Post on 15-Jan-2020
Ambroxol Hydrochloride
7.1 Rational behind selection of Drug
7.2 Need for Study
7.3 Methodology
7.4 Results & Discussion
7.5 Conclusion
7.6 Bibliography
Chapter 7 Ambroxol Hydrochloride - Rational
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 154
7.1 RATIONAL BEHIND SELECTION OF AMBROXOL HYDROCHLORIDE
Ambroxol is an active metabolite of the mucolytic agent bromhexine with similar action
and uses. 1
The drug is chemically trans– 4-[(2-amino-3, 5-dibromobenzyl) amino]
cyclohexanol hydrochloride with molecular weight of 414.6. It is used in the treatment of
bronchitis to improve expectoration. Thus it is an expectoration improver and a mucolytic
agent used in the treatment of acute and chronic disorders characterized by the production
of excess or thick mucous.
Ambroxol has been successfully used for decades in the form of its hydrochloride as a
secretion-releasing expectorant in a variety of respiratory disorders.2 It is widely used in
the treating all forms of Tracheobronchitis, Emphysema with Bronchitis Pneumoconiosis,
Chronic inflammatory pulmonary conditions, Bronchiectasis, and Bronchitis with
Bronchospasm asthma.
The drug is well absorbed from gastrointestinal tract. It is rapidly absorbed after oral
administration followed by elimination with a half-life of 3–4 h. Ambroxol is a sparingly
soluble drug. Its short biological half-life of 3-4 h 3, 4
calls for frequent daily dosing 3 to 4
times.
Thus its therapeutic use in chronic respiratory disease necessitates its formulation into
controlled release dosage form. The development of controlled release formulations of
ambroxol hydrochloride is therefore of therapeutic relevance and can be used to provide a
consistent dosage through controlling an appropriate level of the drug over time.
Chapter 7 Ambroxol Hydrochloride – Need for study
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 155
7.2 NEED FOR THE STUDY
Ambroxol hydrochloride (Ambroxol HCl) has short biological half- life of 3-4 hours and
is administered in a dose of 30 mg, 3-4 times a day.5 Therefore it is an ideal candidate for
design as a Controlled Release (CR) dosage form.
Controlled release delivery systems can achieve predictable and reproducible release
rates, extended duration of activity for short half-life drugs, decreased toxicity, and
reduction of required dose, optimized therapy, and better patient compliance. With the
aim of maximizing the bioavailability of conventional drugs with minimum side effects,
new drug delivery systems continue to attract much attention. The simplest and least
expensive way to control the release of the drug is to disperse it within an inert polymeric
matrix and hydrophilic matrices are an interesting option when formulating an oral
controlled release of a drug because of their flexibility to obtain a desirable drug release
profile, cost effectiveness and broad regulatory acceptance. Different polymers are
employed due to their in situ gel forming characteristics, and their ability to release
entrapped drug in the specific medium by swelling and cross-linking. Among the
hydrophilic polymers, cellulose derivatives are generally considered to be stable and safe
as release retardant excipients in the development of oral controlled release dosage forms.
The dosage release properties of matrix devices may be dependent upon the solubility of
the drug in the polymer matrix or, in case of porous matrices, the solubility in the sink
solution within the particle’s pore network.6 HPMC and carbopols are the dominant
hydrophilic vehicles used for the preparation of oral controlled drug delivery systems.7,8
Thus, one of the objectives of the present study was to formulate Ambroxol HCl CR
matrix tablets by direct compression using different grades of HPMC and Carbopol
polymers and investigate the influence of different polymer concentrations on drug
release in matrices.
Recently, Melt granulation method has been widely used in oral controlled drug delivery
to obtain powdered agglomerations by the use of meltable binder, which can be a molten
liquid, a solid, or a solid that melts or softens during the solvent free process.9 Melt
granulation offers several advantages as it is cost-effective and safe since liquid addition
and the subsequent drying phase required for the wet granulation process are not
necessary. Granules prepared by melt granulation exhibit better physical strength and
have smoother surfaces than those obtained by wet granulation. Waxes 10
, stearic acid11,12
Chapter 7 Ambroxol Hydrochloride – Need for study
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 156
polyethylene glycols13
, fats, fatty acids, fatty alcohols14, 15
, castor oil16, 17
and glycerides18
are typical examples of meltable binders.
Factorial design is an optimization technique, where all the factors are studied in all
possible combinations. This technique is considered most efficient in estimating the
influence of individual variables (main effects) and their interaction using minimum
experimentation. 19
In the proposed research work, hypothesis was that melt granulation of Ambroxol HCl
with different hydrophobic binders might improve not only the overall flowability of the
particle mixtures for direct compression but also the sustainability and predictability of
predetermined drug release from matrix tablets. Thus, another objective of this research
was to prepare a controlled release drug delivery system of Ambroxol HCl by using a
hydrophobic meltable binders (M.P. 50-80°C) by melt granulation using different waxes
as bees wax, paraffin wax, stearic acid, lubritab and polymeg with HPMC K4M and
investigate their different concentrations on drug release profile by 32 full factorial
design.
Chapter 7 Ambroxol HCl - Methodology
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 157
7.3 METHODOLOGY FOR AMBROXOL HCl:
7.3.1 PREFORMULATION STUDIES:
Standardization and calibration curve of Ambroxol HCl had been performed as explained
in section 5.3.1.1 to 5.3.1.4. The concentration range selected for AH was 5-50μg/ml in
pH 1.2 (0.01N HCl) and pH 6.8 phosphate buffer for calibration curve.
DRUG-POLYMER COMPATIBILITY study was done by FTIR and DSC studies.
7.3.2 ORAL CDDS FOR AMBROXOL HCl:
Monolithic matrix tablets were among the several approaches that have been developed in
order to control the drug delivery. Different attempts made by different scientists to make
matrix and oral CDDS: Matrix tablets for the last three decades have been popular
challenging in the formulation of controlled release.
FORMULATION DEVELOPMENT:
Marketed product (ACOCONTIN) was subjected to evaluation to determine weight and
dissolution. Attempts were made to develop formulations with less weight but having
same dissolution profile as explained in the later sections.
7.3.2.1 MATRIX TABLET FORMULATION OF AMBROXOL HCL BY DIRECT
COMPRESSION:
The simplest and least expensive way to control the release of the drug is to disperse the
drug within an inert polymeric matrix. And hydrophilic matrices are an interesting option
for controlling the release of drug. Development of the formulation in the present study
was mainly based on the different grades of polymers as HPMC and Carbopol. Various
polymers in different ratios were used so as to get tablet with good physical properties,
which match with marketed product’s properties. So, in the present study attempts were
made to minimize the concentration of polymer and other excipients as well as to get
quality parameters of the tablets.
Polymers selected for matrix tablets were different grades of HPMC (K100LV CR, K4M,
K100M and K200M) different grades of Carbopol (934 P, 974 P, 971 P and 71 G NF) and
Polycarbophil. Excipients like Avicel PH 102 is selected because of its excellent
compressibility, good moisture stability, rapid disintegration, excellent in absorbing
water, oil and solvents, free flowing, excellent initial color and long-term stability.
Magnesium stearate is selected for glidant action and Talc for lubricant effect.
Chapter 7 Ambroxol HCl - Methodology
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 158
Method: Direct Compression
Direct compression was followed to manufacture the Ambroxol HCl tablets. All the
polymers selected, drug and excipients were passed through sieve no. 40 before using into
formulation. The formulations were prepared according to the composition shown in
Table 7.1 & 7.2
Steps involved in the manufacture of tablets
First the drug and polymer selected were passed through 40- mesh sieve. Required
quantity of drug, polymer and excipients were weighed properly and transferred into
mortar and the blend was mixed for at least 10 min.
The blend obtained was then lubricated by adding required quantity of magnesium
stearate and the prepared blend was evaluated for precompression studies.
Then,the tablets were compressed using 8mm diameter punches in “Remik mini
press-1” tablet punching machine. The compression force was adjusted to achieve
hardness of 5 to 7 Kg/cm2.
7.3.2.2 MATRIX TABLET FORMULATION OF AMBROXOL HCL BY MELT
GRANULATION:
An interesting approach to develop CR formulations is based on melt granulation, which
is a very short one-step technique converting fine powders into granules. Powder
agglomeration is promoted by the addition of a low melting point binder, which is solid at
room temperature and melts at relatively low temperatures (50–80°C). In the present
work, lipophilc binders of different melting ranges selected for the study were Bees wax
with intra and extragranular HPMC K4M and Paraffin wax, Stearic acid, Lubritab and
Polymeg with extragranular HPMC K4M.
Chapter 7 Ambroxol HCl - Methodology
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 159
Table 7.1: Composition of Matrix Tablets by Direct Compression with Various Grades of HPMC Polymers
Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Ambroxol HCl 30 30 30 30 30 30 30 30 30 30
HPMC K 100LVCR 30 15 - - - - - - - -
HPMC K 4M - - 30 60 - - - - - -
HPMC K 100M - - - - 30 15 - - - -
HPMC K 200M - - - - - - 30 15 12 7.5
Avicel 102 38 53 38 8 38 53 38 53 56 61
Magnesium stearate 1 1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1 1
TOTAL 100 100 100 100 100 100 100 100 100 100
Table 7.2: Composition of Matrix Tablets by Direct Compression with Various Grades of Carbopol Polymers
Formulation F11 F12 F13 F14 F15 F16 F17 F18 F19 F20 F21 F22 F23 F24 F25
Ambroxol HCl 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30
Carbopol 934 P NF 30 15 7.5 - - - - - - - - - - - -
Carbopol 974 P NF - - - 30 15 7.5 - - - - - - - - -
Carbopol 971 P NF - - - - - - 30 15 7.5 - - - - - -
Carbopol 71 G NF - - - - - - - - - 30 15 7.5 - - -
Polycarbophil - - - - - - - - - - - - 30 23 15
Avicel 102 38 53 61 38 53 61 38 53 61 38 53 61 38 46 53
Magnesium stearate 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
TOTAL 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
*All ingredients expressed in % w/w
Chapter 7 Ambroxol HCl - Methodology
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 160
OPTIMIZATION USING FULL FACTORIAL DESIGN:
A 32
full factorial design optimization method was used to prepare hydrophilic matrix
tablets by melt granulation using wax polymers. Table 7.3-7.11 summarizes the
composition of the formulations. A laboratory scale method was used to prepare granules
composed by lipophilic binders and HPMC K4M as hydrophilic polymer. The granulation
procedure was optimized on the basis of preliminary trials. The wax polymers were
heated up to the melting point of the hydrophobic binder and the drug Ambroxol HCl was
mixed for 5 min. The lipophilic binders were added to drug in powder form, as flakes
which were reduced to a powder at a low temperature in the mortar or in a molten form
(Paraffin Wax). Melt granulation occurred within 5 min when the lipophilic binder was
added as powder or flakes, or immediately when molten wax was added to drug.20
In order to obtain granules, molten mixture was passed through sieve no. 16. The granules
obtained were sieved again in order to remove lumps, mixed with HPMC K4M and the
diluent Avicel PH 102 for 5-10 min. and then finally mixed with 0.5% magnesium
stearate for 5 min. and evaluated for precompression studies and compressed into tablets
using 8mm diameter punches in “Remik mini press-1” tablet punching machine. The
compression force was adjusted to achieve hardness of 5 to 7 Kg/cm2.
Table 7.3: Composition of Matrix Tablets of Ambroxol HCl by melt granulation
Table 7.4: Actual and Coded Levels of the Factors
Sr. No. Formulation Quantity in % w/w
1 Ambroxol HCl 30
2 Wax polymer 4 – 25
3 HPMC K4M 10- 32
4 Avicel 102 Quantity sufficient to make 100
5 Magnesium stearate 1
6 Talc 1
Total weight 100 % (250 mg)
Factors Wax Polymer Wax Polymers (X1) in % w/w HPMC K4M (X2) in % w/w
Concentration Bees Wax 8 10 12 28 30 32
Coded Levels -1 0 +1 -1 0 +1
Concentration Bees Wax I* 4 8 12 10 20 30
Coded Levels -1 0 +1 -1 0 +1
Concentration Paraffin Wax 8 10 12 28 30 32
Coded Levels -1 0 +1 -1 0 +1
Concentration Stearic Acid 15 20 25 22 24 26
Coded Levels -1 0 +1 -1 0 +1
Concentration Lubritab 20 22 24 20 25 30
Coded Levels -1 0 +1 -1 0 +1
Concentration Polymeg 5 10 15 10 20 30
Coded Levels -1 0 +1 -1 0 +1
Chapter 7 Ambroxol HCl - Methodology
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 161
Table 7.5: Composition of formulations in terms of coded values
Formulations code (X1) (X2)
A1, B1, C1, D1, E1, G1 -1 -1
A2, B2, C2, D2, E2, G2 -1 0
A3, B3, C3, D3, E3, G3 -1 +1
A4, B4, C4, D4, E4, G4 0 -1
A5, B5, C5, D5, E5, G5 0 0
A6, B6, C6, D6, E6, G6 0 +1
A7, B7, C7, D7, E7, G7 +1 -1
A8, B8, C8, D8, E8, G8 +1 0
A9, B9, C9, D9, E9, G9 +1 +1 Table 7.6: Composition of Matrix Tablets with Bees Wax as per 3
2 Factorial Design
Formulation A1 A2 A3 A4 A5 A6 A7 A8 A9
Ambroxol HCl 30 30 30 30 30 30 30 30 30
Bees Wax 8 8 8 10 10 10 12 12 12
HPMC K4M 28 30 32 28 30 32 28 30 32
Avicel 102 32 30 28 30 28 26 28 26 24
Magnesium Stearate 1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1
TOTAL 100 100 100 100 100 100 100 100 100 *All ingredients expressed in % w/w
Table 7.7: Composition of Matrix Tablets with Bees Wax I* as per 32 Factorial Design
Formulation B1 B2 B3 B4 B5 B6 B7 B8 B9
Ambroxol HCl 30 30 30 30 30 30 30 30 30
Bees Wax 4 4 4 8 8 8 12 12 12
HPMC K4M 10 20 30 10 20 30 10 20 30
Avicel 102 54 44 34 50 40 30 46 36 26
Magnesium Stearate 1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1
Total 100 100 100 100 100 100 100 100 100 *All ingredients expressed in % w/w Table 7.8: Composition of Matrix Tablets with Paraffin Wax as per 3
2 Factorial Design
Formulation C1 C2 C3 C4 C5 C6 C7 C8 C9
Ambroxol HCl 30 30 30 30 30 30 30 30 30
Paraffin Wax 8 8 8 10 10 10 12 12 12
HPMC K4M 28 30 32 28 30 32 28 30 32
Avicel 102 32 30 28 30 28 26 28 26 24
Magnesium Stearate 1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1
TOTAL 100 100 100 100 100 100 100 100 100 *All ingredients expressed in % w/w
Table 7.9: Composition of Matrix Tablets with Stearic Acid as per 32 Factorial Design
Formulation D1 D2 D3 D4 D5 D6 D7 D8 D9
Ambroxol HCl 30 30 30 30 30 30 30 30 30
Stearic Acid 15 15 15 20 20 20 25 25 25
HPMC 22 24 26 22 24 26 22 24 26
Avicel 102 31 29 27 26 24 22 21 19 17
Magnesium Stearate 1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1
TOTAL 100 100 100 100 100 100 100 100 100 *All ingredients expressed in % w/w
Chapter 7 Ambroxol HCl - Methodology
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 162
Table 7.10: Composition of Matrix Tablets with Lubritab as per 32 Factorial Design
Formulation E1 E2 E3 E4 E5 E6 E7 E8 E9
Ambroxol HCl 30 30 30 30 30 30 30 30 30
Lubritab 20 20 20 22 22 22 24 24 24
HPMC K4M 20 25 30 20 25 30 20 25 30
Avicel 102 28 23 18 26 21 16 24 19 14
Magnesium Stearate 1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1
TOTAL 100 100 100 100 100 100 100 100 100 *All ingredients expressed in % w/w
Table 7.11: Composition of Matrix Tablets with Polymeg as per 32 Factorial Design
Formulation G1 G2 G3 G4 G5 G6 G7 G8 G9
Ambroxol HCl 30 30 30 30 30 30 30 30 30
Polymeg 5 5 5 10 10 10 15 15 15
HPMC K4M 10 20 30 10 20 30 10 20 30
Avicel 102 53 43 33 48 38 28 43 33 23
Magnesium Stearate 1 1 1 1 1 1 1 1 1
Talc 1 1 1 1 1 1 1 1 1
TOTAL 100 100 100 100 100 100 100 100 100 *All ingredients expressed in % w/w
7.3.3 EVALUATION OF MATRIX TABLETS OF AMBROXOL HCl:
7.3.3.1 PRE COMPRESSION PARAMETERS:
Evaluations of powder blends or melt granules:
All the formulations were evaluated for precompression parameters as angle of repose,
bulk and tapped density, Carr’s index and Hausner’s ratio as described in section 5.3.3.1.
7.3.3.2 POST COMPRESSION PARAMETERS:
Tablets were evaluated for parameters like weight variation, thickness, hardness, and
friability as described in section 5.3.3.2.
DRUG CONTENT UNIFORMITY:
At random 5 tablets were weighed and powdered individually, and the drug was extracted
in pH 6.8 phosphate buffer. The solution was filtered through 0.45 µm membrane filter
and the absorbance was measured at 244.5nm after suitable dilution to calculate the
concentration of the drug.
IN-VITRO DISSOLUTION STUDIES
In-vitro dissolution study of Ambroxol HCl was carried using Electrolab TDT-08L USP
dissolution test apparatus.
Method:
Tablets were introduced into dissolution test apparatus and the apparatus was set at 50
rpm motion. 5 ml of sample was withdrawn for 1st
two hours at 30 min intervals and after
that at 1 h intervals and replaced by the respective buffer solutions and analysed.
The details are given as below.
Chapter 7 Ambroxol HCl - Methodology
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 163
Electrolab TDT-08L USP dissolution test apparatus
Apparatus used USP type 2 dissolution test apparatus
Dissolution medium pH 1.2 and pH 6.8 buffer solutions
Dissolution medium volume 900 ml
Temperature 37±0.5ºC
Speed of paddle in rpm 50 rpm
Sampling intervals 30 min for 1st two h and then 1 h up to 12 h
Sample withdrawn volume 5 ml
Absorption measurement 244.45 nm in pH 1.2 and 244.5 nm in pH 6.8 SWELLING AND EROSION STUDIES:
Optimized matrix tablets were introduced into the dissolution apparatus I containing 900
ml of pH 6.8 at 37°C at 100 rpm. The tablets were removed using a small basket and
swollen weight of each tablet was determined. To determine matrix erosion, swollen
tablets were placed in a oven at 50°C and after 48 hours tablets were removed and
weighed. Swelling (%) and erosion (%) was calculated.
7.3.4 MATHEMATICAL MODELLING:
The release profile of the drug obtained was analysed using different kinetic models such
as zero order, first order, Higuchi, Hixson Crowell and Korsmeyer – Peppas model in
order to evaluate the release mechanism from matrices.
