Ambroxol Hydrochloride - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/45063/15/15_chapter_07.pdf · Ambroxol is an active metabolite of the mucolytic agent bromhexine with

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


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


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


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.



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.



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



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



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


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


Talc 1 1 1 1 1 1 1 1 1


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


Talc 1 1 1 1 1 1 1 1 1




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


Talc 1 1 1 1 1 1 1 1 1


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


Talc 1 1 1 1 1 1 1 1 1


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.



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


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



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



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



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



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



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



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



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



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)



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


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




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


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




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



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



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.


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



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.


& 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-



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.


& 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 crosslinked 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



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.


& 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.



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




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



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



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.



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


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



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


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



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



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


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



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


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



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


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



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



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.



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




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


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




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


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




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



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



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.



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



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


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



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


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


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


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




Table 7.49: Kinetic Data from Various Kinetic Models for Ambroxol HCl by melt granulation with Lubritab as per 32

Factorial Design


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


Table 7.50: Kinetic Data from Various Kinetic Models for Ambroxol HCl by melt granulation with Polymeg as per 32 Factorial Design


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




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.


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.



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



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.


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


X2 1 13066.67 13066.67 106.91 <0.0001 Significant

Prob > F less than 0.05 indicates model terms are significant.



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


effect of Bees Wax & Extragranular HPMC K4M on % CDR at 1st h


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



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


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



Table 7.54: Analysis of Variance Table of Dependent Variables for Bees Wax I*

From Full Factorial Design



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


X22 1 114.41 114.41 11.12 0.0446 Significant


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


2 = 0.8313


X2 1 12880.67 12880.67 28.41 0.0018 Significant



effect of Bees Wax I* HPMC K4M on % Cumulative Drug Release at 1st h


effect of Bees Wax I* HPMC K4M on % Cumulative Drug Release at 12th

h




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


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


h significantly. Increase in concentration of Bees

Wax had no significant effect on % CDR at 12th


h.


st & 12

th hour and


h, Formulation B2 containing low amount of Bees wax and

medium amount of intragranular HPMC K4M was found to be the optimized formulation


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.




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



2 = 0.5242




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


2 = 0.8643


X2 1 1410.67 1410.67 21.62 0.0056 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




effect of Paraffin Wax & HPMC K4M on % Cumulative drug release at 12th

h


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


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



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.


st & 12

th hour and


h, Formulation C1 was found to be the optimized formulation


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.


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


2 = 0.5633




2 = 0.7407

X1 1 164.33 164.33 14.05 0.0095 Significant



2 = 0.8390









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


effect of Stearic Acid & HPMC K4M on % Cumulative drug release at 12th

h


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


h = 127.56 – 7.33X1 + 10.00X2 + 1.00X1X2 –11.33X12 + 16.67X2

2



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


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.


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



Table 7.60: ANOVA Table of Dependent Variables for Lubritab from Full Factorial

Design



2 = 0.9529


X2 1 4.75 4.75 14.74 0.0312 Significant

X12 1 7.56 7.56 23.45 0.0168 Significant


X22 1 5.69 5.69 17.66 0.0246 Significant


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



effect of Lubritab & HPMC K4M on % Cumulative drug release at 1st h


effect of Lubritab & HPMC K4M on % Cumulative drug release at 12th

h




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


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.


st & 12

th hour and


h, Formulation E1 was found to be the optimized formulation


similarity in dissolution profile with marketed formulation (f2 = 63.97). Korsemeyer-



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.


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



2 = 0.7412


X2 1 930.01 930.01 12.36 0.0126 Significant


2 = 0.9273


X2 1 296.24 296.24 50.46 0.0009 Significant



2 = 0.9751


X2 1 5400.00 5400.00 30.37 0.0118 Significant



effect of Polymeg & HPMC K4M on % Cumulative Drug Release at 1st h




effect of Polymeg & HPMC K4M on % Cumulative Drug Release at 12th

h


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


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




h significantly. Increase in concentration of Lubritab

had no significant effect on Swelling Index at 12th

h.


st & 12

th hour and


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


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


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 %


h.

Chapter 7 Ambroxol Hydrochloride - Conclusion


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


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