Formulation and Evaluation of Sustained Release …Formulation and Evaluation of Sustained Release...

Formulation and Evaluation of Sustained Release

Matrix Tablet of BCS Class I Drug

Thesis Submitted in Partial Fulfillment

For the Award of Degree of

Doctor of Philosophy

In

Pharmacy

By

Abhijit Narayanrao Merekar, M. Pharm.,

Registration Number: 0863600008

VINAYAKA MISSIONS UNIVERSITY

(Under section-3 of UGC Act 1956)

NH-47, ARIYANOOR, SALEM, TAMILNADU, INDIA

OCTOBER- 2016

VINAYAKA MISSIONS UNIVERSITY, SALEM

CERTIFICATE BY THE GUIDE

I, Prof. (Dr.) B.S. Kuchekar, certify that the thesis entitled “Formulation and

Evaluation of Sustained Release Matrix Tablet of BCS Class I Drug”

submitted for the degree of Doctor of Philosophy by Mr. Abhijit Narayanrao

Merekar is the record of research work carried out by him during the period

from October 2008 to December 2015 under my guidance and supervision

and that this work has not formed the basis for the award of any degree,

diploma, associateship, fellowship or other titles in this university or any

other university or Institution of higher learning.

Date:

Place:

Dr. Bhanudas S. Kuchekar

M.Pharm, PhD, FIC, LLB

Principal

MAEER’s Maharashtra Institute of

Pharmacy,

Kothrud, Pune

VINAYAKA MISSIONS UNIVERSITY, SALEM

DECLARATION BY THE CANDIDATE

I, Abhijit Narayanrao Merekar, declare that this dissertation/ thesis entitled

“Formulation and Evaluation of Sustained Release Matrix Tablet of BCS

Class I Drug” is a bonafide and genuine research work carried out by me

under the guidance of Dr. Bhanudas S. Kuchekar, Prinicipal, MAEER’s

Maharashtra Institute of Pharmacy and this work has not formed the basis

for the award of any degree, diploma, associateship, fellowship or other

titles in this university or any other University or Institution of higher

learning.

Date:

Place: Abhijit Narayanrao Merekar

Dedicated to

My beloved

Family & Guide

Om Sai Ram

ACKNOWLEDGEMENT

When emotions are profound, words may not be sufficient to express thanks

and gratitude. Many people provided me valuable contributions and gave

helpful comments.

I am extremely grateful & remain highly indebted to my teacher, guide and

mentor Dr Bhanudas S. Kuchekar, Professor and Principal, MAEER’s

Maharashtra Institute of Pharmacy, Pune for his help and everlasting source

of inspiration.

I am very grateful to Dean Research, Vinayaka missions University, Salem

and Dr. B. Jaykar, Principal, Vinayaka Missions College of Pharmacy, Salem

for their kind co-operation and timely help throughout the study.

I am thankful to Hon. Shri. Radhakrishna Vikhe Patil, Chairman, Dr. Vikhe

Patil Foundation, Ahmednagar and Mrs. Shalinitai Vikhe Patil ,Ex.

President ,Zilla Parishad, Ahmednagar for providing me research facility.

I express my deepest gratitude to Dr. Sujay Vikhe Patil, CEO, Dr. Vikhe Patil

Foundation, Ahmednagar and Dr. Abhijit Diwate, Deputy Director, Dr. Vikhe

Patil Foundation, Ahmednagar for his kind support and continuous

encouragement.

I, also take this opportunity to express my heartily thanks to Dr. P.M.

Gaikwad, Dr. Pratap Y. Pawar, Dr. R.W. Gaikwad, Dr. Sunil A Nirmal,

Prof. Ravindra B. Laware, Dr. Nachiket S Dighe, Prof. Anna Warade &

Prof. Sanjay B Bhawar for their timely assistance & cooperation throughout

my studies.

I am highly thankful to my beloved friends Kiran Aher, Mahesh Doke,

Prasad Kajale, Sachin Somvanshi, Ramdas Dolas, Rushi Tambe,Ravi

Gadhve and Jagan Bhane for their timely assistance & cooperation

throughout my studies.

Last but not least my warmest of warm regards and the most important

acknowledgement to my beloved dad Dr. Naryanrao H. Merekar (Padghan),

loving mom Mrs. Shanta N. Merekar, sweet sister Dr. Trupti S. Selokar and

Brother in law Dr. Prashant Selokar with deep appreciation for their

indispensable aid, moral support, encouragement, compassion, and

everlasting love that served a source of my inspiration, strength,

determination and enthusiasm at each & every front of my life to transfer my

dreams in to reality.

I can never forget contributions and devotion made my wife Smita. I thank her

for her immense love, care and emotional support throughout my life. Your

presence around me made me forget all the stress of life. My sweet

remembering to our lovely and sweet daughter Tanaya.

Date: Abhijit Narayanrao Merekar

CONTENTS

Chapter

No. Topic

Page

No.

1. INTRODUCTION 1

1.1 Oral dosage form 2

1.1.1. Oral Modified Release Dosage Form 2

1.1.2. Extended Release Dosage Form 3

1.1.3. Delayed Release 3

1.2. Sustained Release System 4

1.2.1. Advantages of Sustained Release Drug Delivery 4

1.2.2. Disadvantages 5

1.3. Parameter for drug selection 6

1.4. Drug properties relevant to Sustained release formulation 7

1.5. Theory of sustained release 8

1.6. Mechanism of drug release from a sustained dosage form 9

1.6.1. Leaching (Diffusion ) type 9

1.6.2. Erosion (Dissolution) type 10

1.7. Types of sustain-release product 10

1.7.1. Diffusion-controlled products 10

1.7.2. Dissolution-controlled products 11

1.7.3. Erosion products 11

1.7.4. Ion exchange resins 12

1.8. Matrix system 12

1.9. Classification of matrix system 13

1.10 polymer used in matrix tablets 15

1.11. Drug release mechanisms for polymeric drug delivery 16

1.12. Mechanisms of drug release from matrix system 17

1.13. Introduction of disease hypertension 20

1.13.1. Hypertension 20

1.13.2. Classification of Hypertension 21

1.13.3. Symptoms of Hypertension 22

1.13.4. Pathophysiology 22

1.13.5. Complications of Hypertension 23

1.13.6. Treatment of Hypertension 23

1.13.6.1. Calcium Channel Blockers 25

2. LITERATURE SURVEY 26

2.1. HPMC K100LV 26

2.2. EUDRAGIT L100-55 34

2.3. PVAP 38

3. NEED FOR THE STUDY 41

4. OBJECTIVES AND HYPOTHESIS 42

5. INTRODUCTION TO MATERIALS 43

5.1. Drug study 43

5.1.1. Diltiazem Hydrochloride 43

5.1.2. Metoprolol Succinate 45

5.2. General profile of polymers 47

5.2.1. Hydroxypropyl methylcellulose (HPMC) 47

5.2.2. Eudragit L 100-55 49

5.2.3. PVAP ( Kollidon® SR ) 50

5.3. Other Excipients 51

5.3.1. Magnesium stearate 51

5.3.2. Microcrystalline Cellulose 52

5.3.3. Colloidal silicon Dioxide 53

5.3.4. Lactose 54

5.3.5. Dibasic Calcium Phosphate (Dihydrate) 54

6. MATERIALS AND METHODS 57

6.1. Materials used 57

6.2. Equipment used 58

6.3 Methodology 59

6.3.1. Preformulation Study 59

6.3.2. Determination of λ max 60

6.3.3. Preparation of Calibration Curve 60

6.3.3.1 Preparation of Calibration Curve of Diltiazem

Hydrochloride

60

6.3.3.2 Preparation of Calibration Curve of Metoprolol

Succinate

63

6.4. Composition of matrix tablet 66

6.4.1. Composition of matrix tablets containing HPMC,

Eudragit

66

6.4.1.1. Composition of Matrix Tablet Containing

Diltiazem Hydrochloride.

66

6.4.1.2. Composition of HPMC, Eudragit Matrix Tablet

Containing Metoprolol Succinate

67

6.4.2. Composition of matrix tablets containing PVAP 68

6.4.2.1. Composition of PVAP Matrix Tablet Containing

Diltiazem Hydrochloride

68

6.4.2.2. Composition of PVAP Matrix Tablet Containing

Metoprolol Succinate

69

6.5. Prepration of matrix tablets 70

6.5.1. Preparation of Matrix Tablets Containing HPMC and

Eudragit

70

6.5.2. Preparation of Matrix Tablets Containing PVAP 72

6.6. Evaluation of matrix tablets 74

6.6.1. Precompressional Studies 74

6.6.1.1. Bulk Density and Tapped Density 74

6.6.1.2. Compressibility Index 75

6.6.1.3. Hausner’s Ratio 75

6.6.1.4. Angle of repose 76

6.6.2. Post-compressional studies 76

6.6.2.1. Hardness test 76

6.6.2.2. Weight variation test 77

6.6.2.3. Friability test 77

6.6.3. Drug content 78

6.6.3.1. Drug Content of Matrix Tablet Containing


78

6.6.3.2. Drug Content of Matrix Tablet Containing


79

6.6.4. In vitro dissolution study of matrix tablet 80

6.6.4.1. Dissolution Studies of matrix tablet containing


80

6.6.4.2. Dissolution Studies of matrix tablet containing


81

6.6.5. f2 Similarity Factor 82

6.6.6. Release Kinetics Study 82

6.6.7. Statistical analysis 85

6.6.8. Scanning Electron Microscopy (SEM) 85

6.6.9. Differential scanning calorimetry (DSC) 87

6.6.10. In vivo X-ray studies 87

6.6.11. Stability studies 88

7. RESULTS AND DISCUSSION 89

7.1. Analysis of drug 89

7.1.1. Description 89

7.1.2. Determination of melting point 89

7.1.3. Solubility 89

7.1.4. Fourier Transformed Infrared (FT-IR) Spectroscopic

Analysis

90

7.2. Compatibility studies 100

7.2.1. Compatibility Study of matrix tablet containing HPMC,

Eudragit.

100

7.2.1.1. Compatibility Study of HPMC, Eudragit matrix

tablet Containing Diltiazem Hydrochloride (FD11)

100

7.2.1.2. Compatibility Study of HPMC, Eudragit matrix

tablets Containing Metoprolol Succinate (FM11)

103

7.2.2. Compatibility Study of matrix tablet containing PVAP. 106

7.2.2.1. Compatibility Study of PVAP matrix tablet

containing Diltiazem Hydrochloride(FD17).

106

7.2.2.2. Compatibility Study of PVAP matrix tablet

containing Metoprolol Succinate(FM17).

109

7.3. Determination of λ max 111

7.3.1 Determination of λ max of Diltiazem Hydrochloride 111

7.3.2 Determination of λ max of Metoprolol Succinate 111

7.4. Preparation of calibration curve 112

7.4.1. Preparation of Calibration Curve of Diltiazem

Hydrochloride

112

7.4.2. Preparation of Calibration Curve of Metoprolol

Succinate

115

7.5. Evaluation of matrix tablets 118

7.5.1 Evaluation of pre-compression parameters of HPMC,

Eudragit Matrix Tablet

118

7.5.1.1 Evaluation of pre-compression parameters of

HPMC, Eudragit SR Matrix Tablet Containing


118


HPMC and Eudragit Matrix Tablet containing

Metoprolol succinate

120

7.5.2. Evaluation of pre-compression parameters of PVAP

Matrix Tablet

122

7.5.2.1. Evaluation of pre-compression parameters of

PVAP SR Matrix Tablet containing Diltiazem

Hydrochloride

122


PVAP SR Matrix Tablet Containing Metoprolol

succinate

124

7.6. Post-compressional studies 126

7.6.1. Evaluation of Post-compression parameters of HPMC

and Eudragit Matrix Tablet

126

7.6.1.1 Evaluation of Post-compression parameters of

HPMC and Eudragit Matrix Tablet Containing


126

7.6.1.2 Evaluation of post-compression parameters of

HPMC & Eudragit Matrix Tablet Containing

Metoprolol Succinate.

128

7.6.2 Evaluation of Post-compression parameters of PVAP

Matrix Tablet

129

7.6.2.1 Evaluation of Post-compression parameters of

PVAP Matrix Tablet Containing Diltiazem

Hydrochloride.

130

7.6.2.2. Evaluation of post-compression parameters of

PVAP Matrix Tablet Containing Metoprolol

Succinate.

132

7.7 Dissolution studies of matrix tablet 134

7.7.1 Dissolution Studies of matrix tablet containing HPMC,

Eudragit

134

7.7.1.1 Dissolution Studies of matrix tablet of HPMC,

Eudragit containing Diltiazem Hydrochloride.

134

7.7.1.2. Dissolution Studies of matrix tablet of HPMC,

Eudragit containing Metoprolol Succinate.

141

7.7.2 Dissolution Studies of matrix tablet containing PVAP 148

7.7.2.1 Dissolution Studies of matrix tablet of PVAP

containing Diltiazem Hydrochloride

148

7.7.2.2. Dissolution Studies of matrix tablet of PVAP

containing Metoprolol Succinate

155

7.8. Release kinetic study 162

7.8.1 Release Kinetic Study of All Formulation of HPMC,

Eudragit Containing Diltiazem Hydrochloride.

162

7.8.2. Release Kinetic Study of All Formulation of HPMC,

Eudragit Containing Metoprolol Succinate.

164

7.8.3. Release Kinetic Study of All Formulation of PVAP

Containing Diltiazem Hydrochloride.

166

7.8.4 Release Kinetic Study of All Formulation of PVAP

Containing Metoprolol Succinate.

168

7.9 Statistical analysis 170

7.10. Scanning electron microscopy (SEM) 172

7.10.1. SEM study of selected optimized formulation

containing HPMC and Eudragit with Diltiazem

Hydrochloride (FD11)

172


containing HPMC and Eudragit with Metoprolol

Succinate (FM11)

174


containing PVAP with Diltiazem Hydrochloride (FD17)

176


containing PVAP with Metoprolol Succinate (FM17)

178

7.11. Differential scanning calorimetry (DSC) 180

7.11.1 Diltiazem hydrochloride, HPMC and Eudragit 180

7.11.2. Metoprolol Succinate, HPMC and Eudragit. 183

7.11.3. Diltiazem Hydrochloride, PVAP. 186

7.11.4. Metoprolol Succinate, PVAP 189

7.12 In vivo X-ray studies 192

7.12.1 In vivo X-ray Studies of selected optimized matrix

tablet containing Barium sulphate (FD11)

192

7.12.2. In vivo X-ray Studies of matrix tablet containing

Barium sulphate with HPMC(FM11)

193

7.12.3. In vivo X-ray Studies of matrix tablet containing 195

Barium sulphate with PVAP (FD17)

7.12.4 In vivo X-ray Studies of matrix tablet containing

Barium sulphate with PVAP(FM17)

197

7.13 Stability study 198

7.13.1. Effect of stability conditions on physical

characteristics and release of Diltiazem Hydrochloride

from optimized formulation (FD11)

198


characteristics and release of Metoprolol Succinate

from optimized formulation (FM11).

201


characteristics and release of Diltiazem Hydrochloride

from optimized formulation (FD17).

203


characteristics and release of Metoprolol Succinate

from optimized formulation (FM17).

205

CONCLUSION 207

REFERENCES 209

PUBLICATIONS

ANNEXURE

ERRATA

LIST OF FIGURES

Figure

No. Title

Page

No.

1 A hypothetical plasma concentration time profile from 2

2 Schematic representation of sustained release dosage 8

3 A hypothetical plasma concentration time profile from

sustained drug delivery formulation

9

4 Diffusion controlled release mechanism 10

5 Dissolution controlled mechanism 11

6 Schematic representation of diffusion controlled drug

release reservoir system

18

7 Drug release from a matrix tablet 19

8 Counter-Regulatory Responses to fall in Blood Pressure and

sites of Action of Antihypertensive Drugs (in red box)

25

9 Process flow chart for HPMC/Eudragit tablets manufactured

by direct compression

71

10 Process flow chart for PVAP tablets manufactured by direct

compression

73

11 IR spectra of pure diltiazem hydrochloride 90

12 IR spectra of pure Metoprolol Succinate 91

13 IR spectra of HPMCK 100LV 92

14 IR spectra of Eudragit L100-55 93

15 IR spectra of Microcrystalline Cellulose 94

16 IR spectra of Lactose 95

17 IR spectra of magnesium stearate 96

18 IR spectra of PVAP 97

19 IR spectra of dibasic calcium phosphate 98

20 IR spectra of colloidal silicon dioxide 99


22 IR spectra of mixture of optimized formulation (FD11) 101


24 IR spectra of mixture of drug (Metoprolol Succinate) and

polymer- FM11

104


26 IR spectra of mixture of drug (Diltiazem Hydrochloride) and

polymers-FD17

107


28 IR spectra of mixture of drug (Metoprolol Succinate) and

polymers -FM17

110

29 Standard graph of Diltiazem Hydrochloride in distilled water 112

30 Standard graph of Diltiazem Hydrochloride in 0.1 N HCl 113

31 Standard graph of Diltiazem Hydrochloride in pH 7.4

phosphate buffer

114

32 Standard graph of Metoprolol Succinate in distilled water 115

33 Standard graph of Metoprolol Succinate in 0.1 N HCl 116

34 Standard graph of Metoprolol Succinate in pH 7.4 phosphate

buffer

117

35 Effect of HPMC on diltiazem hydrochloride release from SR

matrix tablets

136

36 Diltiazem Hydrochloride release dissolution profile

comparison of HPMC SR matrix tablet & marketed product

(DILZEM SR)

137

37 Effect of Eudragit on Diltiazem Hydrochloride release from

SR matrix tablet

138

38 Effect of HPMC/ Eudragit combination blend on Diltiazem

Hydrochloride release from SR matrix tablets

140

39 Diltiazem Hydrochloride release profile comparison of

HPMC/Eudragit combination SR matrix tablet & Marketed

Product (DILZEM SR)

140

40 Effect of HPMC on Metoprolol succinate release from SR

matrix tablet.