7.3.5 COMPARISON OF DISSOLUTION PROFILES:
Difference factor f1 and similarity factor f2 were calculated for all the formulations by
comparing drug release profile of all formulations with marketed formulation of
Ambroxol HCl as ACOCONTIN CR (Modi-Mundipharma).
7.3.6 DATA ANALYSIS FOR DRUG RELEASE OF MATRIX TABLETS OF
AMBROXOL HCl BY MELT GRANULATION AS PER 32 FACTORIAL DESIGN:
Stat-Ease Design Expert 8.0.4.1 software was used to treat the data statistically using
ANOVA and the individual parameter was evaluated using F-Test.
7.3.7 STABILITY STUDY:
The promising formulations were packed in 0.04 mm thick aluminum foil strips
laminated with PVC. The packed tablets were placed in stability chamber maintained at
40±2oC and 75±5% RH for 3 months. The samples were withdrawn periodically and after
three months and were evaluated for drug content and in vitro dissolution studies.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 164
7.4 RESULTS AND DISCUSSION FOR AMBROXOL HCl
7.4.1 PREFORMULATION STUDIES:
The results of preformulation studies carried out in this study are presented below.
7.4.1.1 IDENTIFICATION OF PURE DRUG:
Identification of Ambroxol HCl was carried out by Infra-Red Absorption
Spectrophotometry and FTIR spectrum of pure drug is shown in Figure 7.1. FTIR
spectrum (Table 7.12) of pure drug was studied and characteristic absorption peaks
obtained for C–H; N–H; C–N; O–H; C-Br etc. groups were found to be confirmed the
drug.
Table 7.12: FTIR characteristic peaks of Ambroxol HCl
Sr.
No
Functional groups Characteristic peaks (nm) Observed peaks (nm)
Stretching Bending Stretching Bending
1 C−H 3150 – 3050 3066
2. =C-H 2966
3 C-H Aromatic Characteristic
shapes
2000 - 1667 900-850,
860 – 790
1760-1700 866, 896
4 C−N (Aromatic) 1350 – 1250 1284
5 C-N (Aliphatic) 1220 – 1020,
1410
1130,
1413
6. Aromatic NH2 (2 Bands) 3500, 3400 1650-1590 3396,
3282
1633
7 N−H Secondary amine 3500 – 3310 1650-1550 3228 1543
8 O−H Intermolecular Hydrogen
bonded
3400 – 3200 1100,
1350-1260
3196 1064,
1284
9 C-O 1100 -1070 1064
10 C−Br (Aryl Bromide) 1250 – 1190 1075-1030 1203 1064
Figure 7.1: FTIR peaks of Ambroxol HCl
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 165
7.4.1.2 MELTING POINT DETERMINATION
Melting point of Ambroxol HCl was found to be 237°C to 238
°C indicating purity of drug
sample.
7.4.1.3 SOLUBILITY STUDIES:
Ambroxol HCl was found to be freely soluble in methanol. The saturation solubility
studies with different pH buffers were carried out and the results are shown in Table 7.13.
With increase in pH, solubility of Ambroxol HCl increases till pH 7.4.
Table 7.13: Saturation Solubility of Ambroxol HCl in various pH buffers
Sr. no. pH Concentration (mg/ml)
1 1.2 4.903
2 2 2.184
3 4.5 16.47
4 6.8 18.42
5 7.2 6.477
6 7.4 38.92
7 7.8 1.404
8 Distilled Water 6.158
7.4.1.4 ANALYTICAL METHOD ESTIMATION :
The ultraviolet spectrophotometric method was used to analyse Ambroxol HCl.
UV Spectrum of Ambroxol HCl in 0.1 N HCl and pH 6.8:
UV spectrum of Ambroxol HCl showed the maximum absorption wavelength at 244.45
nm in pH 1.2 and 244.5 nm in pH 6.8 (Figure 7.2)
Figure 7.2: UV Spectrum of Ambroxol HCl in pH 1.2 and in pH 6.8 Standard Calibration Curve of Ambroxol HCl in pH 1.2 and in pH 6.8:
The calibration curve was found to be linear in the concentration range of 5-35 µg/ml in
pH 1.2(0.01N HCl) and pH 6.8 phosphate buffer at its λmax, 244.45 and 244.5 nm
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 166
respectively. The coefficient of correlation (R2) was found to be 0.9997 and 0.9998 with
slope of 0.023 and 0.024 respectively.
Figure 7.3: Standard calibration curve for Ambroxol HCl in pH 1.2 and in pH 6.8
7.4.1.5 COMPATIBILITY STUDIES
Compatibility studies were confirmed by FTIR and DSC studies.
7.4.1.5.1 FTIR Studies
FTIR techniques have been used to study the physical and chemical interactions between
drug and polymers. In the present study, it has been observed that there were no major
shifts in Ambroxol HCl vibrational frequencies in FTIR spectra of mixture of drug and
polymers (Figure 7.4 and Figure 7.5), indicating no chemical interaction. Hence it can be
concluded that there is compatibility between Ambroxol HCl and the polymers used in
formulations.
Figure 7.4: IR Spectras of Ambroxol HCl with various HPMC and Carbopol
Polymers
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 167
Figure 7.5: IR Spectras of Ambroxol HCl with various Wax Polymers 7.4.1.5.2 DSC Studies:
The thermograms are generated for pure drug and drug-polymer (1:1) mixtures using
DSC-60, Shimadzu, Japan. (Figure 7.6, 7.7 and 7.8) The DSC thermograms of pure
Ambroxol HCl showed a sharp endotherm at 238°C corresponding to its melting
point/transition temperature. There was no appreciable change in the melting endotherm
of drug when mixed with polymers confirming the compatibility between drug and
polymers.
Figure 7.6: DSC thermograms of Drug with various HPMC Polymers
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 168
Figure 7.7: DSC thermograms of Drug with various Carbopol Polymers
Figure 7.8: DSC thermograms of Drug with various Wax Polymers
7.4.2 PRE COMPRESSION PARAMETERS:
7.4.2.1 MATRIX TABLET OF AMBROXOL HCL BY DIRECT COMPRESSION
The lubricated blend of all the formulations showed good flow property and
compressibility index (Table 7.14). Angle of repose ranged from 26.56 to 33.14 and the
compressibility index ranged from 14.90 to 20.20. The Bulk and Tapped Density of the
prepared powder blends of different formulations ranged from 0.391 to 0.420 and 0.463
to 0.510 respectively. The value of Hausner‟s ratio ranged from 1.18 to 1.25 indicating
moderate flow property. The results of angle of repose indicated good and moderate flow
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 169
property of the powder blends and the value of compressibility index further showed
support for the fair flow property. Addition of glidant was done to improve flow property.
7.4.2.2 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION
AS PER 32 FACTORIAL DESIGN:
The flow characteristics, bulk and tapped densities, and compressibility of the powder
mixtures containing melt granules were measured to verify the improvement in physical
characteristics of those melt granules using different wax polymers for tabletting. The
results of precompression parameters are given in Table 7.15 to 7.20. Angle of repose
values less than 30° indicated free flowing property of melt granules. The bulk density
and tapped density were also found to be in acceptable range. The Carr‟s compressibility
index ranged between 10-17% indicated good flow properties for melt granules.
Hausner‟s ratio values less than 1.20 indicated good flowability.
Table 7.14 : Precompression parameters of powder blends of matrix tablets of
Ambroxol HCl by Direct Compression
Formulation
Code
Angle of
repose (θ)
Bulk density
(g/ml)
Tapped density
(g/ml)
Carr’s
index
Hausner’s
ratio
F1 31.29 0.403 0.490 17.76 1.22
F2 29.24 0.410 0.490 16.33 1.20
F3 28.45 0.391 0.472 17.16 1.21
F4 30.96 0.420 0.510 17.65 1.21
F5 33.14 0.417 0.505 17.43 1.21
F6 30.96 0.391 0.490 20.20 1.25
F7 31.67 0.410 0.510 19.61 1.24
F8 30.96 0.417 0.490 14.90 1.18
F9 33.70 0.410 0.500 18.00 1.22
F10 30.24 0.417 0.510 18.24 1.22
F11 31.13 0.417 0.500 16.60 1.20
F12 28.28 0.403 0.481 16.22 1.19
F13 30.45 0.410 0.490 16.33 1.20
F14 28.28 0.410 0.500 18.00 1.22
F15 29.24 0.413 0.490 15.71 1.19
F16 31.46 0.403 0.490 17.76 1.22
F17 29.72 0.403 0.490 17.76 1.22
F18 33.14 0.417 0.505 17.43 1.21
F19 29.98 0.391 0.463 15.55 1.18
F20 29.72 0.391 0.472 17.16 1.21
F21 26.56 0.391 0.481 18.71 1.23
F22 32.61 0.417 0.490 14.90 1.18
F23 31.46 0.410 0.510 19.61 1.24
F24 29.98 0.420 0.510 17.65 1.21
F25 31.29 0.403 0.490 17.76 1.22
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 170
Table 7.15: Precompression Parameters of Melt Granules of AH with Bees Wax
Table 7.16: Precompression Parameters of Melt Granules of AH with Bees Wax I*
Formulation
code
Angle of
repose(θ)
Bulk density
(g/ml)
Tapped density
(g/ml)
Carr’s
Index (%)
Hausner’s
ratio
B1 29.98 0.434 0.521 16.67 1.20
B2 26.56 0.432 0.510 15.25 1.18
B3 26.56 0.434 0.521 16.67 1.20
B4 29.72 0.446 0.500 10.71 1.12
B5 30.02 0.419 0.490 14.53 1.17
B6 29.72 0.404 0.481 15.97 1.19
B7 28.81 0.425 0.510 16.67 1.20
B8 28.59 0.422 0.490 13.79 1.16
B9 30.06 0.429 0.481 10.71 1.12
Table 7.17: Precompression Parameters of Melt Granules of AH with Paraffin Wax
Formulation
code
Angle of
repose(θ)
Bulk density
(g/ml)
Tapped
density (g/ml)
Carr’s
Index (%)
Hausner’s
Ratio
A1 26.13 0.404 0.481 15.97 1.19
A2 27.19 0.393 0.472 16.67 1.20
A3 27.18 0.393 0.472 16.67 1.20
A4 25.00 0.419 0.490 14.53 1.17
A5 26.19 0.404 0.481 15.97 1.19
A6 25.62 0.392 0.463 15.25 1.18
A7 27.74 0.408 0.490 16.67 1.20
A8 28.75 0.401 0.481 16.67 1.20
A9 29.31 0.415 0.490 15.25 1.18
Formulation
code
Angle of
repose (θ)
Bulk density
(g/ml)
Tapped density
(g/ml)
Carr’s
Index (%)
Hausner’s
ratio
C1 28.28 0.424 0.500 15.25 1.18
C2 26.56 0.401 0.481 16.67 1.20
C3 28.59 0.401 0.481 16.67 1.20
C4 29.72 0.422 0.490 13.79 1.16
C5 30.96 0.434 0.521 16.67 1.20
C6 29.70 0.422 0.490 13.79 1.16
C7 28.28 0.417 0.500 16.67 1.20
C8 30.02 0.432 0.510 15.25 1.18
C9 29.24 0.420 0.500 15.97 1.19
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 171
Table 7.18: Precompression Parameters of Melt Granules of Ambroxol HCl with
Stearic acid
Formulation
code
Angle of
repose (θ)
Bulk density
(g/ml)
Tapped density
(g/ml)
Carr’s
index %)
Hausner’s
ratio
D1 29.75 0.463 0.556 16.67 1.20
D2 30.02 0.484 0.581 16.67 1.20
D3 29.29 0.379 0.455 16.67 1.20
D4 29.72 0.404 0.481 15.97 1.19
D5 29.58 0.412 0.490 15.97 1.19
D6 29.46 0.438 0.521 15.97 1.19
D7 29.75 0.422 0.490 13.79 1.16
D8 28.75 0.447 0.510 12.28 1.14
D9 27.34 0.451 0.532 15.25 1.18
Table 7.19: Precompression Parameters of Melt Granules of Ambroxol HCl with Lubritab
Table 7.20: Precompression Parameters of Melt Granules of Ambroxol HCl with Polymeg
Formulation
code
Angle of
repose (θ)
Bulk density
(g/ml)
Tapped density
(g/ml)
Carr’s
index (%)
Hausner’s
ratio
G1 28.59 0.417 0.500 16.67 1.20
G2 29.75 0.412 0.490 15.97 1.19
G3 29.58 0.422 0.490 13.79 1.16
G4 29.72 0.417 0.500 16.67 1.20
G5 29.58 0.422 0.490 13.79 1.16
G6 29.96 0.426 0.481 11.50 1.13
G7 28.81 0.434 0.521 16.67 1.20
G8 29.72 0.439 0.500 12.28 1.14
G9 27.56 0.404 0.481 15.97 1.19
Formulation
code
Angle of
repose(θ)
Bulk density
(g/ml)
Tapped density
(g/ml)
Carr’s
index %)
Hausner’s
ratio
E1 29.98 0.422 0.490 13.79 1.16
E2 28.28 0.408 0.490 16.67 1.20
E3 28.45 0.446 0.500 10.71 1.12
E4 29.24 0.422 0.490 13.79 1.16
E5 26.56 0.417 0.500 16.67 1.20
E6 29.72 0.425 0.510 16.67 1.20
E7 28.28 0.422 0.490 13.79 1.16
E8 29.98 0.426 0.481 11.50 1.13
E9 30.06 0.393 0.472 16.67 1.20
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 172
7.4.3 POST COMPRESSION PARAMETERS
The matrix tablets of all different formulations were subjected to various in vitro
evaluation tests like thickness, diameter, hardness, and friability, uniformity of weight,
drug content, in vitro dissolution studies, swelling studies and stability studies. The
results of post compression parameters for matrix tablets of Ambroxol HCl with different
hydrophilic and wax polymers are depicted in Table 7.21 to 7.27.
Table 7.21: Post compression parameters of powder blends of matrix tablets of Ambroxol
HCl by Direct Compression
Formulation
code
Diameter
(mm)
Thickness
(mm)*
Hardness
(Kg/cm2)
Weight
Variation(mg)*
Friability
(%)
Drug
content(%)*
F1 8 3.90±0.04 5.7±1.02 251.14±0.94 0.118 98.11±0.98
F2 8 4.00±0.05 5.6±0.02 249.16±1.61 0.127 99.80±0.21
F3 8 3.97±0.04 5.5±0.34 250.39±1.43 0.052 101.1±0.01
F4 8 4.17±0.02 6.1±0.17 250.61±1.07 0.199 99.20±0.08
F5 8 4.11±0.03 6.3±0.19 250.63±1.13 0.293 101.1±0.83
F6 8 4.80±0.01 6.2±0.01 249.63±1.62 0.602 98.90±0.01
F7 8 4.01±0.04 6.2±0.02 250.43±1.46 0.275 99.12±1.09
F8 8 4.06±0.06 5.9±0.03 250.06±1.76 0.146 99.20±1.01
F9 8 4.09±0.02 5.7±0.01 251.06±1.19 0.101 98.30±0.21
F10 8 3.82±0.12 6.4±0.01 249.80±1.04 0.171 99.50±0.29
F11 8 3.90±0.04 5.9±0.10 250.25±1.39 0.205 98.11±0.16
F12 8 4.00±0.05 5.8±0.10 250.10±1.60 0.316 99.80±0.19
F13 8 3.97±0.04 5.7±0.11 249.75±1.23 0.115 101.1±0.10
F14 8 4.17±0.02 5.7±0.02 249.97±1.47 0.116 99.20±0.76
F15 8 4.11±0.03 5.7±0.21 250.41±1.27 0.155 101.1±0.87
F16 8 4.80±0.01 5.5±0.01 250.78±1.47 0.057 98.90±0.91
F17 8 4.01±0.04 6.7±0.03 251.05±1.37 0.180 99.12±0.23
F18 8 4.06±0.06 6.5±0.23 250.12±1.36 0.868 99.20±0.23
F19 8 4.09±0.02 5.4±0.31 249.61±1.54 0.091 98.30±0.12
F20 8 3.82±0.12 6.5±0.09 249.89±1.35 0.159 99.50±0.04
F21 8 3.95±0.03 6.5±0.02 250.16±1.64 0.191 101.5±0.80
F22 8 3.97±0.01 5.8±0.01 250.26±1.39 0.259 101.2±0.12
F23 8 3.20±0.04 6.2±0.01 250.61±1.13 0.193 99.10±0.23
F24 8 3.95±0.34 6.1±0.04 249.78±1.70 0.119 98.90±0.21
F25 8 3.95±0.06 5.9±0.02 249.36±1.56 0.047 99.10±0.91
* Values are represented as mean ± SD (n=3)
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 173
Table 7.22: Post compression parameters of Melt Granulation Tablets with Bees wax Formulation
Code
Diameter
(mm)
Thickness
(mm)*
Hardness
(Kg/cm2)*
Weight
Variation (mg)*
Friability
(%)
Drug
content(%)*
A1 8 3.97±0.04 5.6±0.01 250.21±1.22 0.029 98.30±0.01
A2 8 4.10±0.01 5.6±0.01 250.21±1.07 0.020 101.1±0.02
A3 8 4.11±0.03 6.0±0.02 249.38±1.51 0.036 98.90±0.01
A4 8 4.11±0.03 5.6±0.09 250.52±1.35 0.042 99.20±0.19
A5 8 4.11±0.03 5.6±0.21 250.14±1.62 0.039 99.80±0.18
A6 8 4.10±0.01 5.6±0.07 250.66±1.22 0.078 101.1±0.78
A7 8 4.00±0.05 6.1±0.01 250.34±1.40 0.012 99.12±0.29
A8 8 4.01±0.04 5.6±0.02 250.74±1.21 0.038 98.11±0.23
A9 8 4.11±0.03 5.6±0.01 250.81±1.05 0.024 99.20±0.42
* Values are represented as mean ± SD (n=3) Table 7.23: Post compression parameters of Melt Granulation Tablets with Bees wax I* Formulation
Code
Diameter
(mm)
Thickness
(mm)*
Hardness
(Kg/cm2)*
Weight
Variation(mg)*
Friability
(%)
Drug content
(%)
B1 8 4.11±0.03 5.6± 0.02 250.43±1.24 0.051 100.1±0.21
B2 8 4.00±0.05 6.3±0.01 249.81±1.46 0.029 98.80±0.36
B3 8 4.01±0.04 5.6±0.02 250.18±1.39 0.004 100.6±0.01
B4 8 4.10±0.01 5.7±0.03 250.51±0.95 0.019 99.20±0.12
B5 8 4.00±0.05 5.6±0.10 249.94±1.48 0.028 99.51±0.19
B6 8 3.97±0.04 6.2±0.19 250.44±1.48 0.043 98.90±0.97
B7 8 4.11±0.03 5.8±0.28 250.79±0.95 0.029 99.12±0.01
B8 8 3.97±0.04 5.6±0.22 250.25±1.34 0.042 98.01±0.82
B9 8 4.01±0.04 5.2±0.11 249.33±1.48 0.291 98.30±0.75
* Values are represented as mean ± SD (n=3)
Table 7.24: Post compression parameters of Melt Granulation Tablets with Paraffin wax Formulation
Code
Diameter
(mm)
Thickness
(mm)*
Hardness
(kg/cm2)
Weight
Variation(mg)*
Friability
(%)
Drug content
(%)
C1 8 3.98±0.04 5.6±0.01 250.43±1.24 0.051 99.71±0.82
C2 8 3.99±0.05 5.6±0.20 249.81±1.46 0.029 98.98±0.89
C3 8 3.97±0.04 5.6±0.02 250.18±1.39 0.004 99.01±0.76
C4 8 4.17±0.02 6.3±0.03 250.51±0.95 0.019 98.20±0.43
C5 8 4.11±0.03 6.4±0.10 249.94±1.48 0.028 101.1±0.43
C6 8 4.88±0.01 6.5±0.01 250.44±1.48 0.043 98.89±0.65
C7 8 4.01±0.04 5.8±0.10 250.79±0.95 0.029 98.12±0.73
C8 8 4.16±0.06 5.7±0.04 250.25±1.34 0.042 99.92±0.21
C9 8 4.09±0.02 5.8±0.02 249.33±1.48 0.291 98.63±0.21
* Values are represented as mean ± SD (n=3)
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 174
Table 7.25: Post compression parameters of Melt Granulation Tablets with Stearic acid Formulation
Code
Diameter
(mm)
Thickness
(mm)*
Hardness
(Kg/cm2)*
Weight
Variation(mg)*
Friability
(%)
Drug content
(%)*
D1 8 3.08±0.04 5.6±0.01 250.36±1.16 0.008 99.11±0.03
D2 8 4.03±0.05 5.6±0.10 249.99±1.69 0.017 99.68±0.02
D3 8 3.99±0.04 5.5±0.11 250.17±1.73 0.036 101.7±0.23
D4 8 4.12±0.02 6.0±0.20 250.12±1.32 0.020 98.20±0.24
D5 8 4.11±0.03 6.2±0.23 250.40±1.41 0.041 100.1±0.92
D6 8 4.04±0.01 6.1±0.12 249.83±1.42 0.020 98.90±0.91
D7 8 4.01±0.04 5.7±0.07 250.03±1.70 0.010 99.12±0.23
D8 8 4.06±0.06 5.6±0.01 249.86±1.37 0.080 99.80±0.78
D9 8 4.06±0.02 5.7±0.05 249.22±1.52 0.076 99.30±0.21
* Values are represented as mean ± SD (n=3)
Table 7.26: Post compression parameters of Melt Granulation Tablets with Lubritab Formulation
Code
Diameter
(mm)
Thickness
(mm)*
Hardness
(Kg/cm2)*
Weight
Variation(mg)*
Friability
(%)
Drug content
(%)*
E1 8 3.99±0.04 5.9±0.03 249.63±1.26 0.057 98.91±0.27
E2 8 4.00±0.05 5.8±0.20 249.77±1.55 0.028 98.85±0.98
E3 8 3.97±0.04 6.0±0.10 250.39±1.08 0.015 99.51±0.95
E4 8 4.07±0.02 6.1±0.01 250.19±1.29 0.048 99.28±0.34
E5 8 4.12±0.03 5.7±0.10 250.47±0.77 0.060 101.5±0.45
E6 8 4.11±0.01 5.7±0.02 250.88±1.23 0.039 98.93±0.56
E7 8 4.04±0.04 5.6±0.03 250.20±1.52 0.004 99.17±0.65
E8 8 4.05±0.06 5.8±0.01 249.99±1.39 0.051 99.24±0.76
E9 8 4.05±0.02 5.6±0.01 250.62±1.00 0.026 98.63±0.01
* Values are represented as mean ± SD (n=3) Table 7.27: Post compression parameters of Melt Granulation Tablets with Polymeg Formulation
Code
Diameter
(mm)
Thickness
(mm)*
Hardness
(kg/cm2)*
Weight
Variation (mg)*
Friability
(%)
Drug content
(%)*
G1 8 3.90±0.04 5.6±0.02 250.75±1.1 0.047 98.11±0.91
G2 8 4.00±0.05 5.5±0.01 249.51±1.53 0.023 99.80±0.02
G3 8 3.97±0.04 5.6±0.03 250.50±1.59 0.061 101.1±0.83
G4 8 4.17±0.02 6.4±0.02 250.33±1.62 0.071 99.20±0.45
G5 8 4.11±0.03 6.3±0.10 249.54±1.26 0.043 101.1±0.65
G6 8 4.80±0.01 6.4±0.02 250.80±1.08 0.042 98.90±0.61
G7 8 4.01±0.04 5.7±0.30 250.73±1.38 0.035 99.12±0.71
G8 8 4.06±0.06 5-6±0.20 249.98±1.27 0.030 99.20±0.39
G9 8 4..09±0.02 5.9±0.34 250.55±1.60 0.022 98.30±0.27
* Values are represented as mean ± SD (n=3)
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 175
7.4.3.1 THICKNESS AND DIAMETER:
The thickness of the formulations was found in the range of 3.97±0.04 to 4.17±0.02 mm.
