1 and X2

were negative indicate that when concentration of both the variable increase than drug

release was decreased. From the result of 32 full factorial design and regression

analysis for Extended release matrix tablet, it was concluded that factorial batch F016

taken with combination of 35% HPMC and 35% PEO gives better sustaining capacity

than all other combinations.

In present study to check the reproducibility, batch taken with larger batch size and

evaluated for reproducibility. From the result, concluded that reproducible batch taken

with 35% HPMC and 35% PEO had good reproducibility. The result of regression

analysis showed that all the co-efficient bear a negative sign, which indicate that by

increasing the concentration of both the polymers the drug release was sustained. The

drug release followed Higuchi’s model with n value 0.369, which indicate a coupling

of diffusion and erosion mechanisms so called anomalous diffusion. The higher value

of correlation co-efficient of Q2, Q6, and Q10 indicate that a good fit i.e., good

agreement between the dependent and independent variables.

Formulation F037, containing coating of tablets with EC 10cps using 60:40 ratio of

polymer:plasticizer and 10% coating was selected as best formulation and kept for

stability studies according ICH guidelines. From the stability result, it was found that

there was no change in the formulation after 3 months of accelerated stability study

and the prepared formulation was stable.

Chapter -11 BBiibblliiooggrraapphhyy


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