143

41 Metoprolol Succinate release dissolution profile of HPMC

SR matrix tablets & Marketed product (Metal XL)

144

42 Effect of Eudragit on Metoprolol Succinate release from SR

matrix tablets

145

43 Effect of HPMC/Eudragit combination blends on Metoprolol

Succinate release from SR matrix tablets

146

44 Metoprolol Succinate release profile comparison of

HPMC/Eudragit combination SR matrix tablets & marketed

product (Meta XL)

147

45 Effect of high level PVAP polymer (>50%) on Diltiazem

Hydrochloride release from SR matrix tablet

150

46 Effect of high level microcrystalline cellulose excipient

(>50% ) on Diltiazem Hydrochloride release from SR matrix

tablet

151

47 Effect of high level Dicalcium Phosphate (>50%) excipient

on Diltiazem Hydrochloride release from SR matrix tablet

151

48 Effect of PVAP on diltiazem Hydrochloride release from SR

matrix tablet

153

49 Diltiazem Hydrochloride release dissolution profile

comparison of FD16 & FD17 SR tablet & marketed product

(DILZEM SR)

153

50 Effect of PVPA on Diltiazem Hydrochloride release from SR

matrix tablet

154

51 Effect of high level of PVAP polymer (>50%) on Metoprolol

Succinate releasefrom SR matrix tablets

157

52 Effect of high level of microcrystalline cellulose (>50%)

excipient onMetoprolol succinate release from SR matrix

tablets

158

53 Effect of high level of Dicalcium phosphate excipient (>50%)

on Metoprolol Succinate release from SR matrix tablets

158

54 Effect of PVAP on Metoprolol Succinate release from SR

matrix tablets

160

55 Metoprolol Succinate release dissolution profile comparison

of FM16 & FM17 SR tablets & marketed product (Meta XL)

160

56 Effect of PVAP on Metoprolol Succinate release from SR

Matrix tablets

161

57 SEM photomicrographs of optimized matrix tablet (batch

FD11) showing surface morphology after 0 hours (A, 500×),

1 hours (B, 500×), 3 hours (C, 500×), 6 hours (D, 500×), 9

hours (E, 500×), and 12 hours (F, 500×) of dissolution study

172


FM11) showing, surface morphology after 0 hours (A, 500×),

1 hours (B, 500×), 3 hours (C,500×),6 hours (D, 500×), 9


174


FD17) showing surface morphology after 0 hour (A, 500×), 1

hour (B, 500×), 3 hours (C, 500×), 6 hours (D, 500×), 9


176


FM17)showing surface morphology after 0 hours (A, 500×),

1 hours (B, 500×), 3 hours (C, 500×), 6 hours (D, 500×), 9


178

61 DSC thermogram of Diltiazem Hydrochloride 180

62 DSC thermogram of HPMCK100LV+Eudragit L100-55 180

63 DSC thermogram of optimized formulation (FD11) 181

64 DSC thermogram of Metoprolol Succinate 183

65 DSC thermogram of HPMCK100LV+Eudragit L100-55 183

66 DSC thermogram of Metoprolol Succinate+ HPMCK100LV +

Eudragit L100-55

184

67 DSC thermogram of optimized formulation (FM11) 184

68 DSC thermogram of Diltiazem Hydrochloride 186

69 DSC thermogram of PVAP+DCP 186

70 DSC thermogram of Diltiazem hydrochloride + PVAP + DCP 187

71 DSC thermogram of optimized formulation (FD17) 187

72 DSC thermogram of Metoprolol Succinate 189

73 DSC thermogram of PVAP+DCP 189

74 DSC thermogram of Metoprolol Succinate+ PVAP+DCP 190

75 DSC thermogram of optimized formulation (FM17) 190

76 X-Ray photographs taken at 0, 1, 3, 6, 9 and 12 hr after oral

administration of matrix tablets of barium sulphate similar to

(FD11)

192

77 X-Ray photographs taken at 0 (Control), 1, 3 , 6, 9 and 12 hr

after oral administration of matrix tablets of barium sulphate

similar in composition to diltiazem hydrochloride optimized

formulation (FM11)

193

78 X-Ray photographs taken at 0 (Control), 1, 3 , 6, 9 and 12hr

after oral administration of matrix tablets of barium sulphate

similar in composition to diltiazem hydrochloride optimized

formulation (FD17)

195

79 X-Ray photographs taken at 0 hr (control), 1hr, 3 hr, 6hr, 9hr

and 12 hr after oral administration of matrix tablets of barium

sulphate similar in composition to diltiazem hydrochloride

optimized formulation (FM17)

197

80 Effect of storage on Diltiazem Hydrochloride release from

HPMC/Eudragit matrix tablets under long term stability

conditions (FD11 Batch)

200

81 Effect of storage on Metoprolol Succinate release from

HPMC/Eudragit matrix tablets under long term stability

conditions (FM11 Batch)

202

82 Effect of storage on Diltiazem Hydrochloride release from

PVAP matrix tablets under long term stability conditions

(FD17 Batch)

204

83 Effect of storage on Metoprolol Succinate release from

PVAP matrix tablets under long term stability

conditions(FM17 Batch)

206

LIST OF TABLES

TABLE

NO. TITLE

PAGE

NO.

1 Parameter for drug selection 6

2 Properties of drug to be considered for Sustained

Release

7

3 Polymer used in matrix tablets 15

4 Polymer used in oral controlled release technologies 16

5 A Solubility of Metoprolol succinate 46

5 B Partition coefficient of Metoprolol succinate in different

pH.

46

6 A List of materials used 57

6 B List of equipment’s and instruments used 58

7 Composition of HPMC, Eudragit Matrix Tablet

Containing Diltiazem Hydrochloride

66

8 Composition of HPMC,Eudragit Matrix Tablet

Containing Metoprolol Succinate

67

9 Composition of PVAP Matrix Tablet Containing


68

10 Composition of PVAP Matrix Tablet Containing


69

11 Absorbance values for Diltiazem Hydrochloride in

distilled water

112

12 Absorbance values of Diltiazem Hydrochloride in 0.1 N

HCl

113

13 Absorbance values of Diltiazem Hydrochloride in pH

7.4 phosphate buffer

114

14 Absorbance values of Metoprolol Succinate in distilled

water

115

15 Absorbance values of Metoprolol Succinate in0.1 N

HCl

116

16 Standard graph of Metoprolol Succinate in pH 7.4

phosphate buffer

117

17 Pre-compression evaluation of Formulated HPMC,

Eudragit SR Matrix Tablet.

118

18 Pre-compression evaluation of Formulated HPMC,

Eudragit SR Matrix Tablet.

120

19 Pre-compression evaluation of Formulated PVAP SR

Matrix Tablet

122

20 Pre-compression evaluation of Formulated PVAP SR

Matrix Tablet

124

21 Post-compression evaluation of Formulated HPMC,

Eudragit SR MatrixTablet.

126

22 Post-compression evaluation of Formulated HPMC,

Eudragit SR MatrixTablet

128

23 Post-compression evaluation of Formulated PVAP SR

Matrix Tablet

130

24 Post-compression evaluation of Formulated PVAP SR

Matrix Tablet

132

25 Mean cumulative % drug release of all formulation of

HPMC, Eudragit containing Diltiazem Hydrochloride

134


HPMC, Eudragit containing Metoprolol Succinate

141


PVAP containing Diltiazem Hydrochloride

148


PVAP containing Metoprolol Succinate

155

29 Correlation coefficient [R], Constant [k], and Diffusion

exponent [n] after fitting of dissolution data into various

release kinetic models of all formulation of HPMC,

Eudragit containing Diltiazem Hydrochloride

162



release kinetic models of all formulation of HPMC,

Eudragit containing metoprolol succinate

164



release kinetic models of all formulation of PVPA

containing Diltiazem Hydrochloride

166



release kinetic models of all formulation of PVAP

containing Metoprolol

168

33 DSC data of physical mixtures of Diltiazem

Hydrochloride, excipients & Optimized Formulation

(FD11)

181

34 DSC data of physical mixtures of Metoprolol Succinate,

excipients & Optimized Formulation (FM11).

185

35 DSC data of physical mixtures of Diltiazem

Hydrochloride, excipients & Optimized Formulation

(FD17)

188

36 DSC data of physical mixtures of Metoprolol Succinate,

excipients & Optimized Formulation (FM17)

191

37 Effect of long term stability storage on the physical

properties of HPMC/Eudragit tablets (FD11 Batch)

200


properties of HPMC/Eudragit tablets (FM11 Batch)

202


properties of PVAP tablets (FD 17 Batch)

204


properties of PVAP tablets (FM17 Batch)

206

LIST OF ABBREVIATIONS & SYMBOLS

ABBREVIATIONS

AUC Area under the curve

DCP Dibasic Calcium Phosphate

DMSO Dimethyl Sulphoxide

DSC Differential Scanning Calorimetry

DTZ Diltiazem hydrochloride

FDA Food and Drug Administration

FTIR Fourier Transform Infrared

HCL Hydrochloric acid

HDPE High Density Polyethylene

HPLC High Performance Liquid Chromatography

HPMC Hydroxypropyl Methyl Cellulose

ICH International Conference on Harmonization

IP Indian Pharmacopoeia

IR Immediate Release

MCC Microcrystalline Cellulose

Mg Stearate Magnesium stearate

PVAP Polyvinyl Acetate and Povidone

RH Relative Humidity

RSD Relative Standard Deviation

S.D. Standard Deviation

SEM Scanning Electron Microscopy

SR Sustain Release

USP United states Pharmacopoeia

UV Ultraviolet

GIT Gastro-intestinal track

MTC Maximum theraputic concentration

MEC Minimum Effective concentration

CSS Steady state concentration

av Apparent volume

Vd Volume of distribution

SYMBOLS

% Percent

ng nanogram

µg Microgram

mg Milligram

g Grams

kg Kilogram

nm Nanometer

µm Micrometer

mm Milimeter

cm Centimeter

°C Degree celcius

sec Seconds

min Minutes

hr Hour

μL Microlitre

mL Millilitre

L Litre

nM Nanomole

μM Micromole

w/w Weight by weight

w/v Weight by volume

v/v Volume by volume

v/w Volume by weight

λmax Absorption maxima

R2 Regression coefficient

N Normality

ABSTRACT

Diltiazem hydrochloride and Metoprolol Succinate are commonly

used potent calcium chanel blocker and selective β-blocker respectively.

The project was designed with an aim to develop and evaluate sustained

release diltiazem hydrochloride and metoprolol succinate matrix tablet

which will reduce the dosing frequency and have better patient compliance

and less fluctuations in plasma concentration.

The matrix tablets were prepared by the direct compression method.

Effect of various formulation and processing variables like concentration of

HPMC (K100 LV), Eudragit L 100-55, PVAP (Kollidon SR), filler and

excipient on stability, byoancy behavior, dissolution profile, various in-vitro

parameters and in-vivo x-ray study were evaluated. Dissolution data was

fitted to various pharmacokinetic models to study release pattern of drug

from the formulations.

The sustained release tablets were then compared to marketed

product by using FDA dissolution recommended model independent f2

similarity test.

Formulation with HPMC at 20% and Eudragit L 100-55 at 20%

concentration resulted into sustained release matrix tablets that similar to

marketed product as per f2 factor similarity test.

Formulation with polyvinyl acetate/ povidone and dibasic calcium

phosphate at 39.5% level produced sustained release tablets that are

similar to marketed product as per f2 factor similarity test guidelines.

The dissolution data of all formulations was subjected to

pharmacokinetic modeling to study mechanism of drug release and best fit

model. It was observed that optimized formulation has followed root of time

dependent kinetics for drug release suggesting diffusion controlled release

mechanism.

The in-vivo X-ray studies in New Zealand rabbits of optimized

formulation showed sustained drug activity by adhering to various sites in

GIT for 12 hours.

Stability studies conducted for long term storage at 25oC and

60%RH of sustained release matrix tablet formulation showed that there

were no significant changes in the appearance and dissolution profiles.

It was concluded that sustained release diltiazem hydrochloride

and metoprolol succinate tablets were developed using HPMC-K100LV

in combination with Eudragit L100-55 and PVAP as the release retarding

excipients. The post compression study showed that the optimum

formulation had similar behavior as compared to marketed tablet according

to the model independent FDA guidelines.

INTRODUCTION

1

1. INTRODUCTION

Tablets are the most accepted drug delivery systems for oral

administration. They are convenient to manufacture on a large scale with

reproducibility, stability and have high patient acceptability. The major

drawback of conventional tablets is need of frequent administration to

maintain therapeutically effective concentration of drug in blood.1

Conventional oral drug products, such as tablets and capsules release

the active drug for oral administration to obtain rapid and complete

systemic drug absorption. However fluctuations in plasma concentration

below MEC lead to loss of therapeutic activity.

To maintain the therapeutic concentration required for its effect,

next dose has to be immediately administered. An alternative to

administering another dose is to use a dosage form that will provide a

sustained drug release, and therefore maintain plasma drug concentrations

within therapeutic range for longer duration.2

Pharmaceutical dosage forms have been developed to release

active substances in modified manner as compared with conventional

formulations. Modification in release of active substances may have a

number of objectives but the main intention is to maintain therapeutic

activity with out frequent dosing, reduce toxic effect and reduce the work load

of the patient.

INTRODUCTION

2

The European Pharmacopoeia defines modified release in terms of

the rate or the site at which the active ingredient is release. A modified-

release dosage form is defined as “A formulation of medicinal drug taken

orally, releases the active ingredients over several hours in order to

maintain a relatively constant plasma concentration of the drug.3, 4,5,6

Figure 1: A hypothetical plasma concentration time profile from

A = Immediate release, B=Delayed release, C=Repeat action,

D = Prolonged release E = Controlled, sustained release.

1.1 ORAL DOSAGE FORM

1.1.1. Oral Modified Release Dosage Form

These formulations have been based on the conventional tablet

concept utilizing excipients and compression method to impart release

characteristics. Tablets may be coated or uncoated. Capsules containing

pellets are designed to give initial rapid release followed by sustained

release.3

INTRODUCTION

3

1.1.2. Extended Release Dosage Form

Extended release formulation is designed to produce even and

consistent release of active ingredient. These are the dosage forms

which due to special technology of preparation maintain therapeutic drug

levels for 8-12 hrs, after single dose administration.

Types of Extended release dosage form

1) Controlled release

2) Prolong action

3) Sustained release

1) Controlled release (CR): Controlled release systems provide drug

release in an amount sufficient to maintain the therapeutic concentration

over extended period of time.

2) Prolong action : Prolong or long action products are dosage forms

containing prodrug of therapeutic substance having prolong biological

half-life.

3) Sustained release: In case of sustained release (SR) dosage forms the

release of the drug is slower than conventional dosage form.

1.1.3. Delayed Release

A delayed release dosage form releases drug at a time other than

immediately after administration.7

INTRODUCTION

4

1.2. SUSTAINED RELEASE SYSTEM

The goals of sustained drug delivery are to conserve and maintain

effective drug concentration, to improve compliance and to decrease side

effects. Oral sustained release formulations aim at releasing drug at zero

order rate of release. Physicochemical nature of drug generally decides

pharmacokinetic profile of drug. Sustain release drug delivery system are

formulated by decreasing rate of absorption or modifying the structure of

drug.8

1.2.1. Advantages of Sustained Release Drug Delivery:

1. Improved therapy

(a) Sustained blood level

(b) Attenuation of adverse effects

2. Patient Convenience/improved patient compliance

3. Economy

a) Sustained release formulations are less expensive than conventional

dosage forms

b) Economy may also be affected due to decreased cost of nursing

time for administration of drug

c) Blood level oscillation characteristic of multiple dosing of

conventional dosage forms is reduced

d) Administered dose is reduced

e) Maximum drug availability with a minimum dose

INTRODUCTION

5

f) Safety margin of high potency drugs can be increased

1.2.2. Disadvantages

1) Dose Dumping

2) Less flexibility in acute dose adjustment

3) Poor in vitro - in vivo correlation

4) Patient variation

5) Sustained Release dosage forms are expensive

6) Sustained Release medication should not be used with person known

to have impaired gastrointestinal absorption or kidney function

7) Drugs having long biological half-life are not suitable for

presentation in sustained release form. e.g. digitoxin. 9, 10

INTRODUCTION

6

1.3. PARAMETER FOR DRUG SELECTION11

Table No. 1: Parameter for drug selection

Parameters for drug selection

Parameter Preferred value

1 Molecular weight / size < 1000

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

3 Apparent partition coefficient High

4 Absorption mechanism Diffusion

5 General absorbability From all GI segments

6 Release Should not be influenced by pH and

Enzymes

Pharmacokinetic parameterfor drug

1 Elimination half life Between 0.5 to 8 h.

2 Total clearance Should not be dose dependent

3 Elimination rate constant Required for design

4 Apparent volume of distribution

(vd)

The larger (vd) and MEC the larger

will be dose size.

5 Absolute bioavailability Should be 75% or more.

6 Intrinsic absorption rate Must be greater the release rate

7 Therapeutic concentration css The lower sand smaller ad

8 Toxic concentration Apart the values of MTC and MEC,

safer the dosage form.

INTRODUCTION

7

1.4. DRUG PROPERTIES RELEVANT TO SUSTAINED RELEASE

FORMULATION11,12,13

Table No 2: Properties of drug to be considered for Sustained Release

Drug Suitable Drug not Suitable

Physicochemical

1. Low molecular size compound’ s

2. Compounds which are highly water

soluble and pH independent

3. Compounds which are non-

aqueous soluble.

4. Unionized (at least 0.1 to 5%) in

GIT

5. Compounds with very weak acid

and moderately weak acid.

6. Compounds with very weak base

and moderately weak bases.

1. Compounds having large

molecular weight

2. low aqueous soluble compounds

3. Largely in ionized form in the

GIT

4. Strong bases having pKa more

than11.0

5. Strong acids having pKa less

than 2.5

Pharmacokinetic/Pharmacodynamic

1. Compounds having short half-life

from 2 to5 h.

2. Compounds having good

absorption from all areas of

Gastrointestinal tract.

Compounds that show

1. Slow absorption

2. Carrier mediated transport

3. Site definite absorption

4. Irritation in GIT

5. First pass metabolism

6. Those inhibit metabolism

7. Large dose

8. Drug’s metabolites are actives

too

INTRODUCTION

8

1.5. THEORY OF SUSTAINED RELEASE:

Sustained release dosage form contains:

a) Loading dose, and

b) Maintenance dose

The loading dose or immediately available portion achieves the

therapeutic level quickly after administration, while the maintenance

dose or slowly available portion releases the drug slowly and maintains

the therapeutic level for an extended period of time.14

Figure 2: Schematic representation of sustained release dosage

Loading dose

Maintenance dose

Loading dose

Maintenance dose

Absorption Site

INTRODUCTION

9

Figure 3: A hypothetical plasma concentration time profile from sustained

drug delivery formulation

The rate of release of the drug from the maintenance dosage should

be zero order (independent of the concentration) to make the drug available

constantly at the absorption site. The release of the drug from the loading

dose should follow fist order kinetics.14

1.6. MECHANISM OF DRUG RELEASE FROM A SUSTAINED

DOSAGE FORM

1.6.1. Leaching (Diffusion ) type:

Drug is partitioned within a polymeric matrix which is water-insoluble.

Water solubility of the drug in the matrix constitutes the driving force for the

diffusion.

INTRODUCTION

10

1.6.2. Erosion (Dissolution) type:

Partially water soluble polymers mixture of soluble and insoluble

polymers constitutes the matrix. The matrix eroded at various places form

which the drug will be slowly released.15

1.7.TYPES OF SUSTAIN-RELEASE PRODUCT:

1.7.1. Diffusion-controlled products

In this system, the water-insoluble polymer controls the flow of water

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

diffusion and dissolution processes are involved. These products contain

two systems viz. reservoir system (drug coated with polymer) and matrix

system (drug dispersed in polymer).

Figure4: Diffusion controlled release mechanism

INTRODUCTION

11

1.7.2. Dissolution-controlled products

In this system, the rate of dissolution of the drug (and thereby

availability of drug for absorption) is controlled by slowly soluble polymers

or by microencapsulation method. In contact with GI fluid the soluble

polymer or coating is dissolved slowly and the drug becomes available for

absorption. By varying the thicknesses of the coat and its composition, the

rate of drug release can be controlled.