The diameter of the formulations was found to be 8 mm. The tablets exhibited uniform
thickness and diameter among the different formulations prepared.
7.4.3.2 HARDNESS:
Hardness for all formulations was found to be between 5 to 7 Kg/cm2 which ensured good
handling characteristics with all the polymers.
7.4.3.3 FRIABILITY:
The percentage friability of all formulations remained within the range of 0.012 to 0.868.
The friability was found to be below 1% ensuring that all the batches were mechanically
stable.
7.4.3.4 WEIGHT VARIATION:
Weight variation test shown for all the formulations 250 ± 2 mg variation. This ensures
that it is within a limit according to IP specifications of 7.5%.
7.4.3.5 DRUG CONTENT UNIFORMITY:
Good uniformity of drug content was found among different formulations of matrix
tablets of Ambroxol HCl by direct compression and melt granulation using wax polymers
and the percentage drug content estimations showed values in the range of 98.11 to
101.1%.
7.4.3.6 IN VITRO DRUG RELEASE
In the present study, controlled release matrix tablets were prepared for Ambroxol HCl by
direct compression and melt granulation method. The drug has to be released throughout
the gastrointestinal tract. To ascertain the above fact, the in vitro drug release
characteristics of all formulated Ambroxol HCl matrix tablets was performed in 0.1 N
HCl for first 2 h and next 10 h in pH 6.8 Phosphate buffer.
7.4.3.6.1 IN VITRO DRUG RELEASE OF MATRIX TABLETS OF AMBROXOL
HCL BY DIRECT COMPRESSION:
In this study, the effect of various hydrophilic polymers as different grades of HPMC as
HPMC K100LV CR, HPMC K4M, HPMC K100M CR and HPMC K200M and Carbopol
as Carbopol 934P, Carbopol 974P, Carbopol 971P, Carbopol 71G and Polycarbophil on
the release behavior as well as kinetics of Ambroxol HCl from matrix type tablets were
evaluated. The release of Ambroxol HCl was found to be a function of the polymer
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 176
concentration and the drug release from the matrix tablets was found to decrease with
increase in drug polymer ratio. (Table 7.28 &7.29)
Drug Release from Matrix Tablets of Ambroxol HCl with Various HPMC Polymers:
The four grades of HPMC differ in their molecular weight and viscosity. Formulations F1
to F10 were studied to compare the effect of concentration (7.5% - 30%) and viscosity of
HPMC polymer on the release of Ambroxol HCl from tablet matrices. It was found that,
there was an apparent difference in Ambroxol HCl release pattern between the HPMC of
different viscosity grades as the fraction of Ambroxol HCl release decreases with increase
in the viscosity of the polymer.
HPMC of higher viscosity grades result in thicker gel formation with decrease in drug
release. As soon as the matrix tablet comes in contact with the dissolution media,
imbibition of the dissolution medium by the matrix tablet takes place, initiating the
formation of a gel layer of the polymer around the tablet. The diffusion of dissolved drug
through this gel layer was the determining factor in the improvement of dissolution rate.
From the Stokes–Einstein equation, the diffusion coefficient is inversely proportional to
the viscosity. Hence, it can be inferred that increasing the viscosity of polymer decreases
the drug release rate of the drug.
Figure 7.9: In vitro drug release profile of formulations F1 to F4 (with 1:1, 1:0.5
HPMC K100LV CR & 1:1, 1:2 HPMC K4M respectively) The in vitro drug release for formulations F1 and F2 (Figure 7.9) obtained over a period
of 12 h indicated that, the release rate is increased as the concentration of HPMC
K100LV CR is decreased. Formulation F2 composed of HPMC K100LV CR 1:0.5, failed
to control the release at predetermined rate and also to sustain release beyond 10 h. But
formulation F1 with 1:1 HPMC K100LV CR gave CR of Ambroxol HCl over a period of
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 177
12 h due to the fact that low viscosity CR HPMC polymer forms a viscous gel on contact
with dissolution media with the gel controlling delivery of drug. Among formulations F3
and F4 with HPMC K4M (Figure 7.9), F3 yielded a faster drug release i.e. 106.40%
within 5 h only and F4 with 1:2 HPMC K4M released in controlled manner but with only
81.96% release within 12 h.
Figure 7.10: In vitro drug release profile of formulations F5 to F10 (with 1:1, 1:0.5
HPMC K 100M & 1:1, 1:0.5, 1:0.4 & 1:0.25 HPMC K200M respectively)
Formulation F5 and F6 with 1:1 and 1:0.5 HPMC K100M (Figure 7.10) shown 85.61%
and 100.91% drug release in 12 h. Formulation F10 with 1:0.25 HPMC K200M (Figure
7.10) yielded a fastest drug release i.e. 101.13% within 4 h only. Formulation F7, F8 and
F9 contains 1:1, 1:0.5 and 1:0.4 HPMC K200M respectively shown 80.51%, 85.13% and
86.08% drug release within 12 h. It was observed that formulation F7 containing HPMC
K200 M (1:1) showed the slowest release rate of the drug when compared with others,
due to its higher viscosity. The hydration rate of this synthetic polymer relates to its
hydroxypropyl substitutes percentage. HPMC K200M contains the greatest amounts of
these groups and produces strongly viscous gel that plays an important role in controlling
drug release.
Thus, when dissolution profiles of HPMC matrices of same grade but different
concentration ranges were compared, a significant difference was observed (p<0.05).
Formulations F1, F2, F3, F6 and F10 containing 1:1 and 1:0.5 HPMC K100LVCR; 1:1
HPMC K4M; 1:0.5 HPMC K100M and 1:0.25 HPMC K200M showed significant
difference with marketed formulation (p<0.05) whereas formulations F4, F5, F7, F8 and
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 178
F9 containing 1:2 HPMC K4M; 1:1 HPMC K100M and 1:1, 1:0.5 & 1:0.4 HPMC
K200M showed no significant difference with marketed formulation (p>0.05).
Drug Release from Matrix Tablets of Ambroxol HCl with Various Carbopol
Polymers:
In formulations F11 to F25 containing different grades of Carbopol, rapid gel formation
was observed macroscopically during dissolution studies. It may be due to the ionization
of carboxylate group, resulting in repulsion between the negative particles that adds
swelling of crosslinked polymer. This swelling is thought to be responsible for controlling
the release of drug.
Thus, the release of the drug in Carbopol matrices is mainly governed by water
penetration, polymer swelling, drug dissolution, diffusion and matrix erosion. As the
drug: polymer ratio increased the rate of release become slower and linear. The reason for
this could be that the gel layer formed around the tablet becomes stronger, with few
interstitial spaces between the microgels. Initially, a rapid release was observed in all the
carbopol matrices as compared to HPMC matrices (Figure 7.9 to 7.13). The slow rate of
polymer hydration of Carbopol, as exposed to pH environment below its pKa of 6 ± 0.5
might be the reason for this. The rate of hydration of polymer in a hydrophilic matrix
system during dissolution has profound influence on drug release.
Figure 7.11: In vitro drug release profile of formulations F11 to F16 (with 1:1, 1:0.5
& 1:0.25 Carbopol 934P & 1:1, 1:0.5 & 1:0.25 Carbopol 974P respectively) Carbopol 934P is highly cross-linked polymer and have a “fuzz ball” type of gel
structure. It is postulated that the decrease in release rate with increase in the Carbopol
934P concentration may be attributed to strength of gel layer because the gel layer is
thicker and stronger at high concentration. Carbopol 974P is the highest effectively cross-
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 179
linked polymer and having rigid structure. Therefore tablets formed with it have more
channels. If there is more cross-link level in the polymer, the polymer becomes more
porous, therefore more channels are formed in the tablet and hence there is more drug
release. The drug diffuses into the gel particles and it has relatively more channels to
exhibit drug. This causes more release of drug. 21
The in vitro dissolution profile of Carbopol 934P & 974P is shown in Figure 7.11. The
formulations showed a decrease in drug release with increase in the drug: Polymer ratio
but comparatively more release from Carbopol 974P matrices with the same polymer
concentration than Carbopol 934P.
Figure 7.12: In vitro drug release profile of formulations F17 to F22 (with 1:1, 1:0.5
& 1:0.25 Carbopol 971P & 1:1, 1:0.5 & 1:0.25 Carbopol 71G respectively) Carbopol 971P and Carbopol 71G
22 have the most homogeneous gel structure and there
are very few channels through which the drug may diffuse. Both the polymers tend to be
more efficient at low concentration. As Carbopol 971P have a „fishnet‟ gel structure upon
hydration and there are few cross- linked steps to constrain the polymer, it opens up
easily at low concentration, due to which only few channels are formed in the tablet,
hence retard the drug release than Carbopol 71G with little more pores for drug release.
The in vitro dissolution profile of Carbopol 971P & 71G is shown in Figure 7.12. But the
drug retarding capacity decreases as the polymer concentration decreases. The matrix
tablets prepared with Carbopol 971P showed more CR than Carbopol 71 G. Though both
of polymers having same viscosity, Carbopol 971P are available in powder form and
Carbopol 71G is in granular form. In direct compression, Carbopol 971P used make very
little void space for dissolution media to enter initially to exhibit more CR of drug.
The release profile from Polycarbophil matrices is depicted in the Figure 7.13. There is
retardation in the release as the polymer concentration increases. 23-24
It may be due to the
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 180
fact that Polycarbophil particles have a high concentration of ionic groups inside which
causes the large influx of water by osmosis, swelling the particles until the cross-links are
strained. This will lead to rapid diffusion of drug out of polymer matrix with low
Polycarbophil concentration.
Figure 7.13: In vitro drug release profile of formulations F23 to F25 (with 1:1, 1:0.5
& 1:0.25 Polycarbophil respectively) Predominant factor affecting drug release is polymer concentration. When drug is
formulated with 1: 0.25 i.e. very low proportions of different Carbopol polymers,
Carbopol 971 P showed better drug retardation till 9 h (102.83%) as compared to other
polymers. The release rate retardation was in the order: F19-Carbopol 971 P > F16-
Carbopol 974P (4 h - 99.25%) > F22-Carbopol 71G (3 h – 101.89%) > F13-Carbopol
934P (3 h - 103.64%). If concentration of polymers increased i.e. 1:0.5, drug retardation
in 12 h is in the following order: F12-Carbopol 934P (68.14%) > F118-Carbopol 971P
(75.72%) > F15-Carbopol 974P (75.86%) > F21-Carbopol 71G (82.15%) > F24-
Polycarbophil (within 9 h – 100.65%). For 1:1 polymer concentration of different
Carbopol grades, again Carbopol 971P only showed better retardation in 12 h. The
release rate retardation was in the order: F17-Carbopol 971P (40.03%) > F20Carbopol
71G (41.86%) > F11-Carbopol 934P (48.56%) > F14-Carbopol 974P (49.68%) > F23-
Polycarbophil (within 9 h – 100.65%).