Figure 5: Dissolution controlled mechanism

1.7.3. Erosion products

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

of erosion of polymer used. An Osmotic pump system is example of this

formulation e.g. Sinemet CR. The rate of release of drug depends on the

constant inflow of water through semi permeable membrane into a

reservoir containing osmotic agent. The drug is either mixed with the

agent or embedded in a reservoir. The dosage form has orifice from

INTRODUCTION

12

which dissolved drug is pumped at a rate of water inflow due to osmotic

pressure.

1.7.4. Ion exchange resins

Drugs are bound with ion exchange resins. After administration the

release of drug is determined by the ionic environment within the

gastrointestinal tract. 16

1.8. MATRIX SYSTEM:

In this system, a solid drug is dispersed in an insoluble matrix

system. The release of the drug is controlled by dissolution as well as

diffusion method. Among the various methods used to control drug release

from pharmaceutical dosage form, the matrix system is the most

frequently applied. Following are the characters that differentiate it from

other controlled release delivery systems.

a. The chemical nature of support

b. The physical state of drug

c. The shape of matrix shape

d. Change in volume with time

e. The release kinetic model

To control the release of the drug having different solubility

properties, the drug is dispersed in swellable hydrophilic polymer or an

insoluble matrix of hydrophobic materials or plastic materials.

INTRODUCTION

13

1.9. CLASSIFICATION OF MATRIX SYSTEM:

A. On the Basis of Retardant Material Used17, 18, 19

1. Hydrophobic Matrices (Plastic matrices):

In this method drug is mixed with an inert or hydrophobic polymer

and then compressed into a network of channels that exist between

compacted polymer particles. E.g. polyethylene, polyvinyl chloride, ethyl

cellulose and acrylate polymers.

The rate-controlling step is liquid penetration into the matrix. The

drug is released from the matrix by diffusion mechanism.

2. Lipid Matrices:

The drug is mixed with lipid waxes to prepare matrix. The drug is

released from the matrix by erosion and pore diffusion mechanism. The

rate of release is affected by composition of GI fluid.

E.g. Carnauba wax in combination with cetostearyl alcohol or

stearic acid.

3. Hydrophilic Matrices:

Drugs are mixed with hydrophilic polymers with high gelling ability

are used to prepare swellable controlled release matrix formulation.

The polymers used are divided in to three broad groups

a) Cellulose derivatives

b) Non cellulose natural or semi synthetic

c) Polymers of acrylic acid

INTRODUCTION

14

4. Biodegradable Matrices:

These consist of the polymers made up of monomers linked to one

another by unstable linkage which are prone for degradation in biological

environment or erosion by enzymes.

Examples: - natural polymers such as proteins and polysaccharides;

5. Mineral Matrices:

Various polymers obtained from species of seaweeds are used to

prepare matrix. Alginic acid which is a hydrophilic carbohydrate obtained

from species of brown seaweeds.

B. On the Basis of Porosity of Matrix20, 21, 22, 23

Matrix system can also be classified based on their porosity;

1. Macro porous Systems:

In such systems the diffusion of drug occurs through matrix pores

which are of size range 0.1 to 1 μm.

2. Micro porous System:

Diffusion in this type of system occurs through pores of size range 50-

200 A° which is slightly larger than diffusing molecules size.

3. Non-porous System:

In this system the molecules diffuse through the network meshes.4

INTRODUCTION

15

1.10 POLYMER USED IN MATRIX TABLETS24:

TableNo 3: Polymer used in matrix tablets

Sr. No.

Type of Polymer Description Example

1 Hydrophilic

polymer

These are the polymers that

soluble in water and will not

cross link. Soluble polymers

can be used as alone or in

combination with other

hydrophobic polymers

Polyethylene glycol ,

Polyvinyl pyrrolidone,

Hydroxypropyl methyl

cellulose,Sodium

carboxymethylcellulose, Agar-

agar, alginates, chitosan,

2 Hydrophobic

polymer

Non-biodegradable

hydrophobic polymers are

inert in the environment of

use are eliminated intact

from the site of administration

Polyethylene vinyl acetate ,

Polydimethyl siloxane,

Polyether urethane ,

Polyvinyl chloride, Ethyl

cellulose

3 Hydrogels Hydrogels are swells after

coming in contact with water

but will not dissolve in water.

They are inert removed

intact from the site of

administration

Poly hydroxyethyle

methylacrylate , Cross-linked

polyvinyl alcohol, Cross-linked

Polyvinyl pyrrolidone ,

Polyethylene oxide ,

Polyacrylamide,

4 Biodegradable

polymer

Biodegradable polymers

slowly remove from the site

of administration

Polylactic acid, Polyglycolic

acid, Polycaprolactone

5 Mucoadhesive

polymers

These polymers attaches to

mucin layer of mucosal

tissue on hydration and

slowly release the drug

Polycarbophil, Sodium

carboxymethyl cellulose,

Polyacrylic acid, Tragacanth,

Methyl cellulose

6 Natural polymer Xanthan gum, Guar gum,

Karaya gum, Gum Arabic,

Locust bean gum

INTRODUCTION

16

1.11. DRUG RELEASE MECHANISMS FOR POLYMERIC DRUG

DELIVERY:

There are two types of formulating a sustained drug release system -

reservoir and matrix type. Different polymers used for the development of

sustained release are summarized in table 4. 24

Table No 4: Polymer used in oral controlled release technologies

Method of achieving

controlled release dosage

forms

Polymer used Examples of dosage

forms

Matrix or Embedding

Hydrophilic Carriers Methyl Cellulose, Sodium CMC,

Polyacrylic acid, HPMC, Hydroxy

ethyl cellulose, Methacrylate

Hydrogels, Sodium Alginate

Multilayer tablets with

slow releasing cores

Compressed-coated

Tablets

Hydrophobic

Carriers

Soluble

carrier

Glycerides, waxes, fattyalcohols,

fatty Acids

Matrix tablets

Insoluble

carrier

Polyethylene, polyvinyl

chloride,polyvinyl acetate

Reservoir Type

Coating with insoluble

Membrane

Ethyl cellulose Granules,

pellets,Tablets

Osmotic Systems Vapor permeable walls-

polyethylene- polyvinylidene

Fluoride HPMC, Sodium CMC

Ethyl cellulose

Vapor permeable

capsules / tablet

bilayer

tablets

Ion-exchange Resins Amberlite® IRC50 With

polystyrene-based polymeric

backbone

Controlled release

capsules chewable

tablets

Gastric retention Systems HPMC, Agar, Carrageenans,

Alginic acid, Oils, Porous calcium

silicate, Super porous hydrogels

Compressed tablets

Gelatin capsules

INTRODUCTION

17

1.12. MECHANISMS OF DRUG RELEASE FROM MATRIX SYSTEM25,26,27

The drug can be released from the device by either dissolution of

matrix or diffusion of dug through matrix or combination of both

Dissolution controlled systems

A drug with slow dissolution rate will demonstrate sustained

properties, since the release of the drug will be limited by the rate of

dissolution. Highly water soluble drugs can be prepared as extended

release formulation by decreasing its dissolution rate. The dissolution

process at steady-state is described by Noyes-Whitney equation

Dc/dt = kdA (Cs-C) = D/hA (Cs-C)…………1

Where,

dt -Dissoultion time

A -Surface area

Dc - dissolution rate

kd - the dissolution rate constant

h - thickness of the diffusion layer

D - Diffusion coefficient,

Cs - saturation solubility of the solid and

C - Concentration of solute in the bulk solution.

The rate of release remains constant only if parameters like

surface area, diffusion coefficient, diffusion layer thickness and

concentration difference are held constant under normal conditions.

INTRODUCTION

18

Practically these parameters cannot be held constant especially surface

area.

Diffusion controlled system:

Diffusion is process of movement of drug from higher concentration

region to lower concentration region.

a) Reservoir type:

Figure 6: Schematic representation of diffusion controlled drug release:

reservoir system.

In this system drug is encapsulated in polymeric membrane which

controls the drug release. The drug release is explained by Ficks first law of

diffusion,

dm/dh = C0 . dh – Cs/2 …….. 2

INTRODUCTION

19

where,

dm - change in the amount of drug released per unit area

dh - change in the thickness of the zone of matrix that has been

depleted of drug

Co - total amount of drug in a unit volume of matrix

Cs - saturated concentration of the drug within the matrix.

b) Matrix type:

Matrix system is characterized by a homogenous dispersion of solid

drug in a polymer mixture. Bio erodible and combination of diffusion and

dissolution controlled systems

Figure 7: Drug release from a matrix tablet.

INTRODUCTION

20

1.13. INTRODUCTION OF DISEASE: HYPERTENSION

1.13.1. Hypertension28

High blood pressure is leading cause of death across the world.

Apart from heart it also affects other important organs in the body causing

multilevel damage. Hypertension is strong independent risk factor for heart

disease and stroke. This disease is usually asymptomatic until the

damaging effects of hypertension (such as stroke, myocardial infarction,

renal dysfunction, visual problems, etc.) are observed.

Hypertensive is defined as an abnormal rise in diastolic pressure

and/or systolic blood pressure. Though mean arterial pressure is also

elevated it is not usually measured.

According to the latest U.S. national guidelines, the following

represents different stages of hypertension:22

Classification Systolic (mmHg) Diastolic (mmHg)

Normal <120 <80

Prehypertension 120-139 80-89

Stage 1 140-159 90-99

Stage 2 >160 >100

INTRODUCTION

21

1.13.2. Classification of Hypertension:

Two classes of hypertension:-

a. Primary Hypertension

b. Secondary Hypertension

a. Primary Hypertension: In 90-95% of patients presenting with

hypertension, the cause is unknown. This condition is called as Primary or

essential hypertension.

Following are some of the general causes for primary hypertension.

Obesity (very overweight)

Alcohol consumption

Consumption of more salt

Stress

Strong family history.

b. Secondary hypertension:

The hypertension in 5-10% is because of renal disease, endocrine

disorders or other known causes. This is called as secondary

hypertension.

Causes of secondary hypertension

Kidney disease

Adrenal gland disease

Narrowing of the aorta (Coarctation)

Secondary hypertension can also be caused by the contraceptive pill

(rarely), steroids, or by pregnancy causing pre-eclampsia.

INTRODUCTION

22

1.13.3. Symptoms of Hypertension:

Headache

Nosebleed (Epistaxis)

Breathlessness

Sleepiness, insomnia

Confusion

Fatigue

Coma

1.13.4. Pathophysiology

Pathophysiology behind secondary hypertensionis fully understood

as the cause of disease is completely outlined. But primary hypertension is

very less understood. Initially cardiac output is raised and total peripheral

resistance is normal, but over the time cardiac output is decreased and

TPR is increased.

Three theories are proposed-

Inability of the kidneys to excrete sodium, resulting secretion of atrial

natriuretic factor to promote salt excretion. This has side effect of

elevating total peripheral resistance.

An overactive Renin/angiotensin system leads to vasoconstriction

and retention of sodium and water.

An overactive sympathetic nervous system

INTRODUCTION

23

1.13.5 Complications of Hypertension:

While elevated blood pressure alone is not an illness, it often

requires treatment due to its short and long-term effects on many organs.

Cerebrovascular accident

Myocardial infarction

Hypertensive cardiomyopathy

Hypertensive retinopathy

Hypertensive nephropathy

1.13.6 Treatment of Hypertension:29

1. Diuretics:

Chlorthalidone

Furosemide

2. Potassium-sparing diuretics:

Amiloride hydrochloride

Spironolactone

3. Combination diuretics:

Amiloride hydrochloride + hydrochlorothiazide

Spironolactone + hydrochlorothiazide

4. Beta-blockers:

Atenolol

Propranolol hydrochloride

INTRODUCTION

24

5. ACE inhibitors:

Captopril

Trandolapril

6. Angiotensin II receptor blockers:

Candesartan

Losartin potassium

7. Calcium channel blockers:

Diltiazem hydrochloride

Verapamil hydrochloride

8. Alpha blockers:

Doxazosin mesylate

Prazosin hydrochloride

9. Central agonists

Alpha methyldopa

Clonidine hydrochloride

10. Combined alpha and beta-blockers:

Carvedilol

Labetolol hydrochloride

11.Blood vessel dilators:

Hydralazine hydrocholoride

Minoxidil

INTRODUCTION

25

1.13.6.1. Calcium Channel Blockers30:

Calcium Channel blockers are drug of choice to treat hypertension

and angina pectoris. They inhibit slow calcium channel and entry of

calcium ions across the cell membrane thus reducing its concentration in

smooth and cardiac muscle. This decreases heart rate and myocardial

contractility.

Types of calcium channel blockers

a) Benzothiazepines: diltiazem hydrochloride

b) Diphenyl amine: verapamil hydrochloride

c) Dihydropyridines: Nifedipine

Figure 8: Counter-Regulatory Responses to fall in Blood Pressure and

sites of Action of Antihypertensive Drugs (in red box)

LITERATURE SURVEY

26

2. LITERATURE SURVEY

2.1. HPMC K100LV

Ford et al. (1987)31have studied release of water soluble and insoluble

drugs from HPMC matrix and determined n value to predict

mechanism of drug release. The ‘n’ value for soluble drugs

promethazine hydrochloride, aminophylline, propranolol

hydrochloride and theophylline was found to be 0.71, 0.65, 0.67 and

0.64 respectively. While for insoluble drugs, diazepsm and

indomethacin n value was 0.90 and 0.82 respectively indicating zero

order release pattern. However tetracycline release from HPMC

matrix showed n value 0.45 suggesting complex release pattern with

lower release rates. When HPMC is replaced by calcium phosphate

or lactose the dissolution rates were increased for promethazine

hydrochloride with unchanged n value. Linear relationship existed

between release rates and surface of matrix tablets containing

promethazine hydrochloride.

Freely et al (1988)32studied effect of ionic and non ionic polymers on

the drug release form HPMC matrices. It was observed that ionic

polymers have retarded the release of oppositely charged

molecules while non ionic polymers did not change the drug

release.

LITERATURE SURVEY

27

Wan et. al. (1991)33 reported the effect of varying viscosity and

concentration of HPMC on aqueous penetration into matrices. It was

observed that there was improved wetting and water uptake into the

matrix containing HPMC. It was concluded in the research that

intrinsic water intake capacity was increase with increase in

molecular weight of HPMC.

Mitcheli et. al. (1993)34studied the propranalol release from matrix

containing HPMC and methylcellulose. It was observed that as the

drug content in formulation was decreased the release rate from

matrix became disproportionately higher. Various HMPC grades like

K4M, F4M and E4M have performed similarly. But matrix containing

methylcellulose showed burst release at low drug concentration.

This was attributed to failure of the matrix to maintain the integrity.

Rajabi et al. (1996)35studied the water mobility in the gel layer of matrix

tablet containing various grades of HPMC. It was observed that

water mobility in the gel layer varied with concentration and grades

of HPMCs.

Gao et. al. (1996)36studied the effect of HPMC- lactose ratio and viscosity

grades of HPMC on drug release and swelling of matrix tablet. It was

observed that release of drug and lactose was same indicating

similar diffusional release mechanism with no interaction with

HPMC. The drug release was analysed using model for reservoir

LITERATURE SURVEY

28

typre release system to study swelling kinetics. The diffusivity was

greatly influenced by varying HPMC-Lactose ratio. While, dissolution

was affected by viscosity grades of HPMC and gel layer thickness

development. In fast dissolving matrices, swelling is attributed to

higher drug diffusivity and release.

Sung et al (1996)37 studied the effect of HPMC-Lactose ratio and viscosity

grades of HPMC on release of adinazolam mesilate from matrix

tablet. The release was found highest with K100 LV viscosity grade

of HPMC. While formulation containing K4M grade showed slightly

greater drug release than K15M and K100M. It was concluded in the

study that increase in viscosity above 15000cp would no longer

decrease the drug release rate.

Dow Pharmaceutical Excipient ( 1996)38 reviewed various grades of

commercially available HPMC as per increasing amount of

hydrophilic hydroxypropyl and methoxyl group substitutions and

increasing the amount of hydrophilic hydroxypropyl groups and their

effects on rate of hydration.For highly soluble drugs where rapid rate

of hydration is necessary, rapid hydrating Methocel K is preferred.

Dose dumping was observed when an inadequate polymer hydration

rate is observed.

Campos et al. (1997)39have studied the effect of viscosity grade and

particle size of HPMC on release of metronidazole. At 10% of HPMC

LITERATURE SURVEY

29

ratio, a linear relationship was observed with inverse of release rate

and viscosity grade of HPMC. It was also observed that the release

rate and the cube of the diameter of HPMC particle were linear.

There was no difference on release rate was observed upon

changing viscosity and particle size of HPMC at higher HPMC ratio.

It was also observed that by increasing viscosity grades and particle

size of HPMC, a burst effect was increased.

Nellore et. al. (1998)40 studied the effect of varying the polymer level and

filler concentration on in vitro release of metoprolol. It was observed

that higher viscosity gel layers resulted in a slower release of

metoprolol. It was concluded that filler solubility had little effect of

release of drug from the formulation.

Colombo et. al. (1999)41 studied effect of thickness of gel layer on

increasing amount of soluble and colored drug in swellable HPMC

matrix using colorimetric method. Where swelling, erosion and

diffusion was studied. It was observed that with more 30% drug a

diffusion front was visible in the system. The drug solubility and

loading has marked importance in the observation of the diffusion

front as found in the physical analysis of the system.

Velasco et al. (1999)42 studied the effect of particle size for given effective

surface area on the release rate of diclofenac from HPMC tablets. It

was observed that smaller particle size dissolves more rapidly

LITERATURE SURVEY

30

because of penetration of dissolution medium in the matrix. While

larger particles tend to dissolve less rapidly and showed erosion

behavior at the surface of matrix tablet. It was also observed that

increase in polymer: drug ratio decreased the release rate. While

compression force had minimum effect on drug release beside

significant tablet hardness.

Rekhi et al. (1999)43 studied effect of varying HPMC, filler and

compression force on release rate water soluble drug metoprolol. It

was observed that changing filler from 100% dicalcium phosphate to

100% lactose increased release of metoprolol from HPMC K100 LV

matrix tablet. While increase in compression force had little effect on

the release of drug from HPMC matrix tablet beyond the critical

hardness limit. From the study it was concluded that tablet matrices

should be spherical.

Siepmann et al (1999)44 studied the effect of tablet size on the drug

release. It was observed that smaller tablets releases drug more

rapidly that medium and large tablets.

Colombo et. al. (2000)45 have reviewed oral drug delivery system and

considered that majority of them are matrix based. This review

emphasizes on hydrophilic swellable matrix tablets as a controlled

drug delivery system. Front movement, gel-layer behavior and

release was focused with in-vivo behavior of matrix tablets.

LITERATURE SURVEY

31

Siepmann et al (2001)46 studied various mathematical models used to

describe drug release from HPMC based pharmaceutical formulation

by considering effect device design parameters on drug release.

Various parameters like shape, size and composition were

considered.

Bettin et al. (2001)47 have studied the effect of swelling, drug solubility,

diffusion and erosion front on the release mechanism of drugs from

HPMC matrices. Drugs like nitrofutantoin, Diclofenac sodium, and

buflomedil pyridoxal phosphate with varying solubility were studied.

Tiwari et. al. (2003)48 have studied the effect of concentration of HPMC,

ethyl cellulose, lactose and castor oil on the release of tramadol from

matrix tablet. Tramadalol is the drug with high water solubility. Matrix

tablets prepared using castor oil were found to be most suitable for

development of drug delivery for tramadolol.