The dissolution profiles of all carbopol polymer formulations F11 to F25 when compared
within different concentration of same carbopol matrices and also with marketed
formulation showed significant difference (p<0.05). Thus, polymer concentrations were
found to be inversely proportional to release rate of Ambroxol HCl in all matrix tablet
formulations with different hydrophilic polymers prepared by direct compression.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 181
Table 7.28: In Vitro Drug Release profile of Matrix Tablets of Ambroxol HCl by Direct Compression with Various HPMC Polymers
Time
(h)
K100M LV
CR (1:1)
K 100M LV
CR (1: 0.5) K4M (1:1) K4M(1:2)
K100M
(1:1)
K100M
(1:0.5)
K200M
(1:1)
K200M
(1:0.5)
K200M
(1:0.4)
K200M
(1:0.25)
ACOCONTIN F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
0.5 14.34±0.97 16.68±0.76 10.91±0.59 8.47±0.39 8.64±0.21 9.42±0.28 7.85±0.05 8.78±0.48 6.08±0.84 38.11±0.43 05.62±0.19
1 20.92±1.03 24.38±1.53 19.04±0.98 14.66±0.18 12.94±0.21 15.81±0.43 11.88±0.02 14.40±0.25 9.51±0.17 59.80±0.65 14.91±1.09
1.5 28.61±1.14 32.59±1.87 24.13±2.05 18.23±0.32 15.93±0.48 19.97±0.50 14.45±0.09 16.70±0.41 13.27±0.45 69.04±1.23 16.86±1.41
2 36.14±1.13 40.46±2.72 36.01±1.33 21.82±0.79 19.22±0.17 26.01±0.20 18.14±0.16 22.48±.0.37 17.11±0.77 80.57±0.50 19.40±1.43
3 44.75±0.33 46.08±0.64 59.04±1.29 36.94±0.44 29.78±0.16 41.07±0.25 28.12±0.12 37.56±0.39 28.61±0.34 90.01±0.89 31.04±1.53
4 48.49±1.99 53.03±1.47 73.64±0.31 43.33±0.51 38.90±0.40 52.42±0.30 37.02±0.34 44.63±0.29 34.81±0.69 101.12±0.9 39.66±1.62
5 59.77±4.16 64.46±5.38 106.40±1.9 52.35±0.36 47.86±0.04 59.72±1.30 45.10±0.51 53.29±0.09 41.62±0.48 47.39±0.39
6 65.52±1.79 68.94±0.18 56.65±0.74 57.64±1.12 69.80±0.10 52.09±0.34 56.43±0.25 48.45±1.11 56.66±0.36
7 69.94±1.33 76.89±1.01 59.60±2.83 63.47±1.03 76.94±0.24 60.03±0.11 61.40±0.27 53.91±0.87 64.14±3.02
8 75.43±0.69 84.85±1.83 63.94±0.36 68.77±0.94 80.09±0.58 66.31±0.16 68.85±0.44 58.52±1.17 68.64±0.97
9 80.98±0.95 91.80±0.98 70.19±1.03 72.43±1.33 85.43±0.18 69.85±0.69 72.43±0.68 65.95±1.76 72.69±0.24
10 85.15±1.45 102.8±1.76 74.06±0.59 75.57±0.42 90.08±0.63 74.04±0.51 74.91±0.30 74.70±2.20 78.14±0.72
11 89.36±1.28 77.72±0.53 81.65±0.71 95.23±0.06 77.00±0.36 80.49±1.64 80.87±1.57 82.66±1.26
12 94.77±1.75 81.96±0.64 85.61±0.57 100.91±0.2 80.50±1.81 85.12±1.83 86.07±1.37 87.90±1.39
* Values are represented as mean ± SD (n=3)
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 182
Table 7.29: In Vitro Drug Release profile of Matrix Tablets of Ambroxol HCl by Direct Compression with Various Carbomers
Time(h)
934P
(1:1)
934P
(1:0.5)
934P
(1:0.25)
974P
(1:1)
974P
(1:0.5)
974P
(1:0.25)
971P
( 1:1)
971P
(1:0.5)
971P
(1:0.25)
71G
(1:1)
71G
(1:0.5)
Poly#
(1:1)
Poly
(1:0.75)
Poly
(1:0.5) ACOCONTIN
F11 F12 F13 F14 F15 F16 F17 F18 F19 F20 F21 F23 F24 F25
0.5 11.56
±0.29
10.64
±0.17
14.98
±0.78
27.13
±0.28
12.13
±1.02
31.94
±1.42
9.0
±0.31
11.03
±0.58
16.56
±0.04
10.01
±0.12
11.86
±0.33
8.55
±0.89
12.46
±1.52
23.25
±0.82
05.62
±0.19
1 17.32
±0.07
18.53
±0.56
51.39
±0.47
44.42
±0.38
16.41
±1.21
45.06
±1.32
13.15
±0.79
19.54
±1.13
31.77
±0.31
14.91
±0.16
18.81
±0.33
17.55
±1.34
22.81
±2.06
43.99
±0.99
14.91
±1.09
1.5 19.26
±0.39
24.49
±0.14
74.11
±0.74
35.29
±0.34
24.43
±1.64
58.19
±1.16
15.38
±1.27
24.47
±0.43
43.80
±0.38
17.70
±0.43
23.03
±0.10
20.91
±1.32
27.36
±1.60
61.07
±0.92
16.86
±1.41
2 26.42
±0.22
30.31
±0.39
84.87
±0.81
22.66
±0.67
29.96
±1.26
71.32
±3.45
20.00
±0.67
29.41
±1.43
54.94
±0.76
21.30
±0.26
29.49
±0.26
32.75
±3.09
35.77
±2.09
77.31
±0.45
19.40
±1.43
3 33.59
±0.41
40.69
±0.31
103.63
±0.45
30.11
±0.77
38.12
±2.21
84.45
±5.78
28.07
±0.65
45.35
±3.46
88.20
±0.40
28.19
±0.33
57.88
±0.38
45.80
±5.18
43.22
±3.19
87.37
±1.21
31.04
±1.53
4 34.55
±0.21
44.62
±0.36
33.11
±0.53
43.88
±1.33
99.25
±1.80
28.31
±0.73
51.30
±3.45
91.45
±0.47
31.13
±0.09
62.50
±0.26
48.92
±4.10
47.47
±1.24
89.28
±1.58
39.66
±1.62
5 37.15
±0.31
47.63
±0.15
35.68
±0.63
50.44
±1.68
30.04
±1.07
55.56
±2.88
92.68
±0.62
32.54
±0.17
63.97
±0.18
52.70
±3.91
55.51
±1.50
91.52
±0.90
47.39
±0.39
6 38.34
±0.33
51.13
±0.06
37.90
±0.48
55.72
±1.28
31.64
±1.49
59.69
±3.45
96.15
±1.00
34.74
±0.07
67.91
±0.03
55.25
±3.86
64.51
±2.04
93.83
±1.55
56.66
±0.36
7 41.20
±0.38
54.61
±0.31
39.42
±0.41
62.00
±1.36
32.96
±1.09
62.91
±3.01
96.29
±2.15
35.87
±0.19
69.74
±0.32
59.43
±3.02
71.86
±1.14
97.22
±0.16
64.14
±3.02
8 43.25
±0.61
57.14
±0.42
41.68
±0.53
66.28
±1.19
35.79
±0.90
65.80
±4.09
98.57
±1.73
38.39
±0.00
70.58
±0.46
63.46
±3.18
76.63
±0.80
99.19
±0.06
68.64
±0.97
9 44.78
±1.10
60.36
±0.29
43.30
±0.36
69.56
±0.50
36.79
±0.94
70.29
±3.70
102.83
±1.13
38.84
±0.16
74.61
±0.32
66.71
±2.82
81.41
±0.78
100.64
±0.56
72.69
±0.24
10 45.77
±1.07
62.96
±0.32
45.33
±0.09
71.50
±0.87
37.85
±1.27
71.40
±2.94
39.60
±0.05
76.27
±0.05
70.23
±2.75
86.18
±1.09
78.14
±0.72
11 47.10
±0.71
65.60
±0.97
47.24
±0.29
73.11
±1.16
38.70
±1.33
72.95
±2.04
40.98
±0.17
79.06
±0.23
73.18
±2.30
88.71
±0.77
82.66
±1.26
12 48.56
±0.67
68.14
±0.83
49.67
±0.63
75.86
±1.00
40.03
±1.25
75.71
±1.38
41.85
±1.18
82.14
±1.10
75.81
±1.74
91.56
±1.04
87.90
±1.39
* Values are represented as mean ± SD (n=3), # Poly indicates Polycarbophil
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 183
7.4.3.6.2 IN VITRO DRUG RELEASE OF MATRIX TABLETS OF AMBROXOL
HCL BY MELT GRANULATION AS PER 32 FACTORIAL DESIGN:
The release study of matrix tablets of Ambroxol HCl by melt granulation with different
hydrophobic binders as Bees wax, Bees Wax I*, Paraffin wax, Stearic acid, Lubritab and
Polymeg is given in Table 7.30 to 7.35 respectively showed a polymer concentration
dependent profile. The versatility of the drug release profile from matrices with different
lipohilic binders ranging in melting point from 40°C to 80°C and prepared by melt
granulation is demonstrated in Figure 7.14 to 7.19.
The formulations were prepared mainly with hydrophobic meltable binders and HPMC
K4M. Both polymers were chosen as they are well established in the similar studies and
have great swelling and controlled release properties respectively. Hydrophobic meltable
binders impart sufficient integrity to the tablets. HPMC K4M was selected as a matrixing
agent considering its widespread applicability and excellent gelling activity in controlled
release formulations. Range for each meltable hydrophobic binder and HPMC K4M was
done on preliminary trials and such range was selected which can give proper strength to
matrix tablets by sufficiently binding to keep the matrix intact for more than 12 h.
The drug release from different formulations prepared by melt granulation mainly
depends on type and content of lipophilic binder, mechanism and duration of granulation
and granule size.
The granulation mechanism for the molten wax may differ from that for powdered waxes
and is possibly similar to that occurring in conventional wet granulation during which
drug particles are aggregated by a film of liquid. However, as this occurs immediately
there is insufficient time for thorough mixing of the drug and wax and therefore drug
release is rapid. With increasing melting point of the powdered wax, granulation time
increases and this in turn will result in more efficient wax distribution and slower
dissolution rate.
With reducing lipophilic binder content, the time and temperature at which the end point
of granulation occurs will tend to increase due to dilution of meltable binder by the drug
particles. But, granules produced with low wax contents will have a more porous
structure and thus be more friable, giving rise to the drug release. The effect of
compression of melt granulated matix tablets by direct compression will be dependent on
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 184
pre-existing granule characteristics and also on the nature and quantity of extra-granular
excipients.
It was observed that as the amount of hydrophobic binder was increased, % CDR at 12
th h
was decreased. Hence it was decided to optimize the amount of hydrophobic binder. As
the amount of HPMC K4M was increased, the % CDR at 1st and 12
th h was decreased
significantly indicating that high amount of HPMC K4M is undesirable to achieve
required drug release profile.
In vitro release profile of Ambroxol HCl was studied from the matrix tablets prepared by
melt granulation and the decrease in drug release rate was observed when meltable binder
content in the matrix was increased. It may be due to the slower penetration of dissolution
medium in matrices due to increased lipophilicity of waxy substances.25
Initial release
from the matrix could probably be attributed to the dissolution of drug from the gelled
surface of the tablet due to HPMC K4M. Further, penetration of solvent molecule was
hindered due to the hydrophobic coating of the meltable binders on the drug particle
leading to the slow controlled release for a prolonged period.26
Thus, the controlled release of drug depends on the leaching of drug through the granule
matrix and then diffusion of drug through gelled layer of HPMC K4M.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 185
Table 7.30: In Vitro Drug Release profile of matrix tablets of AH by melt granulation with Bees Wax as per 32 Factorial Design
Time(h) A1 A2 A3 A4 A5 A6 A7 A8 A9 ACOCONTIN
0.5 09.11±0.06 06.63±0.42 07.38±1.53 07.64±2.07 07.43±0.24 05.55±0.35 08.12±0.01 07.28±0.26 06.55±0.36 05.62±0.19
1 10.55±0.32 09.88±0.78 08.50±0.31 10.45±0.58 09.69±1.50 08.79±0.47 10.33±0.52 08.46±0.26 07.77±0.15 14.91±1.09
1.5 15.19±1.04 13.78±0.12 11.48±0.47 14.49±1.18 12.23±0.25 12.20±0.71 12.52±0.72 11.13±0.79 10.40±0.36 16.86±1.41
2 19.10±2.14 15.75±0.15 13.75±1.62 17.26±1.74 14.53±0.34 14.41±0.96 15.16±0.93 13.90±0.21 12.43±0.43 19.40±1.43
3 27.53±1.66 27.01±1.32 24.33±1.08 30.06±2.09 29.65±0.67 24.63±1.59 28.04±0.91 28.75±0.48 21.73±0.60 31.04±1.53
4 34.72±1.79 34.38±0.47 30.02±0.52 36.19±1.97 32.03±0.69 30.51±1.75 33.72±0.13 32.98±0.89 28.32±0.38 39.66±1.62
5 41.50±1.72 40.70±0.59 35.68±0.39 42.43±1.98 37.94±0.78 37.18±1.32 41.77±0.65 35.85±0.61 33.98±0.05 47.39±0.39
6 48.06±1.46 46.67±0.17 40.81±0.11 48.31±2.04 41.37±0.74 42.60±1.37 48.57±0.98 39.88±0.67 39.55±0.37 56.66±0.36
7 55.53±1.64 53.06±0.74 45.87±0.10 54.05±2.02 49.33±2.54 47.87±1.67 54.36±0.90 41.78±0.92 45.26±0.28 64.14±3.02
8 63.45±1.95 57.26±0.68 49.93±0.79 55.05±0.29 57.12±0.32 58.64±1.76 59.84±0.97 46.31±0.35 49.20±0.65 68.64±0.97
9 70.83±1.81 62.01±1.37 52.75±0.39 59.32±0.25 60.52±0.96 61.59±1.72 63.61±1.74 48.54±0.35 52.44±0.48 72.69±0.24
10 77.68±0.78 65.52±1.31 55.28±0.25 67.38±0.25 65.19±1.29 64.12±1.24 66.11±1.70 54.37±2.21 54.44±0.21 78.14±0.72
11 84.25±1.42 69.39±2.52 58.05±0.29 71.75±0.77 68.57±1.37 67.14±1.81 69.68±1.68 59.86±1.14 57.53±0.19 82.66±1.26
12 96.20±2.58 74.30±1.67 62.46±0.29 76.25±1.39 73.64±1.12 70.34±1.59 74.25±1.58 66.11±0.68 61.13±1.05 87.90±1.39
* Values are represented as mean ± SD (n=3)
Figure 7.14: In vitro drug release profile of Ambroxol HCl matrix tablets (A1 to A9) by melt granulation with Bees wax as per 32 Factorial Design
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 186
Table 7.31: In Vitro Drug Release profile of matrix tablets of Ambroxol HCl by melt granulation with Bees Wax I*as per 32 Factorial Design
Time(h) B1 B2 B3 B4 B5 B6 B7 B8 B9 ACOCONTIN
0.5 16.52±0.68 09.27±0.70 06.58±0.31 13.54±2.81 05.93±0.38 04.76±0.12 07.62±0.57 04.45±0.26 06.96±0.12 05.62±0.19
1 42.32±4.16 14.13±0.70 10.54±0.09 22.34±0.63 09.65±0.48 08.97±0.51 14.13±1.27 07.50±0.16 09.64±0.49 14.91±1.09
1.5 82.39±3.15 17.41±0.56 13.59±0.09 28.70±0.54 12.32±1.00 12.68±0.93 16.44±0.03 12.24±0.70 12.09±1.16 16.86±1.41
2 84.92±6.16 20.91±0.92 16.24±0.12 33.74±1.40 16.72±0.66 14.03±0.38 20.41±0.17 13.49±0.17 16.22±0.56 19.40±1.43
3 106.89±5.13 36.87±0.88 30.80±0.84 50.48±1.74 30.28±1.33 27.74±0.20 30.21±0.43 22.39±0.10 27.19±0.93 31.04±1.53
4 105.68±3.97 43.29±0.92 36.08±1.23 56.89±1.03 36.03±0.74 32.91±0.45 41.22±1.09 30.70±0.19 34.22±1.64 39.66±1.62
5 104.79±0.59 50.52±1.45 44.88±1.59 63.11±1.39 42.59±0.59 40.26±0.25 45.59±0.51 34.37±0.30 38.05±1.42 47.39±0.39
6 103.87±0.18 57.02±1.31 51.25±1.53 69.46±0.84 48.62±0.53 46.49±0.25 53.23±1.23 42.22±0.35 45.41±1.04 56.66±0.36
7 102.96±3.34 62.69±1.41 57.06±1.42 73.66±0.82 53.86±0.18 50.86±0.63 58.15±1.13 47.97±0.84 51.33±1.50 64.14±3.02
8 102.26±1.72 67.68±1.51 62.68±1.40 77.56±0.38 59.07±0.71 55.38±0.02 62.38±2.26 52.21±1.34 54.86±1.60 68.64±0.97
9 101.95±2.25 75.15±1.52 69.12±1.98 82.79±1.67 63.71±0.15 61.60±0.34 69.12±1.04 58.54±2.70 61.58±2.27 72.69±0.24
10 101.01±0.85 78.15±0.89 72.68±2.28 86.46±2.72 66.86±0.74 63.74±0.62 71.91±1.24 61.51±1.39 63.37±1.81 78.14±0.72
11 100.57±0.18 80.26±0.60 75.05±2.10 89.36±1.10 70.79±0.51 66.44±0.28 74.19±1.44 64.87±1.12 65.88±1.49 82.66±1.26
12 99.89±2.82 83.13±0.41 78.54±0.76 93.59±0.04 73.75±0.33 68.78±0.19 78.60±1.17 68.73±1.04 68.22±1.25 87.90±1.39
* Values are represented as mean ± SD (n=3)
Figure 7.15: In vitro drug release profile of Ambroxol HCl matrix tablets (B1 to B9) by melt granulation with Bees wax I* as per 3
2 Factorial Design
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 187
Table 7.32: In Vitro Drug Release profile of matrix tablets of Ambroxol HCl by melt granulation with Paraffin Wax as per 32 Factorial Design
Time (h) C1 C2 C3 C4 C5 C6 C7 C8 C9 ACOCONTIN
0.5 09.45±0.57 09.45±0.19 09.00±0.99 09.65±1.13 07.77±0.64 07.90±1.35 07.36±0.42 07.73±1.86 06.27±0.35 05.62±0.19
1 11.52±0.14 10.57±0.28 10.52±0.85 13.77±1.48 09.51±0.71 09.40±0.86 09.62±0.22 09.38±1.47 09.03±0.78 14.91±1.09
1.5 16.01±1.44 13.09±0.29 14.63±1.28 14.54±1.15 11.31±0.42 11.53±0.44 12.10±0.51 11.58±1.48 11.61±0.37 16.86±1.41
2 18.06±0.51 15.49±0.33 14.96±0.44 16.91±1.42 13.63±0.30 13.85±0.41 14.08±0.68 14.57±1.12 13.71±0.54 19.40±1.43
3 32.42±1.29 28.75±0.46 28.28±0.37 29.49±0.74 25.40±0.26 27.82±1.26 28.06±1.27 27.18±2.43 27.34±0.99 31.04±1.53
4 38.31±1.06 34.01±0.50 33.95±0.24 34.72±0.77 30.41±0.39 32.74±0.96 33.57±1.54 31.87±1.72 32.99±1.62 39.66±1.62
5 43.61±1.25 40.18±0.16 40.36±0.22 40.27±0.27 36.43±0.19 38.98±0.84 39.67±1.88 37.99±1.78 39.57±2.22 47.39±0.39
6 49.99±1.54 45.84±0.44 45.93±0.19 46.64±0.16 41.61±0.37 44.75±1.21 44.69±2.13 43.81±1.44 45.50±2.81 56.66±0.36
7 56.75±1.19 52.00±0.49 51.91±0.27 53.64±0.53 47.70±0.39 50.52±1.03 50.29±3.15 49.37±2.36 52.12±4.51 64.14±3.02
8 62.72±0.29 61.81±3.31 62.37±4.19 57.48±2.08 55.29±1.43 55.28±0.45 54.94±3.01 53.31±1.32 58.92±0.51 68.64±0.97
9 69.03±1.49 63.54±1.84 63.71±0.52 64.27±1.49 58.58±0.32 59.46±1.66 63.52±2.46 62.65±0.51 60.85±0.66 72.69±0.24
10 71.39±1.99 66.81±0.57 68.67±0.54 67.00±1.14 61.28±0.83 64.04±1.70 67.56±2.36 63.86±1.65 65.84±3.09 78.14±0.72
11 76.07±1.13 71.02±1.28 73.03±1.82 70.67±0.29 66.36±0.88 69.16±2.26 70.76±0.99 67.70±1.41 69.12±2.71 82.66±1.26
12 79.59±0.93 74.88±1.41 73.94±1.18 74.79±0.77 73.78±2.31 70.35±1.57 73.58±1.78 71.91±2.47 70.89±1.98 87.90±1.39 * Values are represented as mean ± SD (n=3)
Figure 7.16: In vitro drug release profile of AH matrix tablets (C1 to C9) by melt granulation with Paraffin wax as per 32 Factorial Design
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 188
Table 7.33: In Vitro Drug Release profile of matrix tablets of Ambroxol HCl by melt granulation with Stearic Acid as per 32 Factorial Design
Time(h) D1 D2 D3 D4 D5 D6 D7 D8 D9 ACOCONTIN
0.5 10.51±0.28 10.14±1.49 08.58±0.92 07.57±0.27 08.01±0.11 07.57±0.27 08.68±0.56 10.40±0.43 08.54±0.24 05.62±0.19
1 19.62±0.31 13.67±1.57 11.45±0.21 11.82±0.29 11.31±0.57 10.85±0.56 12.30±0.42 12.75±0.76 10.35±0.53 14.91±1.09
1.5 23.34±0.33 18.12±2.47 15.01±0.44 15.39±0.20 15.33±0.29 14.67±0.66 16.67±0.45 15.39±0.37 14.50±1.01 16.86±1.41
2 27.16±0.50 21.91±1.32 18.21±0.16 18.52±0.18 17.91±0.24 17.78±0.34 22.72±0.16 18.55±0.38 20.15±0.68 19.40±1.43
3 34.75±1.09 33.91±2.12 27.94±0.11 29.32±0.61 29.21±0.14 30.70±1.02 32.25±1.12 28.35±0.37 30.33±0.92 31.04±1.53
4 40.64±0.34 38.48±1.53 33.69±0.32 34.03±0.52 33.93±0.52 33.16±1.09 38.45±0.72 33.43±0.65 33.96±0.69 39.66±1.62
5 46.69±0.79 45.32±2.03 39.93±0.99 39.92±0.99 40.48±0.34 39.13±0.91 44.46±0.62 39.54±0.74 39.67±0.60 47.39±0.39
6 54.22±0.74 51.16±2.14 45.20±1.04 45.75±1.06 45.85±0.63 44.57±1.06 50.08±0.82 45.79±0.34 45.02±0.79 56.66±0.36
7 59.39±0.38 59.25±0.71 50.92±0.99 51.38±0.41 51.46±1.15 50.82±0.86 55.90±0.54 50.93±0.80 49.66±0.44 64.14±3.02
8 63.57±0.05 62.29±1.33 55.13±0.99 55.76±0.62 56.68±0.71 54.29±1.04 62.27±0.72 55.58±1.57 54.38±0.70 68.64±0.97
9 69.49±0.14 64.99±2.35 58.76±0.67 59.44±0.70 59.67±0.90 58.13±1.98 64.98±0.76 60.47±1.45 58.45±0.81 72.69±0.24
10 74.85±0.48 70.55±1.24 63.26±0.93 63.69±0.86 63.78±1.03 62.43±1.43 68.05±0.09 62.74±1.76 61.70±1.38 78.14±0.72
11 80.58±0.42 76.17±1.43 69.61±0.18 67.63±0.52 69.75±0.60 68.10±1.57 70.52±0.58 65.92±0.36 67.38±0.36 82.66±1.26
12 87.32±0.41 81.87±0.48 75.53±0.82 71.97±1.10 74.44±0.97 73.09±1.62 74.08±0.50 69.23±0.36 70.01±0.90 87.90±1.39
* Values are represented as mean ± SD (n=3)
Figure 7.17: In vitro drug release profile of Ambroxol HCl matrix tablets (D1 to D9) by melt granulation with Stearic Acid as per 3
2 Factorial Design
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 189
Table 7.34: In Vitro Drug Release profile of matrix tablets of Ambroxol HCl by melt granulation with Lubritab as per 32 Factorial Design
Time(h) E1 E2 E3 E4 E5 E6 E7 E8 E9 ACOCONTIN
0.5 07.75±0.65 05.23±0.12 04.69±0.52 06.11±0.42 04.65±0.21 04.78±0.26 05.56±0.33 05.26±0.28 06.54±0.46 05.62±0.19
1 12.79±0.46 08.09±0.07 08.21±0.47 10.23±0.33 07.49±0.61 08.55±0.47 08.69±0.24 08.39±0.18 09.61±0.16 14.91±1.09
1.5 17.46±1.05 11.52±0.21 11.25±0.57 13.12±0.05 10.74±0.37 11.33±0.30 11.58±0.63 11.72±0.45 12.66±0.21 16.86±1.41
2 21.82±1.13 14.63±0.34 13.84±0.65 15.70±0.32 13.10±1.05 14.49±0.41 13.91±0.75 13.76±0.70 14.50±0.33 19.40±1.43
3 40.07±2.09 28.93±1.40 26.25±0.49 31.49±0.70 27.86±1.18 27.90±0.96 25.70±0.57 26.94±0.80 27.03±0.23 31.04±1.53
4 48.37±2.20 35.90±1.56 32.45±0.91 37.70±0.54 34.53±1.30 33.86±0.87 31.61±0.16 33.10±1.02 33.54±0.82 39.66±1.62
5 56.28±1.63 42.35±1.18 38.51±0.24 45.21±0.62 41.16±1.58 41.04±0.98 37.98±0.61 40.03±0.41 40.74±0.31 47.39±0.39
6 60.44±3.45 46.85±1.43 43.01±0.32 49.88±0.56 46.42±1.93 46.48±2.23 41.77±0.54 45.102±0.62 44.89±0.72 56.66±0.36
7 68.83±1.04 53.26±0.48 50.39±2.25 54.13±1.06 51.00±0.98 50.45±1.29 46.57±1.86 50.56±0.13 52.11±0.18 64.14±3.02
8 73.93±1.17 58.25±0.48 52.47±1.85 59.45±0.39 55.68±0.35 55.77±1.48 49.91±1.62 54.29±0.07 54.21±1.38 68.64±0.97
9 80.02±1.26 64.32±2.72 57.67±1.31 63.76±0.17 60.44±0.38 59.45±0.16 54.83±1.37 58.66±0.72 59.79±1.24 72.69±0.24
10 83.73±2.30 66.86±0.28 60.76±2.59 67.85±0.71 64.24±1.44 65.41±0.22 59.09±2.49 63.14±0.37 64.34±0.64 78.14±0.72
11 92.96±2.46 73.40±0.51 66.76±1.04 73.96±0.37 71.46±0.25 70.40±0.67 64.59±3.10 68.07±0.52 69.93±0.73 82.66±1.26
12 96.52±1.72 80.45±1.32 71.88±0.70 80.41±1.69 76.79±0.78 74.37±0.79 71.08±1.54 73.18±0.61 72.69±1.56 87.90±1.39
* Values are represented as mean ± SD (n=3)
Figure 7.18: In vitro drug release profile of (E1 to E9) matrix tablets of Ambroxol HCl by melt granulation with Lubritab as per 3
2 Factorial Design
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 190
Table 7.35: In Vitro Drug Release profile of matrix tablets of Ambroxol HCl by melt granulation with Polymeg as per 32 Factorial Design
Time(h) G1 G2 G3 G4 G5 G6 G7 G8 G9 ACOCONTIN
0.5 43.78±0.96 14.6±0.88 13.86±1.28 25.28±1.06 09.84±0.64 09.64±0.64 17.15±0.37 09.56±0.40 05.87±0.62 05.62±0.19
1 55.58±1.18 19.04±0.35 15.33±0.75 35.44±0.78 14.97±0.53 12.06±0.11 20.54±0.89 13.28±0.33 09.47±0.53 14.91±1.09
1.5 64.78±0.91 24.50±1.15 19.85±0.84 44.56±0.82 19.35±1.08 16.59±0.32 29.99±1.61 19.19±0.42 13.29±0.31 16.86±1.41
2 72.18±1.03 31.61±0.78 24.84±0.44 51.95±0.68 24.56±1.90 21.35±1.12 38.70±0.72 24.24±0.29 17.66±0.83 19.40±1.43
3 94.64±0.81 47.04±1.08 39.78±0.82 68.14±0.69 39.65±1.80 34.55±0.64 61.84±0.65 38.84±0.18 29.75±1.39 31.04±1.53
4 101.02±0.15 59.20±1.80 48.10±1.01 81.57±0.65 51.83±1.13 44.70±1.51 81.24±0.65 50.66±0.41 41.81±0.62 39.66±1.62
5 101.37±0.81 67.17±1.83 53.63±0.65 87.21±1.62 58.00±1.49 50.87±0.27 93.02±1.61 56.02±0.63 47.66±0.45 47.39±0.39
6 101.89±0.27 76.98±0.94 64.38±0.90 97.32±1.43 69.77±1.16 61.34±0.45 110.89±0.56 68.01±0.13 58.45±0.56 56.66±0.36
7 102.28±0.36 80.12±1.57 68.49±0.51 101.11±0.48 72.51±1.12 64.77±1.06 109.27±0.78 70.72±0.31 62.72±0.72 64.14±3.02
8 102.99±0.29 86.19±1.36 72.89±0.58 101.89±0.53 77.43±1.81 70.60±0.63 109.03±0.65 75.73±0.87 66.24±0.66 68.64±0.97
9 102.34±0.58 93.21±0.79 75.28±0.44 102.21±0.67 81.56±0.92 74.82±0.87 108.45±0.39 82.31±0.50 72.23±0.73 72.69±0.24
10 101.92±0.23 98.36±1.15 83.08±0.42 102.01±0.23 88.66±0.73 80.41±1.22 107.13±0.27 89.04±0.69 76.33±1.93 78.14±0.72
11 101.49±1.12 101.76±1.35 87.53±1.43 101.76±0.19 91.61±0.62 83.57±1.10 106.94±1.73 91.13±0.44 81.22±1.22 82.66±1.26
12 101.02±0.93 102.38±0.89 93.38±0.96 101.11±1.38 94.75±0.60 88.43±1.59 106.11±2.86 93.46±0.76 84.27±0.82 87.90±1.39
* Values are represented as mean ± SD (n=3)
Figure 7.19: In vitro drug release profile of (G1 to G9) matrix tablets of Ambroxol HCl by melt granulation with Polymeg as per 3
2 Factorial Design
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 191
7.4.3.7 SWELLING AND EROSION STUDIES:
Swelling studies were carried out for optimized formulations of matrix tablets by direct
compression and all the formulations of matrix tablets by melt granulation.
7.4.3.7.1 MATRIX TABLET OF AMBROXOL HCL BY DIRECT COMPRESSION:
The mechanism of drug release from hydrophilic polymeric matrices involves solvent
penetration, hydration and swelling of the polymer, diffusion of the dissolved drug in the matrix,
and erosion of the gel layer. Initially, the diffusion coefficient of drug in the dehydrated polymer
matrix is low; it increases significantly as the polymer matrix imbibes more and more water and
forms a gel, as time progresses. The hydration rate of the polymer matrix, and thereby the gel
formation depends on the polymer proportion, viscosity, and to a lesser degree on polymer
particle size.27
The swelling index for optimized formulations of directly compressed matrix tablets of
Ambroxol HCl with different grades of HPMC and Carbopol was calculated with respect to time.
As time increases, the swelling index (Table 7.36) and erosion (Table 7.37) increased for all the
formulations. This was probably because proportionally increased weight gain by tablet with rate
of hydration up to certain limit. Later on, it decreases gradually due to dissolution of outermost
gelled layer of tablet into dissolution medium.
Table 7.36: Swelling Index of matrix tablets of Ambroxol HCl by direct compression:
Time (h) F1 F4 F5 F9 F12 F15 F18 F21 F23
2 260 320 350 580 300 410 370 550 330
4 180 410 380 670 460 280 430 880 410
8 160 430 500 780 510 310 520 830 400
12 110 450 730 770 470 280 670 1110 480
Figure 7.20: Swelling Behaviour of Optimized Formulations of Matrix Tablets of Ambroxol
HCl by direct compression with different hydrophilic polymers
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 192
Table 7.37: % Matrix Erosion of matrix tablets of Ambroxol HCl by direct compression:
Time (h) F1 F4 F5 F9 F12 F15 F18 F21 F23
2 44 12 8 12 10 4 16 16 8
4 64 16 24 16 12 64 48 48 8
8 68 18 32 28 48 72 60 60 8
12 88 20 32 44 76 84 60 60 20
Figure 7.21: Eroding Behaviour of Optimized Formulations of Matrix Tablets of Ambroxol
HCl by direct compression with different hydrophilic polymers Swelling studies (Figure 7.20) had shown a maximum swelling with in 2 hours for formulation
F1 (1:1 HPMC K 100LV CR) with 260% swelling and also for F15 (1:0.5 Carbopol 974P) with
410% swelling which was decreased periodically. This is due to increased rate of hydration up to
2 hours and decreased gradually due to dissolution of outermost gelled layer of tablet into
dissolution medium.
The high viscosity grade HPMC exhibited extensive swelling. Low viscosity grade HPMCs are
more erodible. (Figure 7.21) This may be explained by the higher gel strength of the high
viscosity grade HPMC counteracting erosion of the gel. Carbopol 974P shows quick swelling as
it is highly crosslinked polymer but other grades of carbopol exhibited extensive swelling with
time. Carbopol 71G exhibited the highest degree of swelling.
Thus, it has been observed that the similarity was observed between the cumulative percent drug
release and swelling properties of these formulations order. Also, swelling and erosion occurred
simultaneously in the matrix helping to constant release of the drug from the matrices.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 193
7.4.3.7.2 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION AS
PER 32 FACTORIAL DESIGN:
Only Swelling studies were carried out for all the formulations of matrix tablets by melt
granulation as per 32 Factorial Design. The direct relationship was observed between swelling
index of matrix tablets by melt granulation and hydrophilic polymer concentration, and as
hydrophilic polymer concentration increases, swelling index increased. (Table 7.38 to 7.43) It
was observed that there was no any effect of lipophilic binder concentration on the swelling
index of matrix tablets by melt granulation with Bees wax, Paraffin wax, Stearic acid and
Lubritab (Figure 7.22, 7.23, 7.24, 7.25 and 7.26). But with increased concentration of Polymeg,
Swelling index decreased.
Table 7.38: Swelling Index of matrix tablets of Ambroxol HCl by melt granulation with
Bees Wax as per 32 Factorial Design:
Time (h) A1 A2 A3 A4 A5 A6 A7 A8 A9
2 72 80 68 80 88 108 120 104 108
4 68 76 72 120 108 140 160 132 168
8 76 84 84 126 136 168 170 168 176
12 80 86 88 130 138 168 170 180 184
Figure 7.22: Swelling Behaviour of Matrix Tablets of Ambroxol HCl by melt granulation
with Bees wax Table 7.39: Swelling Index of matrix tablets of Ambroxol HCl by melt granulation with
Bees Wax I* as per 32 Factorial Design:
Time (h) B1 B2 B3 B4 B5 B6 B7 B8 B9
2 52 88 92 68 96 104 68 28 104
4 68 116 156 76 128 132 76 104 144
8 74 120 164 84 176 180 84 124 168
12 78 126 168 96 188 192 92 152 184
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 194
Figure 7.23: Swelling Behaviour of Matrix Tablets of Ambroxol HCl by melt granulation
with Bees wax and intragranular HPMC K4M Table 7.40: Swelling Index of matrix tablets of Ambroxol HCl by melt granulation with
Paraffin wax as per 32 Factorial Design:
Time (h) C1 C2 C3 C4 C5 C6 C7 C8 C9
2 104 112 116 80 84 96 64 88 104
4 120 128 136 92 104 104 80 108 132
8 156 156 152 132 128 128 104 136 156
12 160 164 176 156 164 176 120 164 176
Figure 7.24: Swelling Behaviour of Matrix Tablets of Ambroxol HCl by melt granulation
with Paraffin wax Table 7.41: Swelling Index of matrix tablets of Ambroxol HCl by melt granulation with
Stearic Acid as per 32 Factorial Design:
Time (h) D1 D2 D3 D4 D5 D6 D7 D8 D9
2 92 88 80 88 88 84 92 92 80
4 96 108 104 100 96 112 104 116 92
8 128 140 136 124 116 148 108 128 124
12 128 132 144 128 128 160 124 100 136
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 195
Figure 7.25: Swelling Behaviour of Matrix Tablets of Ambroxol HCl by melt granulation
with Stearic Acid Table 7.42: Swelling Index of matrix tablets of Ambroxol HCl by melt granulation with
Lubritab as per 32 Factorial Design:
Time (h) E1 E2 E3 E4 E5 E6 E7 E8 E9
2 44 92 104 80 104 84 84 100 88
4 60 120 120 88 120 104 120 128 116
8 72 144 144 124 140 136 160 184 128
12 84 148 168 124 164 176 176 204 160
Figure 7.26: Swelling Behaviour of Matrix Tablets of Ambroxol HCl by melt granulation
with Lubritab Table 7.43: Swelling Index of matrix tablets of Ambroxol HCl by melt granulation with
Polymeg as per 32 Factorial Design:
Time (h) G1 G2 G3 G4 G5 G6 G7 G8 G9
2 80 116 140 72 120 128 124 132 156
4 24 108 132 56 116 140 92 128 180
8 72 148 284 136 152 208 88 152 160
12 84 154 296 138 162 214 136 216 224
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 196
Figure 7.27: Swelling Behaviour of Matrix Tablets of Ambroxol HCl by melt granulation
with Polymeg Thus, based on Swelling and erosion studies, it was concluded that matrix tablets undergo
swelling as well as erosion during the dissolution study, which indicates that polymer relaxation
had a role in drug release mechanism.
7.4.4 KINETIC ANALYSIS OF DRUG RELEASE
A tablet composed of a polymeric matrix on contact with water builds a gel layer around the
tablet, which governs the drug release. In order to establish the mechanism of drug release and
swelling kinetics, the experimental data were fitted to zero-order, first order, Higuchi and
Korsmeyer–Peppas model. The fitted equation and correlation coefficient of each model is
shown in Table 7.44.
7.4.4.1 MATRIX TABLET OF AMBROXOL HCL BY DIRECT COMPRESSION:
The coefficient of regressions for the matrix tablets of Ambroxol HCl with different proportions
and grades of HPMC were in a range between 0.912–0.990 (zero order), 0.875-0.996(first order),
0.959–0.998 (Higuchi) and 0.984–0.996 (Peppas). The n values for the Peppas model ranged
from 0.482 to 0.94 indicating that the release of the drug followed anomalous non-Fickian
diffusion and Case- II transport from the formulations prepared from various proportions and
grades of HPMC.
Release of drug from a matrix tablet containing HPMC polymer generally involves factors of
diffusion. The relaxation and swelling characteristics of HPMC matrices may influence drug
release kinetics. These matrices have been shown to expand predominantly in an axial direction.
The diffusional release is by molecular diffusion down a chemical potential gradient whereas
relaxational release is by drug transport mechanisms associated with stresses state transitions
involved in the swelling of the polymer. The swelling of the polymer would alter the drug
concentration gradient in the gel layer. 28
As the gradient varies, the drug is released, and the
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 197
distance for the diffusion increases. This could explain why the drug diffuses at a comparatively
slower rate as the distance for diffusion increases, which is governed by square root or Higuchi
kinetics.
Formulations F1, F6 and F8 followed Higuchi model. Formulations F2, F3 and F10 released
maximum drug within 10, 5 and 4 h respectively. F4, F7and F10 showed highest linearity for
First order. F2, F5 and F9 showed good linearity for Korsmeyer Peppas model. All the
formulations containing HPMC shown diffusion is the dominant mechanism of drug release
indicating a coupling of diffusion and erosion mechanisms – so called anomalous diffusion with
the n value of 0.482 to 0.861.
Thus, varying the HPMC grade increased the n value that is indicative of the release mechanism
from diffusion toward a relaxation and erosion controlled process. As expected, an increase in the
polymer content brought about a corresponding decrease in drug release rate. The effect of
polymer content is attributed to an increasing tortuosity and length of the diffusion path through
the matrix as the polymer content increases. Formulation F7 containing HPMC K200M was
found to control the release of drug from the matrix tablets even at a low proportion (1:0.5) of the
polymer.
The results indicated that drug release from the Carbomer matrix could occur both by diffusion
through low microviscosity pores (polymer hydro fusion) and swelling-controlled mechanism.
Formulation F13 and F19 containing 1:0.25 drug: Carbopol 934P and 971P with formulation F23
and F25 containing 1:1 and 1:0.5 drug: Polycarbophil shown first order model is best fit model.