Li et. al. (2005)49 have reviewed the various properties of hypromellose as

release rate controlling agent. The review focus on applicability of

hypromellose, its chemical, mechanical and thermal properties,

hydration of matrix, drug release mechanism etc. This review also

provides on sight of inclusion of release modifier with HPMC,

influence of dissolution media and pH.

Conti et al.(2006)50 have studied the swelling properties of matrix system

containing HPMC and Sodium CMC with water soluble drug to

LITERATURE SURVEY

32

determine the relationship between drug release pattern and

morphology of the formulation.

Miranda et al. (2007)51 have studied the interrelation between drug

penetration threshold and particle size. It was observed that a linear

relationship exist between drug penetration and relative particle size.

These results were found valid for different drugs, excipients and

drug delivery systems.

Tamer et. al. (2007)52 have studied the effect of type and concentrations of

polymers HPMC (K100LV and K15M), eudragit, cellactose,

pharmatose and microcel on release of atenolol from extended

release hydrophilic matrix tablet. The matrix tablet was prepared by

direct compression method. The results showed that formulation with

low viscosity grade HPMC with lactose as direct compression agent

had linear drug release profile for duration of 8 hrs. The mechanism

of drug release was found to be non fickian transport as per the

value of diffusional exponent.

Ravi et. al. (2008)53 have studied the release of zidovudine from oral

controlled release matrix tablet designed using HPMC, ethyl

cellulose and barbopol-971. Various formulation factors and their

effect on in vitro release were studied. It was observed that rate of

release of drug decreased with increase in polymer concentration

and force of compression.

LITERATURE SURVEY

33

Shashikant et al. (2009)54 have formulated floating tablet of

clarithromycine for the treatment of helicobacter pylori using HPMC.

Both low and high viscosity grade HPMC-K4M and K100LV were

used in 1:1 ratio. The tablets were prepared by wet granulation

method. Design expert software was used for the optimization of

formulation with employment of criteria of desirability. The

mechanism of drug release was found to follow zero order release

kinetics.

Chaudhary et. al. (2011)55 have studied the effect of hydrophobic and

hydrophilic polymers, method of granulation over formulation of

extended release tablet of lamotrigine. The tablets were prepared by

wet granulation method using combination of methocel and Eudragit

as release retardant. The combination of polymers showed to control

the release of drug upto 24hrs.

Gunjal et. al. (2015)56 have studied floating sustained relese matrix tablets

of S(-) atenolol by using different polymer combination and

filler.Formulation was optimized by using surface response

methodology. Floating sustained release matrix tablets of were

prepared with Hydroxypropyl methylcellulose. While, sodium

bicarbonate was used as a gas generating agent with polyvinyl

pyrrilidone as a binder and lactose as filler. The full factorial design

(32) was used to study the effects of variables on different properties

LITERATURE SURVEY

34

of tablets viz. buoyancy time, floating lag time and % drug released.

Optimum formulation followed Higuchi drug release kinetics

indicating drug release by anomalous (non-fickian) diffusion

mechanism.

2.2. EUDRAGIT L100-55

McGinity et. al. (1987)57 have studied the matrix tablet of theophylline

containing combination of Eudragit RSPM and Eudragit L 100. The

total polymer content was included at 15% level. Faster release of

drug was seen at pH 7.4 (phosphate buffer) because of higher

solubility of the eudragit L100. There was little influence of tablet

hardness in the range 6.8-15 kg on the dissolution rate of drug.

Vela et al. (1995)58 have studied the effect of phase separation technique

over poor flow properties and compressibility of paracetamol. It was

showed that paracetamol thus obtained has good flow properties

and compressibility. Matrix tablets were formulated using modified

paracetamol and eudragits- R, L and S. Effect of type and

concentration of eudragit was evaluated on flow properties. Matrix

tablets were evaluated for various in vitro parameters with

dissolution study. In the study the importance of geometry of

particles on flow properties was underlined. The release was found

to follow diffusion controlled pattern from the tablets.

LITERATURE SURVEY

35

Khopade et. al. (1995)59have compared the release profile of

nanosuspension contaning eudragit RLPM and RSPM. It was

observed that formulation with eudragit RSPM showed longer

release than eudragit RLPM with excellent drug loading.

Takka et al. (2001)60 have studied the effect of combination of eudragit S,

eudragit L 100-55 and sodium CMC incorporated into HPMC matrix

over propranolol release from polymer matrix. Formulations were

designed by changing ratio of HPMC and polymers and their

dissolution profiles were compared. Marked variation was observed in

propranolol release from various formulations. The matrix containing

HPMC–Eudragit L 100-55 (1:1 ratio) produced pH-independent

extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate

buffer.

Pignatello et. al. (2002)61 have studied formulation of nanosuspension

using eudragits RS 100, RL100 and RL. It was observed that the

formulation did not exert any irritant effect on iris, cornea and

conjunctiva upto 24hr after application.

Małolepsza et al (2003)62 have prepared intravaginal tablets containing

methyl cellulose and eudragit E 100. The tablet was observed to

swell in simulated conditions. The formation of gel around the tablet

gave the durable drug release from the tablet. The tablet with lactic

acid and eudragit in ratio 1:1 were showed to form gel at

LITERATURE SURVEY

36

physiological pH of 3.8- 4.4. Increase in lactic acid proportion

resulted in gels with lower pH value.

Bucolo et. al. (2004)63 have prepared nanoparticles of cloricromene using

eudragit RL 100 as coat forming agent. It was observed that ocular

bioavailability of the drug was increased by delivering it through

nonparticulate drug delivery.

Kale et al. (2007)64 have prepared microspheres of edugragit S 100. The

microspheres were observed to float continuously in the acidic

medium with controlled release of drug in predetermined rate.

Duarte et. al. (2007)65 have compared the potential of eudragit RS 100

and RL 100 as a drug carrier for acetazolamide. It was observed that

acetazolamide was release in controlled manner from the

microparticles.

MonaSemalty et. al. (2008)66 have preparedmucoadhesive buccal films of

glipizide using Eudragit RL-100.

Ali et al. (2008)67 have prepared microparticulate drug delivery of sodium

para aminosalicylate for oral administration. The microparticles were

prepared by extrusion spheronization technique using

microcrystalline cellulose as filler at concentratin 14.4% w/w. Pellets

were coated with eudragit L 30 at varying coating thickness and

evaluated for in vitro dissolution test as per extended release

dissolution test USP. The formulation with 60% coating level of

LITERATURE SURVEY

37

eudragit resulted in most satisfactory resistance to gastric attack. A

seal coat of HPMC was applied to protect the migration of drug into

eudragit coat. The pellets were evaluated for morphological

characteristics by SEM and found to be smooth and spherical.

Degin et al. (2008)68 have successfully prepared suppositories of sildenafil

using eudragit RS100 and witepsol H15 to increase the release time

of it.

Venkatesh et al. (2009)69 prepared various controlled release formulation

of tegaserod maleate used to treat irritable bowel syndrome. Various

approaches like microparticles, modified released tablets and

compressed microcapsules were prepared using Eudragit L 100 abd

S 100 at various concentration ratios. The modified tablets were

prepared using HPMC as inner material and ethyl cellulose as outer

coat using double compression method. In vitro dissolution study

showed that release profile of tegaserod maleate was better for

microcapsules than compressed microcapsules and modified

tablets.

W. Sakr et. al. (2011)70 have formulated extended release matrix tablet of

albuterol sulphate using HPMC, carbopol and Eudragit L100-55. The

drug release from the formulation was best described to control by

more than one kinetic model.

LITERATURE SURVEY

38

Shah et al. (2013)71 have applied experimental design in the development

and optimization of drug release from extended release Ranolazine

matrix tablets by 32 full factorial design. The formulation was

developed using Eudragit L 100-55, Microcrystalline Cellulose,

Hydroxypropyl Methylcellulose and Magnesium stearate. The tablet

was prepared by wet granulation method. The effect of independent

variables such as amount of Eudragit L100-55 (X1) and Sodium

Hydroxide (X2) were studied on drug release at 0.5, 4, 12, 24 hours

(dependent variables) as per 32 factorial designs. The formulations

were evaluated for various physicochemical parameters. Contour

plots were developed for 13 formulation batches and polynomial

equations were derived for each to predict the values of independent

variables. Optimized formulation from DOE had identical dissolution

profile (f2 = 85.95 and f1 = 2.29) with innovator’s tablet. It was

concluded that experimental design was successfully applied for

optimization of amount of excipients.

2.3. PVAP

BASF (1999)72 have studied effect kollidon on compressibility and drug

release of propranolol tablet at drug :polymer ratio 1:1. It was

observed that compression force did not affect release of drug

LITERATURE SURVEY

39

Kolter et al. (2000)73 have prepared the a free-flowing non hygroscopic

powder of polyvinyl acetate (80%, w/w) and polyvinylpyrrolidone

(20%, w/w) combined as a physical mixture .

Draganoiu et al. (2001)74 have studied use of kollidon SR to maintain

geometric shape of tablet till the end of dissolution test with the use

of water insoluble polyvinyl acetate and water soluble

polyvinylpyrrilidone. The tablet had showed diffusion controlled

release of drug.

Shao et al. (2001)75 have studied influence of conditions of accelerated

stability studies on diphenhydramine tablets prepared using Kollidon

SR. It was observed that decrease in dissolution rate and increase in

hardness for the tablet prepared using high level of decreased with

reported the effect of accelerated stability conditions on

diphenhydramine HCl tablets prepared with Kollidon® SR. A

decrease in dissolution rate along with an increase in tablet

hardness was noticed for tablets with high level of Kollidon® SR

(>37%) prepared without diluents or with 15% diluent (lactose,

Emcompress®). At 25% Emcompress®, no changes occurred. Such

changes were not observed for tablets stored at 25°C/ 60%RH or

cured at 60°C for at least one hour.

Siepmann et al.( 2010)76 reported from an economical point of view the

production of sustained release tablets by direct compression is of a

LITERATURE SURVEY

40

great promise. In this respect Kollidon SR, a convincing excipient is

expected to be easily applicable for a broad selection of different

drugs.

Haresh T Mulani et al. (2011)77 reported the effects of the following

formulation and process variables on tablet properties and drug

release were tested: Kollidon® SR concentration in the tablet,

addition of external binder for wet granulation, presence of an

enteric polymer in the matrix, method of manufacturing and

compression force. It was concluded that Kollidon® SR is a

potentially useful excipient for the production of pH-independent

extended release matrix tablets.

NEED FOR THE STUDY

41

3. NEED FOR THE STUDY

In the present study, Diltiazem hydrochloride and metoprolol

succinate were selected as a model drugs. Diltiazem is a calcium channel

blocker. This drug need to be administered frequently (usually 3-5 times a

day & at night) which makes it a good candidate to formulate as sustained

release matrix tablets. Metoprolol succinate is a cardio selective β-blocker

used in the treatment of hypertension, angina pectoris and heart failure.It is

available commercially in 25 mg, 50 mg strength as immediate release

tablets with bioavailability of 50 % following oral administration.

Frequent administration and less bioavailability leads to fluctuations

in plasma concentration, sub optimum therapeutic level, less effective

management of the disease and less patient compliance. These problems

can be solved by formulating drug delivery system of these drugs which

will maintain concentration of drug in blood for longer time with controlled

release of drug from it. One of the most commonly used methods of

modeling drug release is its inclusion within a matrix system.

Matrix systems are extensively used in controlled drug delivery

because of its simple and fast producing technology and low cost.

OBJECTIVES AND HYPOTHESIS

42

4. OBJECTIVES AND HYPOTHESIS

Objectives of the study

The objective of this study was to develop sustained release matrix

tablets of BCS–Class I drug like Diltiazem hydrochloride and Metoprolol

Succinate, by studying the following points:

1. To Study the effects of the Pre-compression & Post-compression

variables on the characteristics of Diltiazem hydrochloride / Metoprolol

Succinate sustained release matrix tablets

2. To compare the In-vitro release profiles of the sustained release matrix

tablets with marketed product like Dilzem®SR and Meta® XL 50.

3. In-vivo X-ray evaluation of sustained release matrix tablets by adhering

to various sites in the gastrointestinal tract of animal.

4. The stability of the drug in the formulation was confirmed by differential

scanning calorimetry (DSC) thermograms.

Hypothesis

Diltiazem hydrochloride / Metoprolol Succinate in combination with

HPMC K 1000 LV, Eudragit L 100-55 alone and in combination, and

Diltiazem hydrochloride / Metoprolol Succinate in combination with PVAP

(Kollidon® SR), MCC, and DCP alone and in combination will produce

sustained release matrix tablet.

INTRODUCTION TO MATERIALS

43

5. INTRODUCTION TO MATERIALS

5.1. DRUG STUDY

5.1.1. Diltiazem Hydrochloride 78,79,80,81,82

Chemical structure of Diltiazem Hydrochloride

Molecular formula : C22H26N2O4S, HCl

Molecular weight : 451.0gm\mole

IUPAC name : : 2S, 3S)-5-[2-

(dimethylamino)ethyl]2(4methoxyphenyl)-4-oxo-2,

3, 4, 5-tetrahydro-1, 5benzothiazepin3ylacetate

Hydrochloride

Description : A white, odorless, crystalline powder, odorless and

has a bitter taste

Solubility : Diltiazem is freely soluble in water, in methanol and

in Methylene chloride, slightly soluble in ethanol.

Melting range : 210ºC-220ºC


44

Storage : Diltiazem hydrochloride must be stored in an

airtight Container, protected from light.

Formulations : Diltiazem tablets, Diltiazem ER Capsules.

Usual dose range : 30 to 60 mg QID.

Absorption : Diltiazem is rapidly and completely absorbed from

the GIT.

Bioavailability : Oral bioavailability is about 40 - 50%.

Distribution : At therapeutic concentration, Diltiazem is

approximately 80% bound to plasma proteins.

Metabolism : Extensively metabolized, due to hepatic

metabolism.

Elimination : Half-life of Diltiazem is approximately 3-4 hrs.

Therapeutic uses : It is an effective calcium channel blocker, used to

treat angina, hypertension and myocardial

infarction.

Mechanism of

action

: The therapeutic effects of Diltiazem hydrochloride

extended-release capsules are believed to be

related to its ability to inhibit the cellular influx of

calcium ions during membrane depolarization of

cardiac and vascular smooth muscle

.


45

5.1.2. Metoprolol Succinate 83.84,85,86

Chemical name :(±)-1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-

propanol succinate (2:1) (salt).

Physical-chemical Characterization of Drug:

Formula: (C15H25NO3)2 • C4H6O4

Structure:

Molecular weight : 652.81

Category : Metoprolol is a beta1-selective (cardio selective)

adrenergic receptor blocking agent

(antihypertensive).

Appearance : Metoprolol succinate is a white crystalline

powder.

Solubility : It is freely soluble in water; soluble in methanol;

sparingly soluble in ethanol; slightly soluble in

dichloromethane and 2-propanol; practically

insoluble in ethyl acetate, acetone, diethylether

and heptane.


46

Table: 5 A Solubility of Metoprolol succinate.

Solvent Solublity (mg/ml)

Water 1-10

Ethanol 1-10

Chloroform <0.1

Diethyl ether <0.1

Partition Coefficient:

Apparent partition coefficient into iso-butanol (2-methyl propanol) at 37oC is:

Table: 5 B. Partition coefficient of Metoprolol succinate in different pH.

Aqueous Phase Partition coefficient(P)

0.1M HCl 0.33

pH 1-3 0.79

pH 5-6 0.13

pH 7-9.5 0.25

Pharmacokinetics:

Bioavailability : 12%

Metabolism : Hepatic

Half life : 3-7 hours

Excretion : Renal


47

Therapeutic Uses:

It is useful in:-

Management of angina pectoris.

Management of hypertension

Treatment of stable, symptomatic heart failure of ischemic,

hypertensive, or cardiomyopathic origin.

5.2. GENERAL PROFILE OF POLYMERS

5.2.1. Hydroxypropyl methylcellulose (HPMC) 87

HPMC is a methylcellulose modified with a small amount of

propylene glycol ether groups attached to the anhydroglucose of the

cellulose. HPMC is available in 4 different chemistries (E, F, J, and K series)

based on the varying degrees of hydroxypropyl and methyl substitutions.

The K series has the fastest hydration rate. The K100LV polymer thus has

fast hydration, has a viscosity of 100cps and is termed low viscosity as per

the “LV” designation.

Structure:

R = - CH2 – CH2 – CH2 - OH


48

Chemical Name : Cellulose, 2 Hydroxy Propyl methyl ether

Functional category: Coating agent, film former, stabilizing agent,

tablet binder, viscosity increasing agent.

Physiochemical Properties:

Description: Hydroxy propyl methyl cellulose is an odorless and

tasteless, white or creamy-white colored fibrous or granular powder.

Particle size: Minimum 99% through a #40 US standard sieve

Methoxyl content: 19-24%

Hydroxypropoxl content: 7-12% Bulk density: 0.5 g/cm3

Solubility: HPMC K100LV is a low viscosity polymer which is soluble

in cold water, forming a viscous colloidal solution. Practically insoluble

in chloroform, ethanol and ether

pH (1% content): 5.5-8

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

Density (Tapped): 0.50–0.70 g/cm3 for pharmacoat.

Melting point : Browns at 190 – 2000C, chars at 225 – 230oC

Moisture content: HPMC absorbs moisture from atmosphere. The

amount of water absorbed depends upon the initial moisture content

temperature and relative humidity of the surrounding air.

Storage: HPMC powder should be stored in a well-closed container in

a cool and dry place.


49

Nonionic cellulose ethers, like HPMC have been very widely

studied for their applications in oral extended release systems. It is very

commonly used to formulate extended release hydrophilic matrix tablets

due to its water solubility. HPMC has broad FDA clearance as a direct

food additive.

5.2.2. Eudragit L 100-5588

Eudragit L is an anionic polymer synthesized from methacrylic acid

and acrylic acid ethyl esters. It becomes soluble in a neutral to weakly

alkaline milieu by forming salts with alkalis.

For Eudragit L: R1, R3 = CH3, R2 = H, R4 = CH3

Physiochemical Properties

Description: white, moderately fine free-flowing powder

Particle size: Minimum 95% less than 0.5 mm

Solubility: Insoluble in water, soluble in isopropyl alcohol.

Eudragit L 100-55 is an FDA approved coating polymer that is widely

used in the pharmaceutical industry. In this instance however, the use

will be in direct compression tablets. The Eudragit is used in granulation


50

for isolation of incompatible ingredients and to improve the long term

keeping properties.

5.2.3. PVAP (Kollidon® SR) 89

Polyvinylacetate/Povidone (PVAP) based polymer (Kollidon® SR)

consists of 80% Polyvinylacetate and 19% Povidone in a physical mixture,

stabilized with 0.8% sodium lauryl sulfate and 0.2% colloidal silica.

Physicochemical properties

Description white or slightly yellowish, free flowing powder;

Particle size

distribution

average particle size of about 100µm; Molecular weight

of polyvinyl acetate 450 000;

Bulk density within the range of 0.30-0.45g/ml; 0.37g/ml

Tap density 0.44g/ml

Flowability Good flow properties with a response angle below 30°

Solubility Polyvinyl acetate is insoluble in water. Povidone

gradually dissolves in water; in tablets it acts as a pore-

former.

pH 3.5-5.5.