For formulation F12, F14, F15, F22 and F24, Higuchi Kinetic is dominant (Table 7.47). When
data were fitted into Korsmeyer Peppas model, formulations F11, F16, F17, F18, F20 and
F21showed good linearity ( R2 = 0.926 to 0.996), with the slope (n value) of 0.438 – 0.62,
indicating Quasi-Fickian diffusion and anomalous (non-Fickian) diffusion. Formulation F21
shown the n value of 1.27 indicating Super-case II transport and drug release is a function of
chain relaxation of macromolecules.
As the amount of the carbomers in their respective formulations increased, drug release rate
decreased and the release mechanism gradually changed from Quasi-Fickian to anomalous type
to the Case II transport mechanism. Other factors responsible for the reduction in the number
and/or size of low microviscosity pores, such as higher pH that increased polymer swelling and
decreased drug release, tended to shift the release profiles towards the swelling controlled, Case
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 198
II (Zero order) transport mechanism. Thus, Carbopol 71G was found to have a tremendous
capability of controlling release of drug
7.4.4.2 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION AS PER
32 FACTORIAL DESIGN:
The drug release data from matrix tablets of Ambroxol HCl by melt granulation with different
hydrophobic meltable binders as per 32 factorial design were fitted to various Kinetic models to
know the release mechanism. Table 7.45 to Table 7.50 shows the best-fit release kinetic data with
the highest values of regression coefficient (R2)
The kinetic data for melt granulated mattix tablets showed that the release of drug followed
diffusion controlled or solvent induced polymer relaxation and swelling in the polymer
mechanism for the matrix tablet formulations. Diffusion is related to transport of drug from the
dosage form in to the in vitro fluid depending up on the concentration. As the gradient varies the
drug is released and the distance for diffusion increases.
In the present study, in vitro release profiles could be best expressed by Higuchi‟s equation as all
formulations showed good linearity (R2 = 0.954 to 0.996) indicates that diffusion is dominant
mechanism of drug release with these formulations. R2 data indicate that zero (R
2 = 0.936 to
0.998), First (R2
= 0.774 to 0.999) and Peppas (R2 = 0.811 to 0.997) models also suitably
described the release of Ambroxol HCl from the matrix tablets prepared by melt granulation.
The values of n were in the range of 0.602 to 0.881 (i.e., more than 0.5) indicating non-Fickian
release i.e. Anomalous transport (diffusion coupled with polymer relaxation controlled). For few
formulations like B8, E6, and G8, value of n is exact 0.890 indicating zero order release which
can be achieved when drug diffusion is rapid copmpared to the constant rate of solvent-induced
relaxation and swelling in the polymer. The value of n is 0.900 and 0.988 (i.e >0.89) in
formulations E2 and E9 respectively indicates that drug transport is Case-II transport. Only for
the matrix tablet with low amount of Polymeg and low HPMC K4M, n value is 0.415 indicating
Fickian diffusion.
Therefore, the release of drug from the prepared matrix tablets is controlled by the diffusion and
swelling of the polymer followed by drug diffusion through the swelled polymer and slow
erosion of the tablet.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 199
Table 7.44: Kinetic Data from Various Kinetic Models for matrix tablets of Ambroxol HCl by direct compression
Formulation Code Zero Order First Order Higuchi Model Korsmeyer Peppas
f1 f2 Best Fit Model R
2 K0 R
2 K1 R
2 Kh R
2 N
F1 0.969 19.99 0.950 2.03 0.998 -6.80 0.996 0.591 14.84 50.5 HIGUCHI
F2 0.984 18.69 0.942 2.02 0.993 -7.36 0.996 0.579 26.61 38.41 KMP
F3 0.990 0.25 0.989 2.07 0.959 -30.96 0.984 0.940 40.71 14.71 ZERO
F4 0.959 12.57 0.994 1.99 0.993 -12.83 0.990 0.724 0.79 74.23 FIRST
F5 0.975 8.66 0.990 2.03 0.989 -18.74 0.990 0.775 1.23 87.8 KMP
F6 0.962 13.21 0.875 2.17 0.994 -18.90 0.991 0.770 15.52 49.01 HIGUCHI
F7 0.976 7.67 0.996 2.02 0.989 -18.60 0.991 0.792 4.9 73.85 FIRST
F8 0.961 12.15 0.991 2.01 0.993 -14.40 0.988 0.739 1.2 76.73 HIGUCHI
F9 0.985 4.49 0.952 2.06 0.983 -22.03 0.996 0.861 9.36 59.76 KMP
F10 0.912 35.71 0.996 1.94 0.971 6.18 0.975 0.482 39.8 10.14 FIRST
F11 0.874 18.48 0.917 1.91 0.958 -6.06 0.968 0.438 19.66 36.31 KMP
F12 0.912 19.78 0.973 1.92 0.981 -0.78 0.973 0.550 13.48 50.82 HIGUCHI
F13 0.943 -1.76 0.999 2.18 0.980 -52.83 0.949 0.620 38.63 11.28 FIRST
F14 0.884 13.59 0.930 1.94 0.964 -0.82 0.957 0.601 14.32 32.21 HIGUCHI
F15 0.944 17.78 0.992 1.95 0.993 -4.87 0.991 0.597 13.17 51.18 HIGUCHI
F16 0.973 27.19 0.844 2.31 0.996 -5.85 0.996 0.553 16.89 11.3 KMP
F17 0.875 14.43 0.907 1.93 0.957 -3.88 0.969 0.462 30.25 30.97 KMP
F18 0.893 20.86 0.969 1.92 0.971 -1.77 0.972 0.594 5.39 56.71 KMP
F19 0.779 31.31 0.960 2.01 0.885 -2.54 0.926 0.643 26.14 16.78 FIRST
F20 0.87 16.06 0.903 1.93 0.959 -5.12 1.975 0.442 26.64 32.66 KMP
F21 0.964 23.82 0.912 1.32 0.937 3.09 0.937 1.270 10.75 62.58 ZERO
F22 0.954 15.26 0.792 2.94 0.984 -32.65 0.969 0.829 30.14 9.58 HIGUCHI
F23 0.900 19.02 0.976 1.94 0.971 -3.50 0.955 0.643 12.98 55.23 FIRST
F24 0.966 19.27 0.986 2.01 0.996 -7.62 0.992 0.608 14.33 50.21 HIGUCHI
F25 0.719 45.05 0.951 1.94 0.843 17.41 0.871 0.475 34.57 14.99 FIRST
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 200
Table 7.45: Kinetic Data from Various Kinetic Models for Ambroxol HCl matrix tablets by melt granulation with Bees Wax as per 32
Factorial Design
Formulation Code Zero Order First Order Higuchi Model Korsmeyer Peppas f1 f2 Best Fit Model
R2
K0 R2
K1 R2
K R2
n
A1 0.990 3.55 0.774 2.13 0.954 -23.35 0.973 0.798 5.83 78.59 ZERO
A2 0.972 6.98 0.995 1.99 0.989 -12.74 0.977 0.757 21.63 41.65 FIRST
A3 0.981 6.89 0.997 2.01 0.993 -16.66 0.992 0.805 13.11 52.87 FIRST
A4 0.991 4.67 0.992 2.02 0.987 -18.78 0.995 0.841 40.71 27.25 KMP
A5 0.989 5.26 0.979 2.02 0.980 -18.13 0.978 0.805 15.96 48.95 ZERO
A6 0.959 9.29 0.995 1.99 0.991 -13.47 0.986 0.760 34.71 30.59 FIRST
A7 0.973 7.23 0.996 0.21 0.987 -16.63 0.997 0.782 11.94 55.35 KMP
A8 0.966 0.73 0.975 1.99 0.978 -11.94 0.967 0.749 22.31 40.29 HIGUCHI
A9 0.974 5.58 0.995 1.99 0.987 -14.22 0.978 0.797 23.43 40.32 FIRST
ACOCONTIN 0.979 8.330 0.982 2.046 0.992 -19.65 0.987 0.831 HIGUCHI Table 7.46: Kinetic Data from Various Kinetic Models for Ambroxol HCl matrix tablets by melt granulation with Bees Wax I* as per 3
2
Factorial Design
Formulation Code Zero Order First Order Higuchi Model Korsmeyer Peppas f1 f2 Best Fit Model
R2
K0 R2
K1 R2
KH R2
n
B1 90 % DRUG RELEASED IN 2 HOURS 41.12 11.58 -
B2 0.964 11.61 0.992 2.01 0.996 -15.14 0.988 0.737 6.01 75.41 HIGUCHI
B3 0.974 7.17 0.997 2.02 0.991 -18.75 0.983 0.833 7.69 65.50 FIRST
B4 0.936 22.29 0.983 1.99 0.991 -5.15 0.988 0.602 18.86 45.93 HIGUCHI
B5 0.969 7.44 0.999 2.01 0.994 -16.79 0.988 0.837 11.06 56.26 FIRST
B6 0.966 6.53 0.996 2.00 0.992 -16.59 0.988 0.867 15.30 49.94 FIRST
B7 0.970 10.34 0.998 2.00 0.994 -14.50 0.994 0.747 3.86 69.47 FIRST
B8 0.998 4.30 0.986 2.01 0.991 -18.12 0.995 0.890 19.08 45.26 ZERO
B9 0.995 7.40 0.994 1.99 0.991 -14.99 0.987 0.787 14.70 49.85 ZERO
ACOCONTIN 0.979 8.330 0.982 2.046 0.992 -19.65 0.987 0.831 HIGUCHI
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 201
Table 7.47: Kinetic Data from Various Kinetic Models for Ambroxol HCl matrix tablets by melt granulation with Paraffin Wax as per
32 Factorial Design
Formulation Code Zero Order First Order Higuchi Model Korsmeyer Peppas f1 f2 Best Fit Model
R2
K0 R2
K1 R2
K R2
n
C1 0.980 9.00 0.964 2.08 0.985 -32.26 0.984 0.740 6.93 65.38 HIGUCHI
C2 0.984 7.01 0.969 2.07 0.985 -30.26 0.970 0.752 11.74 55.44 HIGUCHI
C3 0.985 7.17 0.975 2.07 0.985 -30.29 0.975 0.754 11.20 56.80 HIGUCHI
C4 0.985 8.85 0.974 2.07 0.987 -31.53 0.980 0.699 11.17 54.79 HIGUCHI
C5 0.987 5.59 0.979 2.05 0.984 -27.11 0.975 0.779 18.01 46.28 ZERO
C6 0.984 6.07 0.972 2.05 0.984 -27.65 0.972 0.790 15.69 49.40 ZERO
C7 0.984 5.93 0.973 2.06 0.983 -28.03 0.980 0.804 14.51 51.07 ZERO
C8 0.982 6.14 0.978 2.05 0.984 -27.49 0.977 0.785 16.56 47.98 HIGUCHI
C9 0.976 5.83 0.977 2.05 0.983 -26.60 0.984 0.841 14.10 52.22 KMP
ACOCONTIN 0.979 8.330 0.982 2.046 0.992 -19.65 0.987 0.831 HIGUCHI
Table 7.48: Kinetic Data from Various Kinetic Models for Ambroxol HCl matrix tablets by melt granulation with Stearic Acid as per 32
Factorial Design
Formulation Code Zero Order First Order Higuchi Model Korsmeyer Peppas f1 f2 Best Fit Model
R2
K0 R2
K1 R2
K R2
n
D1 0.990 13.84 0.957 2.01 0.992 -10.29 0.995 0.630 0.74 66.39 KMP
D2 0.992 11.15 0.984 2.00 0.993 -12.98 0.993 0.688 5.28 65.58 KMP
D3 0.989 8.20 0.985 2.00 0.990 -13.97 0.993 0.719 13.85 50.14 KMP
D4 0.988 9.01 0.998 1.99 0.996 -12.94 0.997 0.729 13.11 51.08 KMP
D5 0.985 8.44 0.992 2.00 0.993 -13.98 0.994 0.734 13.14 51.52 KMP
D6 0.983 0.39 0.991 1.99 0.992 -13.51 0.992 0.739 14.86 48.88 KMP
D7 0.965 11.37 0.998 1.98 0.996 -11.84 0.993 0.711 6.46 61.31 KMP
D8 0.980 10.05 0.998 1.98 0.991 -10.94 0.984 0.662 13.30 50.41 HIGUCHI
D9 0.978 9.42 0.997 1.99 0.995 -11.90 0.987 0.713 14.18 48.83 HIGUCHI
ACOCONTIN 0.979 8.330 0.982 2.046 0.992 -19.65 0.987 0.831 HIGUCHI
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 202
Table 7.49: Kinetic Data from Various Kinetic Models for Ambroxol HCl by melt granulation with Lubritab as per 32
Factorial Design
Formulation Code Zero Order First Order Higuchi Model Korsmeyer Peppas f1 f2 Best Fit Model
R2
K0 R2
K1 R2
K R2
n
E1 0.970 10.27 0.832 2.21 0.981 -35.42 0.988 0.818 6.49 63.97 KMP
E2 0.988 5.06 0.954 2.07 0.977 -26.63 0.981 0.900 12.84 53.83 ZERO
E3 0.980 5.24 0.973 2.05 0.978 -24.55 0.991 0.881 18.26 45.79 KMP
E4 0.974 7.22 0.955 2.07 0.980 -28.30 0.986 0.837 10.05 58.10 KMP
E5 0.998 8.63 0.963 2.05 0.977 -24.92 0.996 0.923 15.33 50.10 KMP
E6 0.990 5.47 0.969 2.05 0.975 -25.45 0.979 0.890 14.48 51.22 ZERO
E7 0.984 5.58 0.973 2.05 0.979 -25.09 0.990 0.828 19.79 43.71 KMP
E8 0.979 5.54 0.972 2.05 0.979 -25.41 0.989 0.867 16.32 48.53 HIGUCHI
E9 0.982 6.38 0.973 2.05 0.980 -27.19 0.811 0.988 15.41 49.43 ZERO
ACOCONTIN 0.979 8.33 0.982 2.046 0.992 -19.65 0.987 0.831 HIGUCHI
Table 7.50: Kinetic Data from Various Kinetic Models for Ambroxol HCl by melt granulation with Polymeg as per 32 Factorial Design
Formulation Code Zero Order First Order Higuchi Model Korsmeyer Peppas f1 f2 Best Fit Model
R2
K0 R2
K1 R2
KH R2
n
G1 0.996 34.47 0.892 2.06 0.977 -7.43 0.997 0.415 13.28 10.78 KMP
G2 0.967 15.09 0.887 2.14 0.992 -16.08 0.987 0.690 25.68 38.83 HIGUCHI
G3 0.970 14.05 0.953 2.04 0.990 -13.93 0.977 0.671 8.15 61.52 HIGUCHI
G4 0.975 23.99 0.913 2.10 0.996 -6.23 0.997 0.556 3.01 14.55 HIGUCHI
G5 0.954 13.30 0.973 2.08 0.990 -17.48 0.988 0.758 13.66 51.12 HIGUCHI
G6 0.968 10.41 0.989 2.04 0.992 -17.89 0.985 0.769 3.61 72.69 HIGUCHI
G7 0.990 4.69 0.932 2.17 0.962 -30.44 0.960 0.802 7.12 14.43 ZERO
G8 0.959 12.32 0.979 2.07 0.992 -18.40 0.988 0.774 11.94 53.08 HIGUCHI
G9 0.996 7.02 0.995 2.04 0.991 -21.35 0.989 0.892 2.00 75.92 ZERO
ACOCONTIN 0.979 8.33 0.982 2.05 0.992 -19.65 0.987 0.831 HIGUCHI
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 203
7.4.5 COMPARISON OF DISSOLUTION PROFILES:
The similarity in the release profiles of marketed tablet as ACOCONTIN CR and all the
formulations was compared by making use of “Model Independent Approach”.
Difference factors f1 and similarity factors f2 for all formulations prepared by direct
compression and by melt granulation with different polymers and lipophilic binders were
shown in Table 7.44 to 7.50.
7.4.5.1 MATRIX TABLET OF AMBROXOL HCL BY DIRECT COMPRESSION:
The drug release profile for formulation F1with 1:1 HPMC K100 LV CR only produced
f2 value of 50.5 indicating borderline similarity. Formulation F4 and F5 containing 1:2
HPMC K4M and 1:1HPMC K100M produced f2 value of 74.23 and 87.8 indicating
similarity of dissolution profile with marketed formulation as Acocontin CR. All the
formulations F7, F8 and F9 except F10 containing 1:0.25 HPMC K200M showed f2 value
of 73.85, 76.73 and 59.76 indicating similarity in release profiles. Similarity factors f2 for
formulations containing different grades of carbopols showed f2 value more than 50 only
for F12, F15, F18, F21, F23 and F24. From that formulation F21 containing 1:0.5
Carbopol 71G showed highest f2 value of 62.58 indicating similarity in release profile.
Rest all other formulations showed f2 values of 50 to 55 indicating only borderline
similarity. All other formulations showed f2 value below 50, indicating dissimilar release
profiles with marketed formulation. Thus from model independent approach, F5
containing 1:1 HPMC K100M with f1 and f2 value of 1.23 and 87.8 respectively is the
optimized formulation.
7.4.5.2 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION
AS PER 32 FACTORIAL DESIGN:
Similarity factors f2 for formulations for formulations A1, C1, D1 and E1 with low
amount of Bees wax, Paraffin wax, Stearic Acid, Lubritab and HPMC K4M as 78.59
65.38, 66.39 and 63.97 respectively. Only for formulation B2 and G6 with low amount of
Bees wax and medium level of intragranular HPMC K4M and medium amount of
Polymeg and high amount of HPMC K4M showed f2 value of 75.41 and 72.69 indicating
optimized formulations from model independent approach.
Thus, formulation A1 was found to be optimized one by this model independent approach
which is in good correlation with data analysed using ANOVA by 32 Factorial design for
matrix tablets of Ambroxol HCl prepared by melt granulation with high desirability
function of 0.951.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 204
7.4.6 DATA ANALYSIS OF MATRIX TABLETS OF AMBROXOL HCl BY
MELT GRANULATION AS PER 32 FACTORIAL DESIGN:
The responses were recorded and analysis of the data was carried out using ANOVA in
Stat-Ease Design Expert 8.0.4.1 demo version software. The individual parameters were
evaluated using F test and polynomial equation was obtained using MLRA (Multi Linear
Regression Analysis). The response surface plots for different responses were generated
using (Design Expert 8.0.4.1) software and are presented in figures 7.28 to 7.63. These
figures were used to observe the effects of independent variables on the studied responses
such as % CDR at 1st & 12
th h and swelling index at 12
th h. Graphical presentation of the
data helped to show the relationship between the responses and the independent variables.
The information generated from graph was similar to that of mathematical equation
obtained from statistical analysis.
Full Factorial Design
A 32
full factorial design is used to evaluate two factors simultaneously. The treatments
are combinations of levels of the factors. It is a technique that allows identification of
factor involved in a process and assesses their relative importance. In addition, any
interaction between factors chosen can be identified. The advantages of factorial designs
over one-factor-at-a-time experiments are that they provide sufficient degrees of freedom
to resolve the main effects as well as are more efficient and allow interactions to be
detected. To study all the possible combinations of both factors at all levels, a two factor,
three level full factorial designs were constructed and conducted in a fully randomized
order. The composition and responses of the 32 design are shown in Table 7.5.
Two independent factors, the concentration of wax polymer (X1) and HPMC K4M (X2)
were set at three levels. High, medium and low levels of each factor were coded as +1, 0
and - 1, respectively shown in Table 7.4. The range of a factor must be chosen in order to
adequately measure its effects on the response variables. Stepwise regression analysis was
used to find out the control factors that significantly affect response variables.
Dependent Variables: Y1 = % Cumulative drug release at 1
st hour;
Y2 = % Cumulative drug release at 12th
hour;
Y3 = Swelling index at 12th
hour
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 205
The response values were subjected to multiple regression analysis to find out the
influence of each factor on the response value obtained. A statistical model incorporating
interactive and polynomial terms was utilized to evaluate the responses.
Y = β0 + β1X1 + β2X2 + β12X1X2 + β11X12 + β22X2
2
Where, Y is the dependent variable, β0 is the arithmetic mean response of the nine runs,
and β1 is the estimated coefficient for the factor X1. The main effects (X1 and X2) represent
the average results of changing on factor at a time from low to high value. The interaction
terms (X1X2) show how the response changes when two factors are simultaneously
changed. The polynomial terms (X12 and X2
2) are included to investigate non-linearity.
Response surface and contour plot
The quadratic surface model obtained from the regresion analysis was used to build up 3-
D surface and 2-D contour plots in which the responses were represented by curvature
surface as a function of independent variables.
7.4.6.1 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION
WITH BEES WAX AS PER 32 FACTORIAL DESIGN
Table 7.51: Design & Response summary for Bees Wax
Formulation
Code
Actual
value
Coded
value Y1 %
CDR
at 1sth
Y2 %
CDR at
12th
h
Y3 Swelling
index at
12th
h
f2
value
Best fit
model X1 X2 X1 X2
A1 8 28 -1 -1 10.55 96.2 80 58.59 ZERO
A2 8 30 -1 0 9.88 74.3 86 41.65 FIRST
A3 8 32 -1 +1 8.5 62.46 88 52.87 FIRST
A4 10 28 0 -1 10.44 76.25 130 27.25 KMP
A5 10 30 0 0 9.69 73.64 138 48.95 ZERO
A6 10 32 0 +1 8.79 70.34 168 30.59 FIRST
A7 12 28 +1 -1 10.33 74.25 170 55.35 KMP
A8 12 30 +1 0 8.46 66.11 180 40.29 HIGUCHI
A9 12 32 +1 +1 7.77 61.13 184 40.32 FIRST Table 7.52: ANOVA Table for Bees Wax From Full Factorial Design*
Source Df Sum Square Mean Square F value Prob > F
% Cumulative Drug Release at 1st h: R
2 = 0.8995
X1 1 0.94 0.94 6.73 0.0410 Significant
X2 1 6.53 6.53 46.95 0.0005 Significant
% Cumulative Drug Release at 12th h: R
2 = 0.7330
X1 1 165.06 165.06 4.32 0.0829 Not Significant
X2 1 464.11 464.11 12.15 0.0131 Significant
% Swelling Index at 12th h: R
2 = 0.9491
X1 1 600.00 600.00 4.91 0.0686 Not Significant
X2 1 13066.67 13066.67 106.91 <0.0001 Significant
Prob > F less than 0.05 indicates model terms are significant.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 206
Figure 7.28 & 7.29: Contour plot(2D) & Response surface plot (3D) showing the
effect of Bees Wax & Extragranular HPMC K4M on % CDR at 1st h
Figure 7.30 & 7.31: Contour plot(2D) & Response surface plot (3D) showing the
effect of Bees Wax & Extragranular HPMC K4M on % CDR at 1st h
Figure 7.32 & 7.33: Contour plot(2D) & Response surface plot (3D) showing the
effect of Bees Wax & Extragranular HPMC K4M on Swelling Index at 12th
h Regression Coefficients for the Responses of Bees Wax with Extragranular HPMC
K4M:
% CDR at 1st h = 9.38 – 0.40 X1– 1.04 X2
% CDR at 12th
h = 72.74 – 5.24 X1 - 8.79 X2
Swelling Index at 12th
h = 136.00 + 10.00 X1 + 46.67 X2
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 207
Results of polynomial equation indicated that the effect of X2 (amount of HPMC K4M) is
more significant than X1 (amount of Bees Wax) for % CDR at 1st h. Effect of X1 & X2 is
negative i.e. as concentration of X1 & X2 increased; % CDR at 1st h of matrix tablets
decreased from 10.55% to 7.77% which can be confirmed from the declining linear
contour lines (Figure7.28). But, the effect of X2 is only significant for % CDR at 12th
h
and Swelling Index at 12th
h. Effect of X2 is negative i.e. as concentration of X2 increased;
% CDR at 12th
h of matrix tablets decreased from 96.2% to 61.13% which can be
confirmed from the declining contour lines (Figure 7.30). The effect of X2 is positive i.e.
as concentration of X2 increased; Swelling Index at 12th
h also increased from 80 to 184.
The corresponding contour plot (Figure 7.32) also reveals nearly increasing trend at all
the factor levels and nearly vertical contour lines corroborate that only HPMC K4M
influences the Swelling index at 12th
h significantly. Increase in concentration of Bees
Wax had no significant effect on % CDR at 12th
h and Swelling Index at 12th
h.
From all the three response variables as % cumulative drug release at 1
st & 12
th hour and
Swelling Index at 12th
h, Formulation A1 was found to be the optimized formulation
among the all 9 formulations with desirability function =0.951 and showed a greater
similarity in dissolution profile with marketed formulation (f2 = 78.59). Zero order
model was best fit to drug release data of formulation A1 which was confirmed from the
kinetic data (Table 7.45) showing ideal controlled drug release.
7.4.6.2 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION WITH
BEES WAX I* AS PER 32 FACTORIAL DESIGN
Table 7.53: Design and Response summary for Bees wax I* Formulation
Code
Actual
value
Coded
value
Y1 %
CDR
at 1st h
Y2 %
CDR
at 12th
h
Y3
Swelling
index at
12th
h
f2
value
Best fit
model
X1 X2 X1 X2
B1 4 10 -1 -1 42.32 99.89 78 11.58 -
B2 4 20 -1 0 14.13 83.13 126 85.41 HIGUCHI
B3 4 30 -1 +1 10.54 78.54 168 65.50 FIRST
B4 8 10 0 -1 22.34 93.59 96 45.93 HIGUCHI
B5 8 20 0 0 9.65 73.74 188 56.26 FIRST
B6 8 30 0 +1 8.97 68.78 192 49.94 FIRST
B7 12 10 +1 -1 14.13 78.6 92 69.47 FIRST
B8 12 20 +1 0 7.5 68.73 152 45.26 ZERO
B9 12 30 +1 +1 9.64 68.22 184 49.85 ZERO
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 208
Table 7.54: Analysis of Variance Table of Dependent Variables for Bees Wax I*
From Full Factorial Design
Source Df Sum Square Mean Square F value Prob > F
% Cumulative Drug Release at 1st h: R
2 = 0.9682
X1 1 212.65 212.65 20.66 0.0199 Significant
X2 1 410.69 410.69 39.90 0.0080 Significant
X12 1 186.19 186.19 18.09 0.0238 Significant
X12 1 14.83 14.83 1.44 0.3161 Not Significant
X22 1 114.41 114.41 11.12 0.0446 Significant
% Cumulative Drug Release at 12th h: R
2 = 0.8683
X1 1 352.82 352.82 15.76 0.0074 Significant
X2 1 532.80 532.80 23.80 0.0028 Significant
% Swelling Index at 12th h: R
2 = 0.8313
X1 1 566.67 566.67 1.15 0.3242 Not Significant
X2 1 12880.67 12880.67 28.41 0.0018 Significant
Prob > F less than 0.05 indicates model terms are significant.
Figure 7.34 & 7.35: Contour plot(2D) & Response surface plot (3D) showing the
effect of Bees Wax I* HPMC K4M on % Cumulative Drug Release at 1st h
Figure 7.36 & 7.37: Contour plot(2D) & Response surface plot (3D) showing the
effect of Bees Wax I* HPMC K4M on % Cumulative Drug Release at 12th
h
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 209
Figure 7.38 & 7.39: Contour plot(2D) & Response surface plot (3D) showing the
effect of Bees Wax & Intragranular HPMC K4M on Swelling Index at 12th
h Regression Coefficients for the Responses of Bees Wax I*
% CDR at 1st h = 8.61 – 5.95X1 – 8.27X2 + 6.82X1X2 + 2.72 X1
2 + 7.56X2
2
% CDR at 12th
h = 79.25 – 7.67X1– 9.42X2
Swelling Index at 12th
h = 141.78 + 9.33 X1 + 46.33X2
Results of polynomial equation indicated that the effect of X2 (amount of HPMC K4M) is
more significant than X1 (amount of Bees Wax) for % CDR at 1st h and 12
th h. Effect of
X1 & X2 is negative i.e. as concentration of X1 & X2 increased; % CDR at 1st h and 12
th h
of matrix tablets decreased from 42.32% to 7.5% and 99.89% to 68.22% which can be
confirmed from the declining linear contour lines (Figure 7.34 & 7.36). But, the effect of
X2 is only significant for Swelling Index at 12th
h. The effect of X2 is positive i.e. as
concentration of X2 increased; Swelling Index at 12th
h also increased from 78 to 192. The
corresponding contour plot (Figure 7.38) also reveals nearly increasing trend at all the
factor levels and nearly vertical contour lines corroborate that only HPMC K4M
influences the Swelling index at 12th
h significantly. Increase in concentration of Bees
Wax had no significant effect on % CDR at 12th
h and Swelling Index at 12th
h.
From all the three response variables as % cumulative drug release at 1
st & 12
th hour and
Swelling Index at 12th
h, Formulation B2 containing low amount of Bees wax and
medium amount of intragranular HPMC K4M was found to be the optimized formulation
among the all 9 formulations with desirability function =0.761 and showed a greater
similarity in dissolution profile with marketed formulation (f2 = 75.41). Higuchi model
was best fit to drug release data of formulation B2 which was confirmed from the kinetic
data (Table 7.46) showing diffusion controlled drug release.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 210
7.4.6.3 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION
WITH PARAFFIN WAX
Table 7.55: Design and Response summary for Paraffin wax
Formulation
Code
Actual
value
Coded
value
Y1 %
CDR
at 1st h
Y2 %
CDR at
12th
h
Y3
Swelling
index at
12th
h
f2 value Best fit
model
X1 X2 X1 X2
C1 8 28 -1 -1 11.52 79.59 160 65.38 HIGUCHI
C2 8 30 -1 0 10.57 74.88 164 55.44 HIGUCHI
C3 8 32 -1 +1 10.52 73.94 176 56.80 HIGUCHI
C4 10 28 0 -1 13.77 74.79 156 54.79 HIGUCHI
C5 10 30 0 0 9.51 73.58 164 46.28 ZERO
C6 10 32 0 +1 9.40 70.35 176 49.40 ZERO
C7 12 28 +1 -1 9.62 73.58 120 51.07 ZERO
C8 12 30 +1 0 9.38 71.91 164 47.98 HIGUCHI
C9 12 32 +1 +1 9.03 70.89 176 52.22 KMP Table 7.56: ANOVA Table of Dependent Variables for Paraffin Wax from Full
Factorial Design
Source Df Sum Square Mean Square F value Prob > F
% Cumulative Drug Release at 1st h: R
2 = 0.5242
X1 1 3.50 3.50 2.45 0.1683 Not Significant
X2 1 5.92 5.92 4.16 0.0876 Not Significant
% Cumulative Drug Release at 12th h: R
2 = 0.8603
X1 1 24.12 24.12 17.36 0.0059 Significant
X2 1 27.22 27.22 19.59 0.0044 Significant
% Swelling Index at 12th h: R
2 = 0.8643
X1 1 266.67 266.67 4.09 0.0992 Not Significant
X2 1 1410.67 1410.67 21.62 0.0056 Significant
X12 1 400.00 400.00 6.13 0.0561 Not Significant
Prob > F less than 0.05 indicates model terms are significant.
Figure 7.40 & 7.41: Contour plot (2D) & Response surface plot (3D) showing the
effect of Paraffin Wax & HPMC K4M on % Cumulative Drug Release at 1st h
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 211
Figure 7.42 & 7.43: Contour plot(2D) & Response surface plot (3D) showing the
effect of Paraffin Wax & HPMC K4M on % Cumulative drug release at 12th
h
Figure 7.44 & 7.45: Contour plot(2D) & Response surface plot (3D) showing the
effect of Paraffin Wax & HPMC K4M on Swelling Index at 12th
h Regression Coefficients for the Responses of Paraffin Wax
% CDR at 1st h = 10.37 – 0.76 X1– 0.99 X2
% CDR at 12th
h = 73.72 – 2.01 X1– 2.13 X2
Swelling Index at 12th
h = 161.78 – 6.67 X1 + 15.33X2 + 10.00 X1 X2
Results of polynomial equation indicated that the effect of X1 (amount of Paraffin Wax)
and X2 (amount of HPMC K4M) is not significant for % CDR at 1st h which can be
confirmed from the corresponding contour lines (Figure 7.40). But, the effect of X2 is
more significant than X1 for % CDR at 12th
h. Effect of X1 & X2 is negative i.e. as
concentration of X1 & X2 increased; % CDR at 12th
h of matrix tablets decreased from
79.59% to 70.35% which can be confirmed from the declining diagonal contour lines
(Figure 7.42) indicating effect of both the parameters. X2 is only significant for Swelling
Index at 12th
h. The effect of X2 is positive i.e. as concentration of X2 increased; Swelling
Index at 12th
h also increased from 120 to 176. The corresponding contour plot (Figure
7.44)also reveals nearly increasing trend at all the factor levels and nearly vertical contour
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 212
lines corroborate that only HPMC K4M influences the Swelling index at 12th
h
significantly. Increase in concentration of Paraffin Wax had no significant effect on %
CDR at 12th
h and Swelling Index at 12th
h.
From all the three response variables as % cumulative drug release at 1
st & 12
th hour and
Swelling Index at 12th
h, Formulation C1 was found to be the optimized formulation
among the all 9 formulations with desirability function =0.659 and showed a greater
similarity in dissolution profile with marketed formulation (f2 = 65.38). Higuchi model
was best fit to drug release data of formulation C1 which was confirmed from the kinetic
data (Table 7.47) showing diffusion controlled drug release from the formulation.
7.4.6.4 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION
WITH STEARIC ACID
Table 7.57: Design and Response summary for Stearic Acid
Formulation
Code
Actual
value
Coded
value
Y1 %
CDR at
1sth
Y2 %
CDR at
12th
h
Y3 Swelling
index at
12th
h
f2
value
Best fit
model
X1 X2 X1 X2
D1 15 22 -1 -1 19.62 87.32 128 66.39 KMP
D2 15 24 -1 0 13.67 81.87 132 65.58 KMP
D3 15 26 -1 +1 11.45 75.53 144 50.14 KMP
D4 20 22 0 -1 11.82 71.97 128 51.08 KMP
D5 20 24 0 0 11.31 74.44 128 51.52 KMP
D6 20 26 0 +1 10.85 73.09 160 48.88 KMP
D7 25 22 +1 -1 12.3 74.08 124 61.31 KMP
D8 25 24 +1 0 12.75 69.23 100 50.41 HIGUCHI
D9 25 26 +1 +1 10.35 70.01 136 48.83 HIGUCHI Table 7.58: ANOVA Table of Dependent Variables for Stearic Acid from Full
Factorial Design Source Df Sum Square Mean Square F value Prob > F
% Cumulative Drug Release at 1st h: R
2 = 0.5633
X1 1 14.54 14.54 3.21 0.1233 Not Significant
X2 1 20.50 20.50 4.53 0.0774 Not Significant
% Cumulative Drug Release at 12th h: R
2 = 0.7407
X1 1 164.33 164.33 14.05 0.0095 Significant
X2 1 36.21 36.21 3.10 0.1290 Not Significant
% Swelling Index at 12th h: R
2 = 0.8390
X1 1 322.67 322.67 2.90 0.1871 Not Significant
X2 1 600.00 600.00 5.39 0.1029 Not Significant
X12 1 4.00 4.00 0.036 0.8617 Not Significant
X12 1 256.89 256.89 2.31 0.2260 Not Significant
X22 1 555.56 555.56 4.99 0.1115 Not Significant
Prob > F less than 0.05 indicates model terms are significant.
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 213
Figure 7.46 & 7.47: Contour plot (2D) & Response surface plot (3D) showing the
effect of Stearic Acid & HPMC K4M on % Cumulative drug release at 1st h
Figure 7.48 & 7.49: Contour plot(2D) & Response surface plot (3D) showing the
effect of Stearic Acid & HPMC K4M on % Cumulative drug release at 12th
h
Figure 7.50 & 7.51: Contour plot(2D) & Response surface plot (3D) showing the
effect of Stearic Acid & HPMC K4M on Swelling Index at 12th
h Regression Coefficients for the Responses of Stearic Acid:
% CDR at 1st h = 12.68 – 1.56 X1 – 1.85 X2
% CDR at 12th
h = 75.28 – 5.23 X1 – 2.46 X2
Swelling Index at 12th
h = 127.56 – 7.33X1 + 10.00X2 + 1.00X1X2 –11.33X12 + 16.67X2
2
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 214
Results of polynomial equation indicated that the effect of X1 (amount of Stearic Acid)
and X2 (amount of HPMC K4M) is not significant for % CDR at 1st h which can be
confirmed from the corresponding contour lines (Figure 7.46). But, the effect of X1 only
is significant for % CDR at 12th
h. Effect of X1 is negative i.e. as concentration of X1
increased; % CDR at 12th
h of matrix tablets decreased from 87.32% to 69.23% which
can be confirmed from the declining linear contour lines (Figure 7.48). Increase in
concentration of HPMC K4M had no significant effect on % CDR at 12th
h. The effect of
X1 and X2 is not significant for Swelling Index at 12th
h which can be confirmed from the
corresponding contour lines (Figure 7.50).
From all the three response variables as % cumulative drug release at 1st & 12
th hour and
Swelling Index at 12th
h, Formulation D1 was found to be the optimized formulation
among the all 9 formulations with desirability function =0.686. Korsmeyer-Peppas
model was best fit to drug release data of formulation D1 which was confirmed from the
kinetic data (Table 7.48) showing diffusion controlled drug release. Formulation D1
containing low amount of both the independent variables as Stearic Acid and HPMC
K4M showed a comparatively high slope (n) value of 0.6299 indicating 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. Hence, diffusion coupled with erosion may be the
mechanism of Ambroxol HCl release from formulation D1. Also model independent
method as similarity factor (f2) was greatest i.e. 66.39 for formulation D1 indicating the
most similar formulation to marketed controlled release formulation as Acocontin.