51

5.3. OTHER EXCIPIENTS

5.3.1. Magnesium stearate90

1. Synonyms: Metallic stearic, Magnesium salt.

2. Functional category: Tablet and capsule lubricant,

3. Chemical Names: Octadecanoic acid; Magnesium salt; magnesium

Stearate.

4. Structurla Formula:

5. Emperical Formula: C36H70MgO4

6. Molecular Weight: 591.3

Description:

It is a fine, white, precipitated, or milled, impalpable powder of low

bulk density, having a faint characteristic odor and taste. The powder is

greasy to touch and readily adheres to the skin.

Typical properties:

Solubility

Practically insoluble in ethanol, ether and water, slightly soluble in

benzene and warm ethanol

Stability:

Stable, non-self polymerizable.


52

Incompatibilities:

Incompatible with strong acids, alkalis, iron salts and with strong

oxidizing material.

Applications in Pharmaceuticals Formulation or Technology:

Tablet and capsule lubricant, glidant and antiadherent in the

concentration range of 0.25-2.0%.

5.3.2. Microcrystalline Cellulose91

Synonyms:

Avicel, cellulose gel, crystalline cellulose, Emocel, Vivacel.

Empirical Formula and Molecular Weight: (C6H10O5)n, 36 000 gm/mole

Structural Formula:

Functional Category:

Tablet and capsule diluents, suspending agent, adsorbent, tablet

disintegrant.

Description:

White-colored, odorless, tasteless crystalline powder composed of

porous particles. Available in different particle size grades which have

different properties and applications.


53

Solubility:

Slightly soluble in 5 % w/v NaOH solution, practically insoluble in

water, dilute acids and most organic solvents.

Safety:

It is generally regarded as a nontoxic and nonirritant material.

5.3.3. Colloidal silicon Dioxide 92

Synonym:

Aerosil 200; Amorphous Fumed Silica; Aerosil

Chemical name:

Silicon Dioxide

Description:

Physical state and appearance: Solid

Odor: Odorless

Taste: Tasteless

Molecular Weight: Not available

Color: White

pH (1% soln/water): Not available

Boiling Point: Not available

Melting Point: 1610°C (2930°F)

Specific Gravity: 2.2 (Water = 1)

Pharmaceutical applications: Its small particle size and large specific

surface area give it desirable flow characteristics that are exploited to


54

improve the flow properties of dry powders in a number of processes such

as tableting and capsule filling. Colloidal silicon dioxide is also used to

stabilize emulsions and as a thixotropic thickening and suspending agent

in gels and semisolid preparations.

5.3.4. Lactose 93

It occurs in three forms: α-monohydrate, α- anhydrous and β-anhydrous.

Commercial Lactose is mainly α-monohydrate.

Chemical Name: 4-O-β-D galactopyranosyl-α- glucopyranose 4-(β-D-

galactose)-D-glucose.

Empirical Formula: C12H22O11 (anhydrous), C12H22O11.H2O (monohydrate)

Description: White to off white or creamy white crystalline particles or

powder, odorless, sweet in taste.

Molecular weight: 342.30 (anhydrous) to 360.31. (monohydrate)

Uses: It is used as filler, diluents in pharmaceutical preparations and also

used as dry powder inhaler carrier, lyophilization aid and tablet binder.

5.3.5. Dibasic Calcium Phosphate (Dihydrate)94

Nonproprietary Names

BP: Calcium Hydrogen Phosphate, JP: Dibasic Calcium Phosphate Hydrate

Synonyms

Calcii hydrogenophosphas dihydricus; calcium hydrogen orthopho-

sphate dihydrate; calcium monohydrogen phosphate dihydrate


55

Empirical Formula and Molecular Weight

CaHPO4 2H2O, 172.09

Structural Formula

Functional Category

Tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Dibasic calcium phosphate dihydrate is widely used in tablet

formulations both as an excipient and as a source of calcium and

phosphorus in nutritional supplements.

Description

Dibasic calcium phosphate dihydrate is a white, odorless, tasteless

powder or crystalline solid. It occurs as monoclinic crystals.

Typical Properties

Acidity/alkalinity pH = 7.4 (20% slurry of DI-TAB) Angle of repose

28.38 for Emcompress.

Density (bulk) 0.915 g/cm3

Density (tapped)1.17 g/cm3

Density (true) 2.389 g/cm3

Flowability 27.3 g/s for DI-TAB; 11.4 g/s for Emcompress.


56

Melting point Dehydrates below 10080 C.

Solubility : Practically insoluble in ethanol, ether, and water; soluble in

dilute acids

MATERIALS AND METHODS

57

6. MATERIALS AND METHODS

6.1. MATERIALS USED:

The following materials that were either AR/LR grade were used as

supplied by the manufacturer.

Table No.6 A: List of materials used

S.NO. Material Manufacturer/ Company Name

1. Diltiazem Hydrochloride Piramal Healthcare

Limited,AP(India)

2. Metoprolol Succinate Emcure Pharmaceutical Pvt

Ltd,Pune

3. Polyvinyalcaetate & Povidone

Polymer(PVAP)(Kollidone® SR)

Glenmark Company,Mumbai

4. Hydroxy propyl methyal cellulose

(HPMC100LV)

Glenmark Company,Mumbai

5. Eudragit® L100-55 Evonik Rohm GMBH,Germany

6. Microcrystalline Cellulose

(Avicel®102)

FMC Biopolymer,Ireland

7. Lactose N.F. DMV-Fonterra Excipients(NZ)

Ltd, New Zealand

8. Dibasic Calcium

Phosphate(Dihydrate)

Aptuit Laurus,Hydarabad

9. Colloidal Silicon

Dioxide(Aerosil®200)

Aptuit Laurus, Hydarabad

10. Magnesium Stearate Thomas Baker, Mumbai


58

6.2. EQUIPMENT USED:

Table No.6 B: List of equipment’s and instruments used

Sr.No. Name of Instrument Manufacturer

1 Digital balance Sartorious BS/BT, Mumbai, India.

2 Sieves Jayant Scientific Ind. Bombay,

India.

3 Bulk density apparatus Konark instruments

4 Digital pH Meter Consolidated Electric Industries,

Bangalore

5 Tablet compression machine Rimek tablet press, Ahmadabad.

6 Monsanto hardness tester Cadmach,Ahmedabad, India

7 Dial Vernier Caliper Mitutoyo, Japan

8 Roche friability tester Campbell Electronics, Mumbai,

India

9 Disintegration test apparatus Electro lab, Mumbai

10 Dissolution apparatus

(USP XXIII)

Electro lab, Mumbai

11 Infrared spectrophotometer IR Affinity1, Shimadzu

(Sr. no.A21374801815), Japan.

12 Ultra sonicator Servewell Instruments Pvt. Ltd.,

Bangalore, India

13 UV spectrophotometer

(Model UV-1201)

Shimadzu UV-1700 Pharmaspec

(Sr.No.A11024504164), Japan.

14 Programmable Environmental

Test Chamber

Remi electronics, Mumbai.

15 Scanning Electron

Microscope

Jeol JSM-6360 (SEM), Germany.


59

6.3 METHODOLOGY

6.3.1. Preformulation Study: 95,96,97

Preformulation study is the first step in the development of dosage

form of a drug substance and is the process of optimizing the delivery of

drug through determination of physicochemical properties of the new

compound that could affect drug performance and development of an

efficacious, stable and safe dosage form. Hence, preformulation studies of

obtained sample of drug were performed for identification and compatibility

studies.

6.3.1.1. Determination of melting point:

Melting points of Diltiazem Hydrochloride and Metoprolol Succinate

were determined by capillary method.

6.3.1.2. Solubility:

The solubility of Diltiazem Hydrochloride and Metoprolol Succinate in

various media was observed.

6.3.1.3. FTIR Spectroscopy:

The FT-IR spectrum for the obtained gift sample of pure drug was

obtained by KBr method and compared with the standard FT-IR spectra.

6.3.1.4. Compatibility studies:

FT-IR spectroscopic studies were performed to check the

compatibility between the drug and polymer in formulation and in final

dosage form. The FT-IR spectra of drug alone and with formulation


60

polymers were obtained by KBr method and compared with the standard

FT-IR spectrum of the pure drug.

6.3.2. Determination of λ max:

6.3.2.1 Determination of λ max of Diltiazem Hydrochloride

Stock solution: Diltiazem Hydrochloride in distilled water (100 mg in 100

ml)

Scanning: From the stock solution, a suitable concentration of Diltiazem

Hydrochloride (10 μg/ ml) was prepared in distilled water and UV scan was

taken for the above stock solutions between the wavelengths of 200- 400

nm. The absorption maximum was found to be 237 nm and this

wavelength was selected and utilized for further studies.

6.3.2.2 Determination of λ max of Metoprolol Succinate

Stock solution: Metoprolol Succinate in distilled water (100 mg in 100 ml)

Scanning: From the stock solution, a suitable concentration of Metoprolol

Succinate (10 μg/ ml) was prepared in distilled water and UV scan was

taken for the above stock solutions between the wavelengths of 200- 400

nm. The absorption maximum was found to be 275 nm and this

wavelength was selected and utilized for further studies.

6.3.3. Preparation of Calibration Curve

6.3.3.1. Preparation of Calibration Curve of Diltiazem Hydrochloride

a) In Distilled water:

The standard curve of diltiazem HCl was prepared in distilled water.


61

Procedure:

Standard Solution: Accurately weighed 100 mg of diltiazem hydrochloride

was dissolved in 100 ml of distilled water to give a concentration of 1 mg/

ml.

Stock Solution: From the standard solution, a stock solution was

prepared to give a concentration of 100 mcg/ ml in distilled water. Aliquots

of 0.0, 0.2, 0.4, 0.6, 0.8 and 1.0 ml were pipetted out into 10 ml volumetric

flask. The volume was made up to the mark with distilled water. These

dilutions give 0, 2, 4, 6, 8, 10 μg / ml. Concentration of diltiazem

hydrochloride respectively. The absorbance of prepared solutions of

diltiazem hydrochloride in distilled water were measured at 237 nm

respectively in Shimadzu UV- 1700 spectrophotometer against appropriate

blank. The absorbance data for standard calibration curves are given in

table-11. The standard calibration curve yields a straight line, which shows

that the drug follows Beer’s law in the concentration range at 2 to 10 μg /

ml.

b) In 0.1 N HCl

The standard curve of diltiazem hydrochloride as prepared in 0.1 N HCl.

Procedure:


was dissolved in 100 ml of 0.1 N HCl to give a concentration of 1 mg/ ml.


62


prepared to give a concentration of 100 mcg/ ml in 0.1 N HCl. Aliquots of

0.0, 0.2, 0.4, 0.6, 0.8 and 1.0 ml were pipetted out into 10 ml volumetric

flask. The volume was made up to the mark with d 0.1 N HCl. These

dilutions give 0, 2, 4, 6, 8, 10 μg / ml. Concentration of diltiazem


diltiazem hydrochloride in 0.1 N HCl were measured at 237 nm




that the drug follows Beer’s law in the concentration range at 2 to 10 μg /

ml.

b) In pH 7.4 phosphate buffer :

The standard curve of diltiazem hydrochloride was prepared in pH 7.4

phosphate buffer.

Procedure:


was dissolved in 100 ml of 7.4 phosphate buffer to give a concentration of

1 mg/ ml.


prepared to give a concentration of 100 mcg/ ml in 7.4 phosphate buffer

Aliquots of 0.0, 0.2, 0.4, 0.6, 0.8 and 1.0 ml were pipetted out into 10 ml


63

volumetric flask. The volume was made up to the mark with the7.4

phosphate buffer. These dilutions give 0, 2, 4, 6, 8, 10 μg/ ml.

Concentration of diltiazem hydrochloride respectively. The absorbance of

prepared solutions of diltiazem hydrochloride in 7.4 phosphate buffer were

measured at 237 nm respectively in Shimadzu UV- 1700

spectrophotometer against appropriate blank. The absorbance data for

standard calibration curves are given in table-13. The standard calibration

curve yields a straight line, which shows that the drug follows Beer’s law in

the concentration range at 2 to 10 μg / ml.

6.3.3.2. Preparation of Calibration Curve of Metoprolol Succinate:

a) Distilled water

The standard curve of metoprolol succinate was prepared in distilled water.

Procedure:

Standard Solution: Accurately weighed 100 mg of metoprolol succinate

was dissolved in 100 ml of distilled water to give a concentration of 1 mg/

ml.


prepared to give a concentration of 100 mcg/ ml in distilled water. Aliquots

of 0.0, 0.2, 0.4, 0.6, 0.8 and 1.0 ml were pipetted out into 10 ml volumetric

flask. The volume was made up to the mark with distilled water. These

dilutions give 0, 2, 4, 6, 8, 10 μg/ ml. Concentration of diltiazem



64

diltiazem hydrochloride in distilled water were measured at 275 nm




that the drug follows Beer’s law in the concentration range at 2 to 10 μg/

ml.

c) In 0.1 N HCl

The standard curve of metoprolol succinate was prepared in 0.1 N HCl.

Procedure:


was dissolved in 100 ml of 0.1 N HCl to give a concentration of 1 mg/ ml.


prepared to give a concentration of 100 mcg/ ml in 0.1 N HCl. Aliquots of

0.0, 0.2, 0.4, 0.6, 0.8 and 1.0 ml were pipetted out into 10 ml volumetric

flask. The volume was made up to the mark with d 0.1 N HCl. These

dilutions give 0, 2, 4, 6, 8, 10 μg / ml. Concentration of metoprolol

succinate respectively. The absorbance of prepared solutions of

metoprolol succinate in 0.1 N HCl were measured at 275 nm respectively

in Shimadzu UV- 1700 spectrophotometer against appropriate blank. The

absorbance data for standard calibration curves are given in table-15. The

standard calibration curve yields a straight line, which shows that the drug

follows Beer’s law in the concentration range at 2 to 10 μg/ ml.


65

c) In pH 7.4 phosphate buffer

The standard curve of metoprolol succinate was prepared in pH 7.4

phosphate buffer.

Procedure:


was dissolved in 100 ml of 7.4 phosphate buffer to give a concentration of

1 mg/ ml.


prepared to give a concentration of 100 mcg/ ml in 7.4 phosphate buffer

Aliquots of 0.0, 0.2, 0.4, 0.6, 0.8 and 1.0 ml were pipetted out into 10 ml

volumetric flask. The volume was made up to the mark with the 7.4

phosphate buffer. These dilutions give 0, 2, 4, 6, 8, 10 μg / ml.

Concentration of diltiazem hydrochloride respectively. The absorbance of

prepared solutions of diltiazem hydrochloride in 7.4 phosphate buffer was

measured at 275 nm respectively in Shimadzu UV- 1700

spectrophotometer against appropriate blank. The absorbance data for

standard calibration curves are given in table-16. The standard calibration

curve yields a straight line, which shows that the drug follows Beer’s law in

the concentration range at 2 to 10 μg / ml.


66

6.4. COMPOSITION OF MATRIX TABLET

6.4.1. COMPOSITION OF MATRIX TABLETS CONTAINING HPMC, EUDRAGIT

6.4.1.1. Composition of Matrix Tablet Containing Diltiazem Hydrochloride.

Table No 7: Composition of HPMC, Eudragit Matrix Tablet Containing Diltiazem Hydrochloride

Ingredients

(mg)

All batches quantity in mg/tablet

FD1 FD2 FD3 FD4 FD5 FD6 FD7 FD8 FD9 FD10 FD11 FD12

Diltiazem Hydrochloride 90 90 90 90 90 90 90 90 90 90 90 90

HPMC K100LV 45 90 180 270 - - - - 22.5 45 90 135

Eudragit L100-55 - - - - 45 90 180 270 22.5 45 90 135

Microcrystalline cellulose 155.25 132.75 87.75 42.75 155.25 132.75 87.75 42.75 155.25 132.75 87.75 42.75

Lactose 155.25 132.75 87.75 42.75 155.25 132.75 87.75 42.75 155.25 132.75 87.75 42.75

Magnesium Stearate 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5

Total weight 450 450 450 450 450 450 450 450 450 450 450 450


67

6.4.1.2. Composition of HPMC , Eudragit Matrix Tablet Containing Metoprolol Succinate

Table No 8: Composition of HPMC,Eudragit Matrix Tablet Containing Metoprolol Succinate

Ingredients

(mg)


FM1 FM2 FM3 FM4 FM5 MF6 FM7 FM8 FM9 FM10 FM11 FM12

Metoprolol Succinate 47.50 47.50 47.50 47.50 47.50 47.50 47.50 47.50 47.50 47.50 47.50 47.50

HPMCK 100LV 24 48 96 144 - - - - 12 24 48 72

Eudragit L100-55 - - - - 24 48 96 144 12 24 48 72

Microcrystalline

cellulose 82.80 70.80 46.80 22.80 82.80 70.80 46.80 22.80 82.80 70.80 46.80 22.80

Lactose 82.80 70.80 46.80 22.80 82.80 70.80 46.80 22.80 82.80 70.80 46.80 22.80

Magnesium Stearate 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4

Total weight 239.5 239.50 239.50 239.50 239.50 239.50 239.50 239.50 239.50 239.50 239.50 239.50


68

6.4.2. COMPOSITION OF MATRIX TABLETS CONTAINING PVAP

6.4.2.1. Composition of PVAP Matrix Tablet Containing Diltiazem Hydrochloride.

Table No 9: Composition of PVAP Matrix Tablet Containing Diltiazem Hydrochloride

Ingredients(mg) All batches quantity in mg/tablet

FD13 FD14 FD15 FD16 FD17 FD18 FD19 F20 FD21 FD22

Diltiazem Hydrochloride 90 90 90 90 90 90 90 90 90 90

PVAP 355.50 - - 177.75 177.75 - 237 59.25 59.25 118.50

Microcrystalline cellulose - 355.50 - 177.75 - 177.75 59.25 237 59.25 118.50

Dibasic Calcium Phosphate dihydrate - - 355.50 - 177.75 177.75 59.25 59.25 237 118.50

Colloidal silicon dioxide 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25

Magnesium Stearate 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25 2.25

Total weight 450 450 450 450 450 450 450 450 450 450


69

6.4.2.2. Composition of PVAP Matrix Tablet Containing Metoprolol Succinate

Table No 10: Composition of PVAP Matrix Tablet Containing Metoprolol Succinate

Ingredients(mg)


FM13 FM14 FM15 FM16 FM17 FM18 FM19 FM20 FM21 FM22

Metoprolol Succinate 47.50 47.50 47.50 47.50 47.50 47.50 47.50 47.50 47.50 47.50

PVAP 189.60 - - 94.80 94.80 - 126.40 31.60 31.60 63.20

Microcrystalline cellulose - 189.60 - 94.80 - 94.80 31.60 126.40 31.60 63.20

Dibasic Calcium Phosphate

dehydrate - - 189.60 - 94.80 94.80 31.60 31.60 126.40 63.20

Colloidal silicon dioxide 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2

Mg.Stearate 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2

Total weight 239.5 239.5 239.5 239.5 239.5 239.5 239.5 239.5 239.5 239.5


70

6.5. PREPRATION OF MATRIX TABLETS

6.5.1. Preparation of Matrix Tablets Containing HPMC and Eudragit

The corresponding amounts of active ingredient (drug-Diltiazem

hydrochloride/Metoprolol succinate), HPMC, Eudragit, microcrystalline

cellulose and lactose were accurately weighed. The powders were sieved

using screen #25. The screened powder was then transferred into the

turbula mixer jar and mixed for 10 minutes. Magnesium stearate was

accurately weighed, sieved through screen #25 and added to the turbula jar

and mixed for an additional 2 minutes. The powder mix was then

compressed into tablets using the instrumented tablet press, using a 7 mm

round punch. Tablets were collected during compression for in-process

testing (weight and hardness)

The tablets were then stored in airtight high density polyethylene

(HDPE) bottles until further testing.