7.4.6.5 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION
WITH LUBRITAB
Table 7.59: Design and Response summary for Lubritab
Formulation
Code
Actual
value
Coded
value
Y1 %
CDR at
1sth
Y2 %
CDR at
12th
h
Y3 Swelling
index at 12th
h
f2
value
Best fit
model
X1 X2 X1 X2
E1 20 20 -1 -1 12.79 96.52 84 63.97 KMP
E2 20 25 -1 0 8.09 80.45 148 53.83 ZERO
E3 20 30 -1 +1 8.21 71.88 168 45.79 KMP
E4 22 20 0 -1 10.23 80.41 124 58.10 KMP
E5 22 25 0 0 7.49 76.79 164 50.10 KMP
E6 22 30 0 +1 8.55 74.37 176 51.22 ZERO
E7 24 20 +1 -1 8.69 71.08 176 43.71 KMP
E8 24 25 +1 0 8.39 73.18 204 48.53 HIGUCHI
E9 24 30 +1 +1 9.61 72.69 160 49.43 ZERO
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 215
Table 7.60: ANOVA Table of Dependent Variables for Lubritab from Full Factorial
Design
Source Df Sum Square Mean Square F value Prob > F
% Cumulative Drug Release at 1st h: R
2 = 0.9529
X1 1 0.97 0.97 3.01 0.1813 Not Significant
X2 1 4.75 4.75 14.74 0.0312 Significant
X12 1 7.56 7.56 23.45 0.0168 Significant
X12 1 0.58 0.58 1.81 0.2715 Not Significant
X22 1 5.69 5.69 17.66 0.0246 Significant
% Cumulative Drug Release at 12th h: R
2 = 9582
X1 1 169.65 169.65 40.22 0.0014 Significant
X2 1 140.84 140.84 33.39 0.0022 Significant
X12 1 172.33 172.33 40.86 0.0014 Significant
Ambroxol HCl % Swelling Index at 12th h: R
2 = 0.7512
X1 1 294.00 294.00 0.22 0.6533
X2 1 23562.67 23562.67 17.89 0.0055 Significant
Prob > F less than 0.05 indicates model terms are significant.
Figure 7.52 & 7.53: Contour plot(2D) & Response surface plot (3D) showing the
effect of Lubritab & HPMC K4M on % Cumulative drug release at 1st h
Figure 7.54 & 7.55: Contour plot(2D) & Response surface plot (3D) showing the
effect of Lubritab & HPMC K4M on % Cumulative drug release at 12th
h
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 216
Figure 7.56 & 7.57: Contour plot(2D) & Response surface plot (3D) showing the
effect of Lubritab & HPMC K4M on Swelling Index at 12th
h Regression Coefficients for the Responses of Lubritab:
% CDR at 1st h = 7.63 – 0.40 X1– 0.89 X2 + 1.37 X1 X2 + 0.54 X1
2 + 1.69 X2
2
% CDR at 12th
h = 77.48 –5.32 X1– 4.85 X2 + 6.56 X1 X2
Swelling Index at 12th
h = 180.44 + 7.00 X1 + 62.67 X2 Results of polynomial equation indicated that the effect of X2 (amount of HPMC K4M) is
only significant. Effect of X2 is negative i.e. as concentration of X2 increased; % CDR at
1st h of matrix tablets decreased from 12.79% to 7.49% and both the factors involved
shows an interaction between X1 and X2 which can be confirmed from the contour plot
(Figure 7.52). Increase in concentration of Lubritab had no significant effect on % CDR
at 1st h. The effect of X1 is more significant than X2 for % CDR at 12
th h. Effect of X1 &
X2 is negative i.e. as concentration of X1 & X2 increased; % CDR at 12th
h of matrix
tablets decreased from 96.52% to 71.08% which can be confirmed from the declining
linear contour lines (Figure 7.54). Also it shows an significant interaction between both
the factors with the F-value of 40.86 (p-value = 0.0014). But, the effect of X2 is only
significant for Swelling Index at 12th
h. The effect of X2 is positive i.e. as concentration of
X2 increased; Swelling Index at 12th
h also increased from 84 to 204. Nearly vertical
contour lines (Figure 7.56) corroborate that only HPMC K4M influences the Swelling
index at 12th
h significantly. Increase in concentration of Lubritab had no significant
effect on Swelling Index at 12th
h.
From all the three response variables as % cumulative drug release at 1
st & 12
th hour and
Swelling Index at 12th
h, Formulation E1 was found to be the optimized formulation
among the all 9 formulations with desirability function =0.909 and showed a greater
similarity in dissolution profile with marketed formulation (f2 = 63.97). Korsemeyer-
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 217
Peppas model was best fit to drug release data of formulation E1 which was confirmed
from the kinetic data (Table 7.49) showing diffusion and erosion controlled drug release.
7.4.6.6 MATRIX TABLETS OF AMBROXOL HCL BY MELT GRANULATION
WITH POLYMEG
Table 7.61: Design and Response summary for Polymeg
Formulation
Code
Actual
value
Coded
value
Y1 %
CDR
at 1sth
Y2 %
CDR at
12th
h
Y3 Swelling
index at
12th
h
f2
value
Best fit
model
X1 X2 X1 X2
G1 5 10 -1 -1 55.58 101.02 84 10.78 KMP
G2 5 20 -1 0 19.04 102.38 154 38.83 HIGUCHI
G3 5 30 -1 +1 15.33 93.38 296 61.52 HIGUCHI
G4 10 10 0 -1 35.44 101.11 138 14.55 HIGUCHI
G5 10 20 0 0 14.97 94.75 162 51.12 HIGUCHI
G6 10 30 0 +1 12.06 88.43 214 72.69 HIGUCHI
G7 15 10 +1 -1 20.54 106.11 136 14.43 ZERO
G8 15 20 +1 0 13.28 93.46 216 53.08 HIGUCHI
G9 15 30 +1 +1 9.47 84.27 224 75.92 ZERO Table 7.62: ANOVA Table for Polymeg from Full Factorial Design
Source Df Sum Square Mean Square F value Prob > F
% Cumulative Drug Release at 1st h: R
2 = 0.7412
X1 1 362.86 362.86 4.82 0.0705 Not Significant
X2 1 930.01 930.01 12.36 0.0126 Significant
% Cumulative Drug Release at 12th h: R
2 = 0.9273
X1 1 27.91 27.91 4.75 0.0811 Not Significant
X2 1 296.24 296.24 50.46 0.0009 Significant
X12 1 50.41 50.41 8.59 0.0326 Not Significant
% Swelling Index at 12th h: R
2 = 0.9751
X1 1 128.00 128.00 0.72 0.4585 Not Significant
X2 1 5400.00 5400.00 30.37 0.0118 Significant
Prob > F less than 0.05 indicates model terms are significant.
Figure 7.58 & 7.59: Contour plot(2D) & Response surface plot (3D) showing the
effect of Polymeg & HPMC K4M on % Cumulative Drug Release at 1st h
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 218
Figure 7.60 & 7.61: Contour plot(2D) & Response surface plot (3D) showing the
effect of Polymeg & HPMC K4M on % Cumulative Drug Release at 12th
h
Figure 7.62 & 7.63: Contour plot(2D) & Response surface plot (3D) showing the
effect of Polymeg & HPMC K4M on Swelling Index at 12th
h Regression Coefficients for the Responses of Polymeg
% CDR at 1st h = 21.75 – 7.78 X1 – 12.45X2
% CDR at 12th
h = 96.10 – 2.16 X1 – 7.03X2 - 3.55X1X2
Swelling Index at 12th
h = 149.33 – 8.00 X1 + 30.00X2 Results of polynomial equation indicated that the effect of X2 (amount of HPMC K4M) is
only significant for % CDR at 1st h, % CDR at 12
th h and Swelling Index at 12
th h. Effect
of X2 is negative i.e. as concentration of X2 increased; % CDR at 1st h and at 12
th h of
matrix tablets decreased from 55.58% to 9.47% and 106.11% to 84.27%. Increase in
concentration of Polymeg had no significant effect on % CDR at 1st h and 12
th h. The
declining contour lines (Figure 7.58) confirmed the decrease in % CDR at 1st h with
increase in the concentration of X2. The contour plot (Figure 7.60) for % CDR at 12th
h in
Figure 7.38 shows an significant interaction between Polymeg (X1) and HPMC K4M (X2)
and the F value of 8.59 (p-value = 0.0326) from Table 7.62. The effect of X2 is positive
i.e. as concentration of X2 increased; Swelling Index at 12th
h also increased from 84 to
296. Nearly vertical contour lines (Figure 7.62) corroborate that only HPMC K4M
Chapter 7 Ambroxol HCl – Results & Discussion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 219
influences the Swelling index at 12th
h significantly. Increase in concentration of Lubritab
had no significant effect on Swelling Index at 12th
h.
From all the three response variables as % cumulative drug release at 1
st & 12
th hour and
Swelling Index at 12th
h, Formulation G6 was found to be the optimized formulation
among the all 9 formulations with desirability function =0.841. Higuchi matrix model
was best fit to drug release data of formulation G6 which was confirmed from the kinetic
data (Table 7.50) showing diffusion controlled drug release. Formulation G6 containing
medium amount of Polymeg and high amount of HPMC K4M showed a comparatively
high slope (n) value of 0.7685 indicating a coupling of diffusion and erosion
mechanisms- so called anomalous diffusion. Also model independent method as
similarity factor (f2) was more than 50 i.e. 72.69 for formulation G6 indicating the similar
formulation to marketed controlled release formulation as Acocontin.
7.4.7 STABILITY STUDIES:
Optimized formulations from in vitro drug release study, kinetics and similarity factor
Formulations F5 prepared by direct compression with 1:1 HPMC K100M subjected for
stability studies. From data analysis of optimization for 32 Factorial Designed
formulations for melt granulation with different meltable waxy binders, kinetic analysis,
similarity factors and maximum Desirability function; Formulation A1 prepared by melt
granulation with Bees wax was subjected for stability studies.
The results (Table 7.63) of drug content and dissolution studies at 40° C / 75% RH,
indicated no significant difference before and after stability studies (p > 0.05).
Table 7.63: Drug Content after Stability studies
* Values are represented as mean ± SD (n=3)
Formulation Code Time in days % Drug Content* % Drug released after 12 h*
F5 0 101.1±0.83 85.61±0.57
30 100.63±0.16 85.05±0.46
60 100.89±0.24 84.41±1.18
90 100.10±1.13 84.73±1.29
A1 0 98.30±0.01 96.20±2.58
30 97.36±0.06 95.09±0.74
60 98.09±0.14 95.41±1.82
90 97.10±1.11 94.97±1.43
Chapter 7 Ambroxol Hydrochloride - Conclusion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 220
7.5 CONCLUSION
The present study was aimed at developing an oral controlled release matrix tablets for
with the use of different hydrophilc polymers and hydrophobic binders.
Preformulation studies indicated good flow property and compressibility for
different formulation blends of powders and melt granules for direct compression.
There was no any interaction between drug and polymers which was evident from
FTIR and DSC studies.
The matrix tablets prepared by direct compression method were found to be
within the in-house limits for all postcompressional parameters.
Matrix tablets of Ambroxol HCl were fabricated by direct compression to give
controlled release effect by using different grades of HPMC and Carbopol. The
drug release was controlled due to gel layer formation around the tablets and
swellable matrix of polymers.
The viscosity and proportion of polymers were major factors affecting the drug
release.
The order of drug release in a controlled manner with respect to 1:1 polymers was
found to be- HPMC K4M < HPMC K100LV CR < HPMC K100M < HPMC
K200M < Polycarbophil < Carbopol 974P < Carbopol 934P < Carbopol 71 G <
Carbopol 971P
But 1:1 Carbopol polymers give highly controlled release as there less proportion
only is sufficient to control the release as 1:0.5. Also 1:0.5 drug: HPMC K200M
was only sufficient to give same controlled release as 1:1 HPMC K100M.
In vitro release data were fitted to various kinetic models and drug release
predominantly followed non-Fickian diffusion for HPMC and Carbopol polymers
showing diffusion coupled with polymer relaxation and erosion mechanism for
drug release.
The optimization study was done using a 3
2 full factorial design to study the effect of
independent variables i.e. concentration of different lipophilc binders as Bees Wax,
Paraffin Wax, Stearic Acid, Lubritab and polymeg – A and the concentration of HPMC
K4M – B on dependent variables as % cumulative drug release at 1st and 12
th h and %
Swelling Index at 12th
h.
Chapter 7 Ambroxol Hydrochloride - Conclusion
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 221
The results depicted clearly indicate that all the dependent variables are
strongly dependent on the selected independent variables as they show a wide
variation among the nine batches.
The polynomial equations can be used to draw conclusions after considering
the magnitude of coefficient and the mathematical sign it carries, i.e. positive
or negative and significance. Also it gives estimates of the response since
small error of variance was noticed in the replicates.
It was found that % Cumulative Drug Release at 12th h was decreased
significantly with increase in concentration of lipophilic binder and HPMC
K4M both. HPMC K4M was the most significant factor in controlling the drug
release at 1st h and % Swelling Index at 12
th h.
Thus, the controlled release properties of the Ambroxol HCl depend on the
leaching of the drug through the melt granule matrix due to coating of
granules with lipophilic binders and concentration and swelling of hydrophilic
polymers.
The choice of experimental design, 32 factorial designs, was found to be
highly appropriate, as it can detect any non-linearity in factor-response
relationship with minimal expenditure of developmental effort and time. A
satisfactory controlled release profile can be achieved with low wax content
and low HPMC K4M except for Polymeg. In case of Polymeg, 10% of
polymeg and 30% of HPMC K4M was suitable to show the desired dissolution
properties.
Formulation A1, B2, C1, D1, E1 and G6 was found to be the optimized
formulation among the all 9 respected formulations with desirability function
of 0.951, 0.761, 0.659, 0.686, 0.909 and 0.841 respectively.
Stability study for all optimized formulations also exhibited good stability of
matrix tablets after three months.
The optimized formulations exhibited good controlled release vouching the
success of the experimental approaches followed.
Chapter 7 Ambroxol Hydrochloride - Bibliography
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 222
7.6 BIBLIOGRAPHY FOR AMBROXOL HYDROCHLORIDE:
1. Barar FSK, Eds., In; Essentials of Pharmacotherapeutics, 3rd
Edn., S. Chand and
Company Ltd., New Delhi, 2005; 550.
2. Sweetman C, Eds., In; Martindale, The Complete Drug Reference, 33rd
Edn., The
Pharmaceutical Press, London, 2002; 1084.
3. Vergin H, Bishop-Freudling GB, Miczka M, Nitsche V and Strobel K, Arzneim.
Forsch-Drug Res., 1985; 35: 1591.
4. Alighieri T, Avanessian S, Berlini S, Bianchi SG, Deluigi P, Valducci R et.al.
Arzneim. Forsch-Drug Res., 1988; 38: 92.
5. Ramanaiah G, Ramesh KVRNS et.al. Design and evaluation of CR oral
formulations of Ambroxol Hydrochloride. The Indian Pharmacist, 2005; 71-4.
6. Sing P, Desai SJ, Simonelli AP and Higuchi WI, J. Pharm. Sci., 1968; 57: 217.
7. Colombo P, Adv. Drug Deliv. Rev., 1993; 11:37.
8. Jivraj M, Martini L G, Thomson C M, B. F. Goodrich Bulletin®, Controlled
Release Tablet and Capsule - An Overview of different excipients useful for direct
compression of tablets. Pharm Science Technology Today, 2003; 3: 58-63.
9. Tu J S, Wang L B, et.al. Formulation and Pharmacokinetic studies of acyclovir
controlled-release capsules. Drug Dev. Ind. Pharm., 2001; 27: 687- 92.
10. Zhou F, Vervaet C and Remon JP, Matrix pellets based on the combination of
waxes starches and maltodextrins. Int. J. Pharm., 1996; 133: 155- 60.
11. Voinovich D, Moneghini M, Perissutti B et.al. Preparation in high-shear mixer of
sustained release pellets by melt palletisation. Int. J. Pharm., 2000; 203: 235- 44.
12. Grassi M, Voinovich D, Moneghini M et.al. Preparation and evaluation of a melt
pelletised paracetamol/stearic acid sustained release delivery system. J. Control.
Release, 2003; 88: 381- 91.
13. Voinovich D, Campisi B, Moneghini M et.al. Screeining of high shear mixer melt
granulation process variables using an asymmetrical factorial design. Int. J.
Pharm., 1999; 190: 73-81.
14. Thies R and Kleinebudde P, Melt pelletisation of a hygroscopic drug in a high
shear mixer: Part 1. Int. J. Pharm., 1999; 188: 131- 43.
15. Thies R and Kleinebudde P, Melt pelletisation of a hygroscopic drug in a high
shear mixer: Part 2. Eur. J. Pharm. Sci., 2000; 10: 103-10.
Chapter 7 Ambroxol Hydrochloride - Bibliography
Comparative Study of Formulation and Evaluation of Controlled Release drug with different Polymeric Substances 223
16. Maejima T, Osawa T, Nakajima K and Kobayashi M, Application of tumbling
melt granulation (TMG) method for controlled enteric release beads by coating
mixture of hydrogenated castor oil, Chem. Pharm. Bull., 1997; 45: 71-8.
17. Maejima T, Osawa T, et.al. Application of tumbling melt granulation (TMG)
method for controlled enteric release beads by coating mixture of hydrogenated
castor oil and higher fatty acid, Chem. Pharm. Bull., 1997; 45: 1332-8.
18. Kidokoro M, Haramiishi Y, Sagasaki S et.al. Application of fluidized hot-melt
granulation (FHMG) for the preparation of granules for tabletting; properties of
granules and tablets prepared by FHMG, Drug Dev. Ind. Pharm., 2002; 28: 67-76.
19. Doornbos DA, Haan P, Optimization Techniques in formulation and Processing.
In: Swarbrick J. Boylan JC, editors. Encyclopedia Pharmaceutical Technology.
Vol. 11. New York: Marcel Dekker Inc; 1995; 77: 160.
20. Celia M, McTaggart, et.al. The evaluation of formulation and processing
conditions of a melt granulation process. Int. J. Pharmaceutics. 1984; 19: 139- 48.
21. Controlled release tablet and capsules, Noveon pharmaceutical polymers, Bulletin
17, 1-46. Search engine: www.Pharma.noveonic.com.
22. Application of Carbopol 71G NF; Polymer in controlled release tablets, Bulletin
20, 1-21. Search engine: www.Pharma.noveonic.com.
23. Hosny EA , Al- Gohary OMN, Release kinetics and availability of Mebeverine
hydrochloride from Polycarbophil loaded matrix by swelling. Drug Dev. and Ind.
Pharm., 1994; 20 (16): 2593- 605.
24. Markus R.L., United state patentNo: 3202577, 1965.
25. Hamdani J, Moes A J et.al. Development and evaluation of prolonged release
pellets obtained by the melt pelletization process. Int. J. Pharm. 2002;245:167–77.
26. Yonezava Y, Ishida S et.al. Release from or through a wax matrix system: I basic
release properties of the wax matrix system. Chem Pharm Bull. 2001;49:1448-51.
27. Ford J. L. Thermal analysis of hydroxypropyl methylcellulose and methyl
cellulose: powders, gels and matrix tablet. Int. J. Pharm., 1999; 179: 209- 28.
28. Vazquez M J, Casalderrey M, et.al. Atenolol release from hydrophilic matrix
tablets with hydroxypropylmethylcellulose (HPMC) mixtures as gelling agent:
effects of the viscosity of HTML mixture. Eur. J. Pharm. Sci. 1996; 4: 39-48.