71

Figure 9: Process flow chart for HPMC/Eudragit tablets manufactured by

direct compression

Weigh and screen through #25

mesh the following ingredients:

Active ingrident

HPMC K100LV and/or

Eudragit L100-55

Microcrystalline cellulose

Lactose N.F

Mix for 10 minutes in Turbula

Mixer

Screen through #25 mesh

Magnesium Stearate and

add to mix

Final Mixing for 2 minutes in

Turbula Mixer

Tablet compression by using 7

mm round punch


72

6.5.2. Preparation of Matrix Tablets Containing PVAP

The corresponding amounts of amounts of active ingredient (drug-

Diltiazem hydrochloride/Metoprolol succinate), PVAP, microcrystalline

cellulose, dibasic calcium phosphate dehydrate and colloidal silicon

dioxide were accurately weighed. The powders were sieved using screen

#25. The screened powders were then transferred into the turbula mixer jar

and mixed for 15 minutes. Magnesium stearate was accurately weighed,

sieved through screen #25 and added to the turbula jar and mixed for an

additional 3 minutes. The powder was then compressed into tablets using

the instrumented tablet press, using a 7 mm round punch. Tablets were

collected during compression for in-process testing (weight and hardness)

The tablets were then stored in airtight high density polyethylene

(HDPE) bottles until further testing.


73

Figure 10: Process flow chart for PVAP tablets manufactured by direct

compression

Weigh and screen through#25

mesh the following ingredients:

Active ingrident

PVAPand/or

Microcrystalline celluloseand/or

Dibasic calcium phosphate

dihydrateand/or

Colloidal silicon dioxide

Mix for 15 minutes in Turbula

Mixer

Screen through #25 mesh

Magnesium Stearate and

add to mix

Final Mixing for 3 minutes in

Turbula Mixer

Tablet compression by using 7

mm round punch


74

6.6. EVALUATION OF MATRIX TABLETS

6.6.1. Precompressional Studies95

Mixed powder were evaluated for various properties like bulk

density, tapped density, compressibility index, Hausner ratio, flow

properties (angle of repose) by using standard procedures. All studies

were carried out in triplicate (n=3) and average values are reported with

respective standard deviation.

6.6.1.1. Bulk Density and Tapped Density:

Both loose bulk density (LBD) and tapped bulk density (TBD) of

prepared granules were determined. A quantity of 10 gm of blend from

each formula, previously shaken to break any agglomerates formed

was introduced in to 50ml measuring cylinder. The initial volume was

noted, the cylinder was allowed to fall under its own weight on to a hard

surface from a height of 2.5 cm by using bulk densitometer. The

tapping was continued until no further change in volume was noted.

LBD and TBD were calculated using the following equations. (According

to the USP-NF Guidelines 100 gm of sample was taken. If it is not possible

to use 100 gm, the amount of the test sample and the volume of cylinder

may be modified).

LBD= Weight of the Granules/Untapped Volume of the packing

TBD=Weight of the Granules/Tapped Volume of the packing


75

6.6.1.2. Compressibility Index:

The Compressibility Index of the blend was determined by

Carr’s compressibility index. It is a simple test to evaluate the LBD and

TBD of a powder and the rate at which it is packed down. The formula for

Carr’s Index is as below:

Carr’s Index (%) = [(TBD-LBD) x100]/TB

Effects of Carr’s Index and Hausner’s ratio on flow property

Carr’s Index (%) Flow Character Hausner’s Ratio

< 10 Excellent 1.00-1.11

11-15 Good 1.12-1.18

16-20 Fair 1.19-1.25

21-25 Passable 1.26-1.34

26-31 Poor 1.35-1.45

32-37 Very poor 1.46-1.59

>38 Very, very poor 1.60

6.6.1.3. Hausner’s Ratio:

Hausner’s Ratio was determined by Following Equation

Hausner’s Ratio = Tapped Density / Bulk Density


76

6.6.1.4. Angle of repose:

Angle of repose was determined by measuring the height and radius

of the heap of the granules. A funnel was fixed to a stand and bottom of

the funnel was fixed at a height of 3 cm from the plane. Granules were

placed in funnel and allowed to flow freely and the height and radius of the

heap of granules was measured. Similar studies were carried out after

incorporating lubricants / glidants calculated using the equation.

tan θ = h /r

Where, h and r are the height and radius of the powder cone respectively.

Effect of Angle of repose (Ө) on flow property

Angle of Repose (Ө) Type of Flow

< 20 Excellent

20-30 Good

30-34 Passable

>35 Very poor

6.6.2. POST-COMPRESSIONAL STUDIES 95.97:

6.6.2.1. Hardness test:

It indicates the ability of a tablet to withstand mechanical shocks while

handling. Hardness of tablets was determined using a validated Monsanto

hardness tester. It is expressed in kg/cm2. Six tablets according to USP


77

Guidelines were randomly picked from each batch and analyzed for

hardness. The mean and standard deviation were also calculated.

6.6.2.2. Weight variation test:

According to USP-NF twenty tablets were selected randomly from

each batch and weighed individually to check for weight variation. The

specifications for weight variation and percentage deviation mentioned in

U.S. Pharmacopoeia are given in Table.

Limits for Weight Variation

Average weight of a

tablet

(mg) (IP Limit)

Percentage

deviation

Average weight of a tablet

(mg) (USP Limit)

80 or less 10 130 mg or less

80 to 250 7.5 More than 130 mg and

less than 324 mg

More than 250 5 324 mg or more

6.6.2.3. Friability test:

Roche friabilator was used for friability test. According to IP

guidelines Pre weighed tablet(WInitial) sample (20 tablets) were placed in

the friabilator apparatus and rotated at 25 rpm for a period of 4 min.

Tablets were again weighed (W final) and the percentage weight loss in

tablet was determined using formula:


78

𝐹𝑟𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦 =𝐼𝑛𝑡𝑖𝑎𝑙 𝑡𝑎𝑏𝑙𝑒𝑡 𝑤𝑒𝑖𝑔ℎ𝑡 − 𝐹𝑖𝑛𝑎𝑙 𝑇𝑎𝑏𝑙𝑒𝑡 𝑤𝑒𝑖𝑔ℎ𝑡

𝐼𝑛𝑡𝑖𝑎𝑙 𝑇𝑎𝑏𝑙𝑒𝑡 𝑤𝑒𝑖𝑔ℎ𝑡× 100

% Friability of tablets less than 1% are considered acceptable.

6.6.3. DRUG CONTENT:

6.6.3.1. Drug Content of Matrix Tablet Containing Diltiazem

Hydrochloride:

a) Standard Solution:

100 mg of pure drug was weighed accurately and dissolved in 5 ml

of distilled water. A sufficient quantity of distilled water was added to

produce 100 ml and mixed well. From this 1 ml taken and distilled water

was added to produce 100 ml.

b) Sample Solution:

20 tablets were weighed accurately and finely powdered. To powder

equivalent to 100 mg of Diltiazem hydrochloride, 15 ml of distilled water

was added and dispersed with the aid of shaker for 15 minutes. Sufficient

quantity of distilled water was added to produce 100 ml, mixed well and

filtered. To 1 ml of the filtrate distilled water was added to produce 100 ml

and mixed well. The absorbance of the resulting solution was measured at

the 237 nm using blank in the reference cell. The total content of diltiazem

hydrochloride in the solution was calculated using the absorbance of a

standard solution. The above test was done in triplicate.


79

Drug content was determined by crushing the tablet in a glass

mortar and pestle and extracting the drug in phosphate buffer pH 7.4 with

continuous shaking on a rotary shaker (Remi instruments Ltd, Mumbai,

India) for 24 h. The drug content in extracted fluid was analyzed using a

UV-Spectrophotometer (UV- 1601, Shimadzu, Japan) at 237nm against

suitable blank.

6.6.3.2. Drug Content of Matrix Tablet Containing Metoprolol

Succinate:

a) Standard Solution:

100 mg of pure drug was weighed accurately and dissolved in 5 ml

of distilled water. A sufficient quantity of distilled water was added to

produce 100 ml and mixed well. From this 1 ml taken and distilled water

was added to produce 100 ml.

b) Sample Solution:

20 tablets were weighed accurately and finely powdered. To powder

equivalent to 100mg of metoprolol succinate, 15 ml of distilled water was

added and dispersed with the aid of shaker for 15 minutes. Sufficient

quantity of distilled water was added to produce 100 ml, mixed well and

filtered. To 1 ml of the filtrate distilled water was added to produce 100 ml

and mixed well. The absorbance of the resulting solution was measured at

the 275 nm using blank in the reference cell. The total content of


80

metoprolol succinate in the solution was calculated using the absorbance

of a standard solution. The above test was done in triplicate.

Drug content was determined by crushing the tablet in a glass

mortar and pestle and extracting the drug in phosphate buffer pH 7.4 with

continuous shaking on a rotary shaker (Remi instruments Ltd, Mumbai,

India) for 24 h. The drug content in extracted fluid was analyzed using a

UV-Spectrophotometer (UV- 1601, Shimadzu, Japan) at 275nm against

suitable blank.

6.6.4. IN VITRO DISSOLUTION STUDY OF MATRIX TABLET:

6.6.4.1. Dissolution Studies of matrix tablet containing Diltiazem

Hydrochloride98,99:

To understand the release profiles of the drug from the tablets,

dissolution experiments were performed in simulated gastric (0.1 N HCl,

i.e., pH 1.2) and intestinal (pH 7.4) conditions. The release of Diltiazem

hydrochloride from the tablet was studied using USP XXIII paddle

apparatus (Electrolab). Drug release profile was carried out in 750 ml of

0.1N HCl for 2 h and then in 900 ml of phosphate buffer solution (PBS) pH

7.4 maintained at 37 ± 0.5˚C and 100 rpm. Ten ml of samples were

withdrawn at predetermined time intervals of every 1 h up to 12 h. The

samples were replaced by its equivalent volume of dissolution medium and

were filtered through 0.45 μm whatman filter paper and assayed at 237 nm


81

by UV spectrophotometer (Evolution 201, UV-visible spectrophotometer,

Thermo Fisher Scientific, USA).

Dissolution studies of the marketed product:

Dissolution studies were performed for marketed (DILZEM SR) tablet

of Diltiazem Hydrochloride and compared with optimized formulation.

6.6.4.2. Dissolution Studies of matrix tablet containing Metoprolol

Succinate100, 101,102,103:

Dissolution studies for tablets were performed in simulated gastric

(0.1 N HCl) and intestinal (pH 7.4) conditions. The release of Metoprolol

Succinate from the tablet was studied using USP XXIII paddle apparatus

(Electrolab). Dissolution study was carried out in 750 ml of 0.1N HCl for

initial 2hr and then in 900ml of phosphate buffer solution (PBS) pH 7.4

maintained at 37 ± 0.5˚C and 100rpm.Ten ml of samples was withdrawn at

predetermined time intervals for every 1 h up to 12 h and replaced with

equal volume of dissolution medium. Samples withdrawn were filtered

through 0.45 μm whattman filter paper and analysed at 275 nm by UV

spectrophotometer (Evolution 201, UV-visible spectrophotometer, Thermo

Fisher Scientific, USA).

Dissolution studies of the marketed product:

Dissolution studies were performed for marketed (MetaXL) tablet of

metoprolol succinate.


82

6.6.5. f2Similarity Facto: 104,105,106

Different dissolution profiles were compared to establish the effect of

formulation or process variables on the drug release. The dissolution

similarity was assessed using f2 similarity factor. The similarity factor is a

logarithmic reciprocal square root transformation of the sum of squared

errors, and it serves as a measure of the similarity of two respective

dissolution profiles

𝑓2. = 50. log {[1 +1

𝑛] ∑ 𝑛

𝑡=1 ( 𝑅𝑡 − 𝑇𝑡 )2]−0.5 . 100}

Where;

n = number of sample points

Rt = percent of marketed product release profile

Tt = percent of test formulations release observed

FDA has set a public standard of f2 value between 50-100 to

indicate similarity between two dissolution profiles. For extended release

products, the coefficients of variation for mean dissolution profile of a

single batch should be less than 10%. The average difference at any

dissolution sampling point should not be greater that 15% between the test

and the reference product.

6.6.6. Release Kinetics Study107,108,109,110

To analyze the mechanism for the drug release and drug release

rate kinetics of the dosage form, the data obtained was fitted in to Zero

order, First order, Higuchi matrix, Korsmeyer-Peppas and Hixson Crowell


83

model. In this by comparing the R-values obtained, the best-fit model was

selected.

i) Zero order kinetic model

Zero order describes the system where the release rate of drug is

independent of its concentration. The equation is

At = A0 + K0t

Where, At is the amount of drug dissolved in time t, A0 is the initial amount

of drug and K0 is the zero order release constant. This relationship

describe the dissolution of drug from modified release Pharmaceutical

dosage form like some transdermal system and matrix tablet with low

soluble drugs in coated forms.

ii) First order kinetic model

The dissolution phenomenon of a solid particle in a liquid media is because

of surface action and dependent on concentration of drug in reservoir.

𝐿𝑜𝑔𝑄𝑡 = 𝐿𝑜𝑔𝑄0 +𝐾1

2.303

Where, Qt is the amount of drug dissolved in time t, Q0 is the initial amount

of drug in the solution and K1 is the first order release constant. The plot of

log cumulative drug release vs. time yields a straight line with slope of-

K/2.303. This relationship describes the drug dissolution in pharmaceutical

dosage forms such as those containing water soluble drugs in porous

matrices.


84

iii) Higuchi matrix model

Higuchi describes drug release as a diffusion process based in the Fick’s

law, proportional to square root of time. This model is based on following

equation

𝑄 = 𝐾𝐻 √𝑡

Where, KH is the Higuchi dissolution constant.

iv) Hixson Crowell model

For this model to be valid drug powder should have uniformed size

particles. This model is based on equation which expresses rate of

dissolution based on cube root of weight of particles. This is expressed by

the equation,

M01/3 - Mt

1/3 = k t

Where, M0 is the initial mass of drug in the pharmaceutical dosage form, Mt

mass of powder dissolved in time ‘t’ and k cube root dissolution rate

constant. It evaluates the dissolution with changes in surface area.

v) Korsmeyer-Peppas model

Korsmeyer Peppas derived a simple relationship which describes drug

release from a polymeric system.

𝑄𝑡

𝑄∞

= 𝑘𝑡𝑛

Where Qt/Qαis fraction of drug dissolved at time t


85

K is constant includes structural and geometrical characteristics of

formulation

n= diffusion exponent which represent drug release mechanism

Where, n=1 signifies that release follows zero order kinetics

n=0.5 signifies that release is by fickian diffusion

0.5< n<1 signifies that release is through anomalous diffusion

6.6.7. STATISTICAL ANALYSIS

All the results were expressed as mean values ± standard deviation

(SD), unless otherwise specified elsewhere. The release rate constants,

calculated based on the best model, were compared using a single-factor

analysis of variance (ANOVA) with a Tukey post hoc test. The level of

statistical significance was chosen as less than 0.05(P<0.05). All data

analysis were performed using a Graph pad prism version 5 (Graph pad

prism Software, Inc).

6.6.8. Scanning Electron Microscopy (SEM) 111,112

In the pharmaceutical industry, SEM is used as a qualitative tool

for theanalysis of drug substance and drug product in order to obtain

information on the shape and surface structure of the material.

Procedure for SEM Analysis:

1) Dehydration: As with SEM high vacuum is requirement for image

formation and samples must be thoroughly desiccated before


86

entering the vacuum chamber, therefore samples were thoroughly

dried before analysis.

2) Mounting: The dried sample was attached to the brass sample

holder or stud using an adhesive substance.

3) Coating: Thin coating of an electron dense metal (gold) was

applied to the mounted sample using the JOEL JFC 110E Ion

Sputter which is having a vacuum chamber. The chamber was

evacuated using a rotary pump and an inert carrier gas, argon was

introduced to produce partial vacuum of 10-2 mmHg. The argon

atmosphere ionize by electrodes located near gold metal foil,

thereby heavy metal atoms were ejected from the foil, covering

the mounted sample with finely dispersed coating.

4) Imaging: The sample were removed from the Ion Sputter and

mounted on a sample holder and placed in a link analytical Electron

microscope column and scanned in a controlled raster pattern by an

electron beam Scanning Microscope These electrons were collected

with detector which produced three dimensional images of the

sample surface on TV screen attached to the microscope. The

images were printed on photographic film using at different

magnifications.


87

6.6.9. DIFFERENTIAL SCANNING CALORIMETRY (DSC) 113,114:

Differential Scanning Calorimetry (DSC) studies were carried out

using DSC 60, having TA60 software, Shimadzu, Japan. DSC is used to

evaluate melting point, enthalpy changes and glass transition temperatures

of drug with excipients and polymers. Active ingredient was mixed with the

excipients and the DSC analysis of each sample was done under the

analogous conditions of temperature range 40–450º C, heating rate

10ºC/min, nitrogen atmosphere (20ml/min) and alumina as reference.

6.6.10. IN VIVO X-RAY STUDIES: 115,116,117,118

In vivo X-ray studies were conducted to study the behavior of the

optimized formulation in New Zealand rabbits. In optimum formulation the

drug was replaced with barium sulfate. Healthy New Zealand rabbits

weighing 1.5–2 kg was used for the study. The matrix tablets were

administered by oral route through a stomach tube and flushing 15ml of

water from the syringe. The animals were held on a board. Radiographs

were obtained at 0, 1, 3, 6, 9 and up to 12 h. The X-ray parameters were

kept constant throughout. Permission was obtained from the Animal Ethics

Committee (CPCSEA/C/01/448/11-12/21, 22, 23, 24) for the use of

experimental animals prior to the experiment.


88

6.6.11. STABILITY STUDIES 119:

Stability studies were carried out as per ICH (Q1A (R2), 2003)

guidelines. The long term stability was carried out on optimized matrix

tablets at temperature and relative humidity (RH) conditions (25o C and 60

% RH) in stability chambers (Thermo lab, Mumbai, India) for 9 months.

Test samples were withdrawn every month and subjected to various tests

like weight, hardness, effect of storage on drug/active ingredient release

from optimized matrix tablets formulation.

RESULTS AND DISCUSSION

89

7. RESULTS AND DISCUSSION

7.1. ANALYSIS OF DRUG

7.1.1. Description:

Visual inspection of drug is done

Drug Description

Diltiazem

Hydrochloride

A white, odorless, crystalline powder and has a

bitter taste

Metoprolol Succinate It is a white crystalline powder.

7.1.2. Determination of melting point:

Melting point of Diltiazem Hydrochloride and Metoprolol Succinate were

determined by capillary method.

Drug Melting point

Diltiazem Hydrochloride 212 0C

Metoprolol Succinate 136 0C

7.1.3. Solubility:

Diltiazem hydrochloride was found to be soluble in water, formic

acid, methanol & chloroform. It was slightly soluble in ethanol.


90

Metoprolol succinate was found to be soluble in water; methanol;

sparingly soluble in ethanol; slightly soluble in dichloromethane; practically

insoluble in ethyl acetate, acetone, diethyl ether.

7.1.4. Fourier Transformed Infrared (FT-IR) Spectroscopic Analysis:

Figure 11: IR spectra of pure diltiazem hydrochloride

Ar-CH str. 3008.41 cm-1

CH3 str. 2838.7 cm-1

C=O str. (amide) 1685.48 cm-1

C=O str. (ester) 1743.33 cm-1

C-S-C str. 1373.07 cm-1

C-N-C str. 1226.5 cm-1

C-O-C str. 1029.8 cm-1


91

Figure 12: IR spectra of pure Metoprolol Succinate

NH str 3139.54 cm-1

Ar-CH str. 2992.98 cm-1

CH3 str. 2827.13 cm-1

OH str. 3671.8 cm-1

C-O-C str. 1049.09 cm-1

C=O str. 1704.76 cm-1


92

Figure 13: IR spectra of HPMCK 100LV

OHstr. 3240.76

CH2 str. 2865.54

C-O-C str 1056.76


93

Figure 14: IR spectra of Eudragit L100-55

CH2 str. 2711.42

C=O str. 1727.91

C-O-C str. 1022.09


94

Figure 15: IR spectra of Microcrystalline Cellulose

OH str 3289.96

CH2 str. 2904.27

C-O-C str. 1041.37


95

Figure 16: IR spectra of Lactose

OH str. 3252.16

CH2 str. 2900.41

C-O-C str. 1037.52


96

Figure 17: IR spectra of magnesium stearate

CH2 str. 2867.99

C=O str. 1720.19

C-O-C str. 1029.8


97

Figure 18: IR spectra of PVAP

CONH str 1654.62

C=O str 1751.05

CH2 str. 2861.84

C-O-C str 1022.09


98

Figure 19: IR spectra of dibasic calcium phosphate

OH str. 3270.68


99

Figure 20: IR spectra of colloidal silicon dioxide


100

7.2. COMPATIBILITY STUDIES:

7.2.1. Compatibility Study of matrix tablet containing HPMC, Eudragit.

7.2.1.1. Compatibility Study of HPMC, Eudragit matrix tablet Containing

Diltiazem Hydrochloride (FD11)


Ar-CH str. 3008.41 cm-1

CH3 str. 2838.7 cm-1



C-S-C str. 1373.07 cm-1

C-N-C str. 1226.5 cm-1

C-O-C str. 1029.8 cm-1


101

Figure 22: IR spectra of mixture of optimized formulation (FD11).

Ar-CH str. 2904.27cm-1

CH3 str. 2838.70 cm-1

C=O str. (amide) 1684.48cm-1

C=O str. (ester) 1748.65cm-1

C-S-C str. 1295.93cm-1

C-N-C str. 1222.65cm-1

C-O-C str. 1033.66cm-1


102

Drug excipients interactions were characterized by FTIR

spectroscopy studies, the FTIR spectrum of diltiazem hydrochloride and

drug with polymers mixture is shown in figure 21 and 22. The IR spectrum

of diltiazem hydrochloride showed characteristics peaks which confirm the

drug structure. IR spectrum of diltiazem hydrochloride pure, optimized

formulation (FD11) were taken, the IR spectra’s obtained indicates good

compatibility between drug and polymers. So, it was revealed that there

was not chemical incompatibility between the selected drug and polymers.


103

7.2.1.2. Compatibility Study of HPMC, Eudragit matrix tablets

Containing Metoprolol Succinate (FM11).


NH str 3139.54 cm-1

Ar-CH str. 2992.98 cm-1

CH3 str. 2827.13 cm-1

OH str. 3671.8 cm-1

C-O-C str. 1049.09 cm-1

C=O str. 1704.76 cm-1


104

Figure 24: IR spectra of mixture of drug (Metoprolol Succinate) and

polymer- FM11

NH str 3252.65cm-1


CH3 str. 2884.99cm-1

OH str. 3455.81cm-1

C-O-C str. 1045.23cm-1

C=O str. 1716.34cm-1

FT-IR spectrum of Metoprolol Succinate and drug with polymer

mixture is shown in figure 23 and 24. The IR spectrum of Metoprolol

Succinate shows the characteristic peaks which confirm the drug structure.


105

IR spectrum of Metoprolol Succinate and optimized formulation (FM11)

was recorded; the IR spectrum obtained indicates good compatibility

between drug and polymers. So, it was revealed that there was not a

chemical incompatibility between the selected drug and polymers.


106

7.2.2. Compatibility Study of matrix tablet containing PVAP.

7.2.2.1. Compatibility Study of PVAP matrix tablet containing



Ar-CH str. 3008.41 cm-1

CH3 str. 2838.7 cm-1



C-S-C str. 1373.07 cm-1

C-N-C str. 1226.5 cm-1

C-O-C str. 1029.8 cm-1


107

Figure 26: IR spectra of mixture of drug (Diltiazem Hydrochloride) and

polymers-FD17


CH3 str. 2846.42cm-1

C=O str. (amide) 1685.40cm-1

C=O str. (ester) 1743.33cm-1

C-S-C str. 1365.35cm-1

C-N-C str. 1249.55cm-1

C-O-C str. 1025.94cm-1


108

The IRSpectrum of diltiazem hydrochloride and drug with polymer

mixture is shown in figure 25 and 26. The FTIR spectrum of diltiazem

hydrochloride shows the characteristic peaks which confirm the drug

structure. FTIR spectrum of diltiazem hydrochloride and optimized

formulation (FD17) was recorded. An FTIR spectrum obtained indicates

good compatibility between drug and polymers. So, it was revealed that

there was not a chemical incompatibility between the selected drug and

polymers.


109

7.2.2.2. Compatibility Study of PVAP matrix tablet containing



NH str 3139.54 cm-1

Ar-CH str. 2992.98 cm-1

CH3 str. 2827.13 cm-1

OH str. 3671.8 cm-1

C-O-C str. 1049.09 cm-1

C=O str. 1704.76 cm-1


110

Figure 28: IR spectra of mixture of drug (Metoprolol Succinate) and

polymers -FM17

NH str 3174.26cm-1

Ar-CH str. 2996.84 cm-1

CH3 str. 2828.37 cm-1

OH str. 3405.67cm-1

C-O-C str. 1049.09cm-1

C=O str. 1697.05 cm-1


111

FTIR spectrum of Metoprolol Succinate and drug with polymers

mixture is shown in Figure 27 and 28. The IR spectrum of Metoprolol

Succinate shows the characteristic peaks, confirms the drug structure. IR

spectrum of Metoprolol Succinate and optimized formulation (FM17) was

recorded. FTIR spectra obtained indicate good compatibility between drug

and polymers. So, it was revealed that there was not a chemical

incompatibility between the selected drug and polymers.

7.3. DETERMINATION OF λ max :

7.3.1 Determination of λ max of Diltiazem Hydrochloride

The absorption maximum Diltiazem Hydrochloride was found to be

237 nm and this wavelength was selected and utilized for further studies.

7.3.2 Determination of λ max of Metoprolol Succinate

The absorption maximum of Metoprolol Succinate was found to be

275 nm and this wavelength was selected and utilized for further studies.


112

7.4. PREPARATION OF CALIBRATION CURVE

7.4.1. Preparation of Calibration Curve of Diltiazem Hydrochloride

a) In Distilled water

Table No 11: Absorbance values for Diltiazem Hydrochloride in distilled

water

Sr. No. Concentration in mcg/ml Absorbance mean ± SD*(237nm)

1 0 0

2 2 0.116±0.004

3 4 0.216±0.002

4 6 0.318±0.001

5 8 0.418±0.001

6 10 0.519±0.000

Standard deviation n=3

Figure No.29: Standard graph of Diltiazem Hydrochloride in distilled water

y = 0.0515x + 0.0071R² = 0.9994

0

0.1

0.2

0.3

0.4

0.5

0.6

0 2 4 6 8 10 12

Ab

so

rba

nc

e /

AU

C

Concentration

Calibration Curve


113

b) In 0.1 N HCl

Table No 12: Absorbance values of Diltiazem Hydrochloride in 0.1 N HCl

Sr. No. Concentration in mcg/ml Absorbance mean ± SD*

(237nm)

1 0 0

2 2 0.116±0.002

3 4 0.224±0.003

4 6 0.332±0.004

5 8 0.434±0.001

6 10 0.536±0.001


Figure No 30: Standard graph of Diltiazem Hydrochloride in 0.1 N HCl

y = 0.0535x + 0.0064R² = 0.9994

0

0.1

0.2

0.3

0.4

0.5

0.6

0 2 4 6 8 10 12

Ab

so

rba

nc

e /

AU

C

Concentration

Calibration Curve


114

c)In pH 7.4 phosphate buffer

Table No.13: Absorbance values of Diltiazem Hydrochloride in pH 7.4

phosphate buffer

Sr. No. Concentration in mcg/ml Absorbance mean ± SD*(237nm)

1 0 0

2 2 0.116 ± 0.001

3 4 0.226 ± 0.002

4 6 0.338 ± 0.001

5 8 0.452 ± 0.003

6 10 0.558 ± 0.000


Figure No.31: Standard graph of Diltiazem Hydrochloride in pH 7.4

phosphate buffer

y = 0.0559x + 0.0024R² = 0.9999

0

0.1

0.2

0.3

0.4

0.5

0.6

0 2 4 6 8 10 12

Ab

so

rba

nc

e /

AU

C

Concentration

Calibration Curve


115

7.4.2. Preparation of Calibration Curve of Metoprolol Succinate:

a) In Distilled water

Table No. 14: Absorbance values of Metoprolol Succinate in distilled water

Sr. No. Concentration in mcg/ml Absorbance mean ± SD*(275 nm)

1 0 0

2 2 0.067 ± 0.002

3 4 0.134 ± 0.001

4 6 0.205 ± 0.003

5 8 0.268 ± 0.004

6 10 0.331 ± 0.000


Figure No 32: Standard graph of Metoprolol Succinate in distilled water

y = 0.0333x + 0.0011R² = 0.9996

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 2 4 6 8 10 12

Ab

so

rba

nc

e /

AU

C

Concentration

Calibration Curve


116

b) In 0.1 N HCls

Table No 15: Absorbance values of Metoprolol Succinate in0.1 N HCl


(275 nm)

1 0 0

2 2 0.063 ± 0.003

3 4 0.12 ± 0.002

4 6 0.176 ± 0.002

5 8 0.231 ± 0.001

6 10 0.283 ± 0.002


Figure No 33: Standard graph of Metoprolol Succinate in 0.1 N HCl

y = 0.0282x + 0.0044R² = 0.9991

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 2 4 6 8 10 12

Ab

so

rba

nc

e /

AU

C

Concentration

Calibration Curve


117

c) In pH 7.4 phosphate buffer

Table No 16: Standard graph of Metoprolol Succinate in pH 7.4 phosphate

buffer


(275 nm)

1 0 0

2 2 0.057 ± 0.004

3 4 0.108 ± 0.002

4 6 0.158 ± 0.001

5 8 0.219 ±0.003

6 10 0.266 ±0.002


Figure No 34: Standard graph of Metoprolol Succinate in pH 7.4

phosphate buffer

y = 0.0267x + 0.0014R² = 0.9992

0

0.05

0.1

0.15

0.2

0.25

0.3

0 2 4 6 8 10 12

Ab

so

rba

nc

e /

AU

C

Concentration

Calibration Curve


118

7.5. EVALUATION OF MATRIX TABLETS:

7.5.1 Evaluation of pre-compression parameters of HPMC and


7.5.1.1 Evaluation of pre-compression parameters of HPMC, Eudragit

SR Matrix Tablet Containing Diltiazem Hydrochloride.

Table No. 17: Pre-compression evaluation of Formulated HPMC, Eudragit

Matrix Tablet.

Formul-

ation

Bulk

Density*

(g/Cm3)

Tapped

Density*

(g/Cm3)

Compressib-

ility

Index* (%)

Hausner

Ratio*

Angle of

Repose*(O)

FD1 0.517±0.004 0.564±0.004 8.33±0.021 1.09±0.08 23.62±0.12

FD2 0.510±0.003 0.555±0.002 8.10±0.022 1.08±0.07 23.89±0.26

FD3 0.513±0.006 0.575±0.007 10.78±0.026 1.12±0.10 22.84±0.62

FD4 0.521±0.006 0.564±0.004 7.62±0.020 1.08±0.07 25.64±0.21

FD5 0.500±0.002 0.553±0.002 9.58±0.024 1.10±0.10 21.58±0.15

FD6 0.526±0.004 0.555±0.002 5.22±0.018 1.05±0.05 22.46±0.21

FD7 0.490±0.003 0.565±0.004 13.27±0.031 1.15±0.10 23.76±0.10

FD8 0.516±0.005 0.567±0.004 8.99±0.022 1.09±0.08 25.26±0.20

FD9 0.526±0.006 0.572±0.005 8.04±0.021 1.08±0.07 24.29±0.32

FD10 0.515±0.004 0.566±0.004 9.01±0.022 1.09±0.08 26.48±0.12

FD11 0.515±0.003 0.573±0.005 10.12±0.026 1.11±0.10 22.15±0.21

FD12 0.494±0.004 0.576±0.007 14.23±0.031 1.16±0.11 24.35±0.23

*mean (n = 3)


119

Results of the pre-compression parameters performed on the blend

for batch FD1 to FD12 are reported in Table No 17. The angle of repose of

all the formulations was in the range of 21.580 ± 0.15 to 26.480 ± 0.12. The

Compressibility Index for all formulations was in range of 5.22 to 14.23%,

bulk density 0.490 to 0.526 g/cm3. The angle of repose for all formulations

was < 30 indicating good flow properties of the powder. This was further

supported by lower compressibility index values. Compressibility index

values up to 15% results in good to excellent flow properties


120

7.5.1.2 Evaluation of pre-compression parameters of HPMC and

Eudragit Matrix Tablet containing Metoprolol succinate

Table No 18: Pre-compression evaluation of Formulated HPMC, Eudragit

Matrix Tablet.

Formul-

ation

Bulk

density*

(g/cm3)

Tapped

Density*

(g/cm3)

Compress-

ibility

Index* (%)

Hausner’s

Ratio*

Angle of

Repose* (o)

FM1 0.466±0.003 0.494±0.005 5.66±0.012 1.06±0.07 25.37±0.023

FM2 0.446±0.002 0.471±0.003 5.30±0.011 1.05±0.04 26.33±0.024

FM3 0.497±0.004 0.531±0.007 6.40±0.018 1.06±0.07 23.69±0.013

FM4 0.477±0.003 0.508±0.005 5.73±0.015 1.06±0.07 24.13±0.022

FM5 0.458±0.002 0.486±0.004 5.76±0.015 1.06±0.07 24.54±0.011

FM6 0.469±0.004 0.497±0.005 5.63±0.014 1.05±0.04 27.61±0.030

FM7 0.458±0.003 0.485±0.003 5.56±0.013 1.05±0.04 19.09±0.020

FM8 0.465±0.004 0.492±0.005 5.48±0.011 1.05±0.04 23.73±0.014

FM9 0.442±0.003 0.467±0.003 5.35±0.012 1.05±0.04 24.76±0.010

FM10 0.434±0.002 0.458±0.003 5.24±0.011 1.05±0.04 26.55±0.013

FM11 0.458±0.005 0.485±0.003 5.56±0.011 1.05±0.04 19.09±0.020

FM12 0.428±0.003 0.451±0.003 5.09±0.010 1.05±0.04 27.46±0.011

*mean (n = 3)

The results of the pre-compression parameters performed on the

blend for batch FM1 to FM12 are reported in Table No 18. The angle of

repose all the formulations was in the range of 19.090±0.020 to 27.610 ±


121

0.030. The Compressibility Index for all formulations was in range of 5.09

to 6.40%, bulk density 0.428-0.497g/cm3. The angle of repose for all

formulations was < 30 indicating good flow properties of the powder. This

was further supported by lower compressibility index values.

Compressibility index values up to 15% results in good to excellent flow

properties.


122

7.5.2. Evaluation of pre-compression parameters of PVAP Matrix

Tablet

7.5.2.1. Evaluation of pre-compression parameters of PVAP SR Matrix

Tablet containing Diltiazem Hydrochloride

Table No. 19: Pre-compression evaluation of Formulated PVAP SR Matrix

Tablet

Formu-

lation

Bulk

density*

(g/cm3)

Tapped

Density*

(g/cm3)

Compress-

ibility

Index* (%)

Hausner

Ratio*

Angle of

Repose*

(o)

FD13 0.526±0.006 0.555±0.004 5.22±0.010 1.05±0.04 22.46±0.21

FD14 0.490±0.003 0.565±0.006 13.27±0.230 1.15±0.09 23.76±0.10

FD15 0.516±0.005 0.567±0.004 8.99±0.015 1.09±0.07 25.26±0.20

FD16 0.526±0.006 0.572±0.007 8.07±0.013 1.12±0.08 24.29±0.32

FD17 0.513±0.003 0.575±0.008 10.95±0.024 1.12±0.06 22.84±0.62

FD18 0.513±0.003 0.575±0.008 10.78±0.020 1.12±0.06 22.84±0.62

FD19 0.521±0.004 0.564±0.006 7.62±0.010 1.08±0.05 25.64±0.21

FD20 0.500±0.003 0.553±0.003 9.58±0.024 1.10±0.07 21.58±0.15

FD21 0.526±0.005 0.555±0.003 5.22±0.010 1.05±0.04 22.46±0.21

FD22 0.490±0.002 0.565±0.004 13.27±0.231 1.15±0.08 23.76±0.10

*mean (n = 3)


123


for batch FD13 to FD 22 are reported in Table No19. The angle of repose

all the formulations were in the range of 21.580 ± 0.15 to 25.640 ± 0.20.

The Compressibility Index for all formulation was in range of 5.22 to

13.27%, bulk density 0.490 to 0.526g/cm3. The angle of repose for all

formulations was < 30 indicating good flow properties of the powder. This

was further supported by lower compressibility index values.

Compressibility index values up to 15% results in good to excellent flow

properties


124

7.5.2.2 Evaluation of pre-compression parameters of PVAP SR Matrix

Tablet Containing Metoprolol succinate

Table No. 20: Pre-compression evaluation of Formulated PVAP SR Matrix

Tablet

Formul-

ation

Bulk

density*

(g/cm3)

Tapped

Density*

(g/cm3)

Compress-

ibility

Index* (%)

Hausner’s

Ratio*

Angle of

Repose* (o)

FM13 0.458±0.004 0.485±0.003 5.56±0.011 1.05±0.02 19.09±0.020

FM14 0.465±0.003 0.492±0.004 5.48±0.011 1.05±0.02 23.73±0.014

FM15 0.442±0.002 0.467±0.003 5.35±0.010 1.05±0.03 24.76±0.010

FM16 0.434±0.004 0.458±0.003 5.24±0.009 1.05±0.02 26.55±0.013

FM17 0.497±0.003 0.531±0.005 6.40±0.015 1.06±0.04 23.69±0.013

FM18 0.477±0.004 0.508±0.004 6.10±0.013 1.06±0.04 24.13±0.022

FM19 0.458±0.005 0.486±0.004 5.76±0.013 1.06±0.04 24.54±0.011

FM20 0.466±0.005 0.494±0.004 5.66±0.012 1.06±0.04 25.37±0.023

FM21 0.446±0.004 0.471±0.003 5.30±0.010 1.05±0.03 26.33±0.024

FM22 0.469±0.006 0.497±0.004 5.63±0.011 1.05±0.02 27.61±0.030

*mean (n = 3)


for batch FM13 to FM 22 are reported in Table No 20. The angle of repose

all the formulations was in the range of19.09 ± 0.020 to27.61 ± 0.030. The

Compressibility Index for all formulation was in range of 5.24 to 6.40%,


125

bulk density 0.434 to 0.477g/cm3. The angle of repose for all formulations

was < 30 indicating good flow properties of the powder. This was further

supported by lower compressibility index values. Compressibility index

values up to 15% results in good to excellent flow properties


126

7.6. POST-COMPRESSIONAL STUDIES

7.6.1. Evaluation of Post-compression parameters of HPMC and


7.6.1.1 Evaluation of Post-compression parameters of HPMC and

Eudragit Matrix Tablet Containing Diltiazem Hydrochloride.

Table No.21: Post-compression evaluation of Formulated HPMC, Eudragit

SR MatrixTablet.

Formul-

ation

Hardness*

(kg/cm2)

Weight

Variation*(mg)

Friability*

%

Content

Uniformity (%)

FD1 5.0 ± 0.04 449 ± 2.57 0.80 ± 0.02 98.6 ± 0.05

FD2 5.2 ± 0.05 449 ± 2.28 0.51 ± 0.03 99.5 ± 0.03

FD3 5.2 ± 0.08 448 ± 3.57 0.43 ± 0.02 99.5 ± 0.02

FD4 5.4 ± 0.04 446 ± 2.39 0.42 ± 0.03 97.7 ± 0.03

FD5 4.6 ± 0.04 439 ± 2.13 0.38 ± 0.01 98.5 ± 0.03

FD6 4.8 ± 0.04 441 ± 2.58 0.45 ± 0.01 99.1 ± 0.01

FD7 4.8 ± 0.05 440 ± 2.30 0.30 ± 0.03 98.9 ± 0.07

FD8 5.2 ± 0.08 431 ± 2.58 0.38 ± 0.01 99.0 ± 0.04

FD9 5.2 ± 0.08 449 ± 2.57 0.28 ± 0.01 99.4 ± 0.02

FD10 5.2 ± 0.05 439 ± 2.30 0.40 ± 0.03 99.6 ± 0.02

FD11 5.2 ± 0.07 450 ± 2.47 0.38 ± 0.01 99.8 ± 0.03

FD12 5.4 ± 0.04 439 ± 2.13 0.84 ± 0.02 98.8 ± 0.04

Marketed

(DILZEM SR) 5.0 ± 0.08 188 ± 2.57 0.28 ± 0.01 99.4 ± 0.02

*mean (n = 3)


127

Matrix tablets of diltiazem hydrochloride were prepared by the dry

granulation method and subjected to different evaluation tests reported in

table No.21. As per IP, drug content of each tablet should be in the range

of 90-110% of the theoretical label claim. All formulations showed good

uniformity in drug content and the percentage of drug content was 97.7 ±

0.03 to 99.8 ± 0.03 %. Tablets hardness for all formulations were in the

range of 4.6 ± 0.04 to 5.4 ± 0.04 kg/cm2.Theformulation (FD5 to FD8)

containing only Eudragit had low tablet hardness values of ranging from 4.6

± 0.04kg/cm2 with 10% level to 5.2 ± 0.08 kg/cm2 with 60% Eudragit

level.

The formulations containing only HPMC(FD1 to FD4) at 10 to 60%

levels generated tablets with hardness valuesof 5.0 ± 0.04 kg/cm2 to 5.4

± 0.04 kg/cm2 respectively. The hardness of tablets containing only HPMC

was higher than that of tablets containing only Eudragit. The higher

hardness of HPMCK100LV is the result of relatively low methoxy and also

the high moisture content resulting in stronger hydrogen bonds lets.

For all the prepared formulations, friability percentage was less than

1% and results were in acceptable limit. For tablets weighing more than

250 mg, 5% deviation from the mean weight is acceptable. The average

weight variation percentage of 20 tablets taken from each formulation was

less than ±0.5%.


128

7.6.1.2 Evaluation of post-compression parameters of HPMC &

Eudragit Matrix Tablet Containing Metoprolol Succinate.

Table No. 22: Post-compression evaluation of Formulated HPMC, Eudragit

SR MatrixTablet

Formulation Hardness*

(kg/cm2)

Weight

Variation*(mg)

Friability*

%

Content

Uniformity* (%)

FM1 4.8 ±0.15 240±0.04 0.75 ±0.01 99.60±0.05

FM2 4.8 ±0.31 239±0.17 0.88 ±0.02 99.20±0.05

FM3 4.8 ±0.15 240±0.41 0.82 ±0.03 99.40±0.03

FM4 5.0 ±0.31 242±0.17 0.85 ±0.01 98.80±0.06

FM5 4.4 ±0.15 240±0.19 0.76 ±0.02 99.10±0.08

FM6 4.6 ±0.31 241±0.05 0.72 ±0.03 99.20±0.41

FM7 4.2 ±0.24 242±0.12 0.71 ±0.04 99.00±0.17

FM8 4.4 ±0.11 241±0.06 0.68 ±0.05 99.60±0.17

FM9 5.0 ±0.21 239±0.07 0.55 ±0.02 99.10±0.05

FM10 4.2 ±0.13 241±0.05 0.81 ±0.02 99.70±0.06

FM11 4.6 ±0.10 240±0.05 0.77 ±0.01 99.60±0.21

FM12 4.4 ±0.16 240±0.06 0.67 ±0.01 99.10±0.25

Marketed

(Meta XL 50) 4.8 ±0.31 285±0.05 0.72 ±0.03 99.00±0.41

*mean (n = 3)


129

Matrix tablets of Metoprolol succinate were prepared by the dry


table No.22. As per USP, drug content of each tablet should be in the

range of 85-115% of the theoretical label claim(47.50 mg/tablet).All

formulations showed good uniformity in drug content and the percentage of

drug content was 98.80±0.06 to 99.70±0.06 %. Tablets hardness for all

formulations was in the range of 4.2 ±0.13to 5.0 ±0.31kg/cm2.

The formulation (FM5 to FM8) containing only Eudragit had low tablet

hardness values of ranging from4.4 ±0.15 kg/cm2 with10% level to 4.4

±0.11 kg/cm2 with 60% Eudragit level.

The formulations containing only HPMC (FM1 to FM4) at 10 to 60%

levels generated tablets with hardness values of 4.8 ±0.15 kg/cm2 to 5.0

±0.31 kg/cm2 respectively.

The hardness of tablets containing only HPMC was higher than

that of tablets containing only Eudragit.


1% and was in acceptable limit. For tablets weighing more than 130 mg,

7.5% deviation from the mean weight is acceptable. As the result shows,

the average weight deviation percentage of 20 tablets taken from each

formulation was less than ±7.5%, and all the formulations met the

requirement.


130

7.6.2 Evaluation of Post-compression parameters of PVAP Matrix

Tablet

7.6.2.1 Evaluation of Post-compression parameters of PVAP Matrix

Tablet Containing Diltiazem Hydrochloride.

Table No. 23: Post-compression evaluation of Formulated PVAP SR

Matrix Tablet.

Formu-

lation

Hardness*

(kg/cm2)

Weight

Variation*(mg)

Friability*

(%)

Content

Uniformity* (%)

FD13 5.2 ± 0.04 441 ± 2.58 0.45 ± 0.01 98.1 ± 0.01

FD14 4.8 ± 0.04 440 ± 2.30 0.30 ± 0.03 99.4 ± 0.02

FD15 2.2 ± 0.08 431 ± 2.58 All Capped 99.4 ± 0.02

FD16 5.4 ± 0.08 449 ± 2.57 0.28 ± 0.01 99.4 ± 0.02

FD17 5.4 ± 0.08 449 ± 2.58 0.28 ± 0.01 99.4 ± 0.02

FD18 4.6 ± 0.04 449 ± 2.57 0.80 ± 0.02 99.4 ± 0.02

FD19 5.0 ± 0.04 449± 2.28 0.51 ± 0.03 97.7 ± 0.03

FD20 5.2 ± 0.05 448 ± 3.57 0.43 ± 0.02 99.4 ± 0.02

FD21 2.8 ± 0.07 446 ± 2.39 All Capped 99.4 ± 0.02

FD22 4.8 ± 0.05 430 ± 2.13 0.38 ± 0.01 99.2 ± 0.03

Marketed

DILZEM SR 5.0 ± 0.08 188 ± 2.57 0.28 ± 0.01 99.4 ± 0.02

*mean (n = 3)


131

Matrix tablets of diltiazem hydrochloride were prepared by the dry


table No.23. As per IP, drug content of each tablet should be in the range

of 90-110% of the theoretical label claim. All the formulations showed good

uniformity in drug content and the percentage of drug content was 98.1 ±

0.01 to 99.4 ± 0.02 %. Tablets hardness for all formulations were in the

range of 2.2 ± 0.08 to 5.4 ± 0.08 kg/cm2.The matrix tablet formulation

(FD13 & FD19)which contains PVAP polymer greater than 50% showed

high tablet hardness 5.2 ± 0.04 kg/cm2 and 5.0 ± 0.04 kg/cm2 respectively.

The matrix tablet formulation (FD14 & FD20)which contains

microcrystalline cellulose polymer greater than 50% ,showed high tablet

hardness 4.8 ± 0.04 kg/cm2 and 5.2 ± 0.05 kg/cm2 respectively.

The matrix tablet formulation (FD15 & FD21)which contains dibasic

calcium phosphate dehydrate greater than 50%, showed low tablet

hardness 2.2 ± 0.08 kg/cm2 and 2.8 ± 0.07 kg/cm2 respectively. The

formulation FD15 and FD21 showed capping of the tablets


1% (except formulation FD15 &FD21) and was in the acceptable range.

For tablets weighing more than 250 mg, 5% deviation from the mean

weight is acceptable. As the results shows, the average weight deviation

percentage of 20 tablets taken from each formulation was less than ±0.5%.


132

7.6.2.2. Evaluation of post-compression parameters of PVAP Matrix

Tablet Containing Metoprolol Succinate.

Table No. 24: Post-compression evaluation of Formulated PVAP SR Matrix

Tablet.

Formulation Hardness*

(kg/cm2)

Weight

Variation*(mg)

Friability*

(%)

Content

Uniformity * (%)

FM13 4.8 ±0.31 239±0.05 0.72 ±0.03 98.70±0.41

FM14 4.8 ±0.15 240±0.12 0.71 ±0.04 99.70±0.17

FM15 1.8 ±0.31 241±0.06 All Capped 99.60±0.17

FM16 4.8 ±0.21 240±0.07 0.55 ±0.02 98.90±0.05

FM17 4.2 ±0.13 240±0.05 0.81 ±0.02 99.70±0.06

FM18 4.4 ±0.15 241±0.04 0.75 ±0.01 99.30±0.05

FM19 4.6 ±0.11 241±0.17 0.88 ±0.02 98.80±0.05

FM20 4.2 ±0.24 242±0.41 0.82 ±0.03 99.40±0.03

FM21 4.4 ±0.11 240±0.17 All Capped 99.30±0.06

FM22 4.0 ±0.15 240±0.19 0.76 ±0.02 99.20±0.08

Marketed

(MetaXL 50) 4.8±0.31 285±0.05 0.72 ±0.03 98.80±0.41

*mean (n = 3)


133

Matrix tablets of Metoprolol succinate were prepared by the dry


table No.24. Based on USP, drug content of each tablet should be in the

range of 85-115% of the theoretical label claim (47.5 mg/tablet). All the

formulations showed good uniformity in drug content and the percentage of

drug content was 98.70±0.41 to 99.70±0.17 %. Tablets hardness for all

formulations was in the range of 1.8 ±0.31 to 4.8 ±0.31 kg/cm2.

The matrix tablet formulation (FM13 & FM19) which contains PVAP

polymer greater than 50% showed high tablet hardness 4.8 ±0.31kg/cm2

and 4.6 ±0.11kg/cm2 respectively. The formulation (FM14 & FM20) which

contains microcrystalline cellulose polymer greater than 50%, showed high

tablet hardness 4.8 ±0.15kg/cm2 and 4.2 ±0.24kg/cm2 respectively.

The matrix tablet formulation (FM15 & FM21) which contains dibasic

calcium phosphate dehydrate greater than 50%, showed low tablet

hardness1.8 ±0.31 kg/cm2 and4.4 ±0.11kg/cm2 respectively. The

formulation FM15 & FM21 showed capping of the tablets.


1% (except formulation FM15 and FM21), and was in the acceptable

range. For tablets weighing more than 130 mg, 7.5% deviation from the

mean weight is acceptable. The average weight deviation percentage of

20tablets taken from each formulation was less than ±7.5%, and all the

formulations met the requirement


134

DISSOLUTION STUDIES OF MATRIX TABLET:

7.7.1 Dissolution Studies of matrix tablet containing HPMC, Eudragit.

7.7.1.1 Dissolution Studies of matrix tablet of HPMC, Eudragit containing Diltiazem Hydrochloride.

Table No.25: Mean cumulative % drug release of all formulation of HPMC, Eudragit containing Diltiazem

Hydrochloride .

Time

(HRS)

Mean Cumulative % Drug Release of all Formulation (Mean SD, n=3)

Formulation

FD1 FD2 FD3 FD4 FD5 FD6 FD7 FD8 FD9 FD10 FD11 FD12 M k d

1 96.4±0.46 52.2±0.28 20.22±0.80 16.23±0.78 98.1±0.45 65.5±0.79 79.06±0.46 60.44±0.40 94.4±0.40 75.24±0.22 28.10±0.24 18.25±0.14 26.25±0.35

2 98.4±0.79 82.2±0.90 30.12±0.10 22.26±0.36 98.1±0.64 84.68±0.13 90.14±0.68 73.2±0.66 96.5±0.29 87.2±0.42 42.38±0.03 26.27±0.71 38.12±0.19

3 98.4±0.40 90.2±0.85 38.21±0.19 31.63±0.16 98.1±0.64 90.7±0.48 98.4±0.80 80.6±0.93 98.4±0.69 94.5±0.83 53.47±0.68 34.62±0.33 48.26±0.71

4 98.4±0.40 94.6±0.92 50.14±0.69 39.67±0.92 98.1±0.64 94.7±0.32 98.4±0.80 86.1±0.01 98.4±0.69 95.6±0.57 62.52±0.02 42.64±0.10 58.16±0.87

5 98.4±0.40 97.1±0.66 60.23±0.03 44.76±0.35 98.1±0.64 96.6±0.06 98.4±0.80 88.2±0.14 98.4±0.69 97.2±0.45 71.97±0.84 48.77±0.25 68.22±0.62

6 98.4±0.40 99.1±0.53 67.92±0.05 52.9±0.14 98.1±0.64 98.2±0.65 98.4±0.80 94.1±0.58 98.4±0.69 99.0±0.24 78.48±0.65 54.9±0.02 76.95±0.46

7 98.4±0.40 99.1±0.53 78.44±0.19 60.25±0.57 98.1±0.64 98.2±0.65 98.4±0.80 98.1±0.55 98.4±0.69 99.0±0.24 84.87±0.23 62.24±0.84 84.40±0.70

8 98.4±0.40 99.1±0.53 83.8±0.29 66.15±0.78 98.1±0.64 98.2±0.65 98.4±0.80 98.1±0.55 98.4±0.69 99.0±0.24 89.89±0.60 69.16±0.04 90.79±0.39

9 98.4±0.40 99.1±0.53 90.43±0.12 73.65±0.84 98.1±0.64 98.2±0.65 98.4±0.80 98.1±0.55 98.4±0.69 99.0±0.24 95.13±0.20 74.67±0.94 94.44±0.32

10 98.4±0.40 99.1±0.53 97.35±0.83 80.16±0.04 98.1±0.64 98.2±0.65 98.4±0.80 98.1±0.55 98.4±0.69 99.0±0.24 96.6±0.38 80.2±0.87 96.38±0.73

11 98.4±0.40 99.1±0.53 98.43±0.31 82.14±0.34 98.1±0.64 98.2±0.65 98.4±0.80 98.1±0.55 98.4±0.69 99.0±0.24 98.32±0.51 82.15±0.88 98.46±0.34

12 98.4±0.40 99.1±0.53 99.22±0.89 84.18±0.85 98.1±0.64 98.2±0.65 98.4±.80 98.1±0.55 98.4±0.69 99.0±0.24 99.57±0.33 84.13±0.26 99.17±0.92


135

The effect of the amount of HPMC 10, 20, 40 and 60 % on the

diltiazem hydrochloride release is shown in Figure 35. The Diltiazem

hydrochloride release decreased as the percent amount of HPMC level in

the tablet increased. Drug release is controlled by the hydration of HPMC,

which forms a gelatinous barrier layer at the surface of the matrix. By using

viscosity grade of the HPMC the resistance of such a gel layer to erosion is

controlled. HPMC K100LV is a low viscosity polymer (100 cps), therefore,

10% and 20% polymer level showed a fast drug release from the matrix. It

was observed that for the 10% HPMC level, within 1 hour, near about

100% of the diltiazem hydrochloride was released while for the 20% HPMC

level after 3 hours, 90.2 % of the diltiazem hydrochloride was released in

the dissolution media. An increase in polymer amount causes an increase

in the viscosity of the gel and gel layer with a longer diffusional path. The

ultimate effect was a decrease in the effective diffusion coefficient of the

drug with a reduction in the drug release rate. The results from the HPMC

polymer show this predictable behavior. The diltiazem hydrochloride

release from the formulations containing 40% and 60% HPMC was found

to be 99.22% and 84.18%, respectively at 12 hours. Release rate data

from table 29 shows a very high r2 for the HPMC 40 and 60% formulations

suggesting diffusion release kinetics. The gel thickness might have

prolonged the drug release from the formulations. Table 29 (release

kinetics) - shows the release rate data.


136

Dissolution profiles of the HPMC alone SR matrix tablets showed

that at levels of 40% and 60%, the profiles were close to the profile

obtained by the marketed product.

The FDA recommended f2 similarity test was then applied to

compare the HPMC at 40% and 60% levels to the marketed product as

shown below.

a) HPMC 40%, f2 value of 58.99

b) HPMC 60%, f2 value of 35.68

The f2 values show that the HPMC SR matrix tablet with a level of

40% was similar to the marketed product.

Figure No 35: Effect of HPMC on diltiazem hydrochloride release from

SR matrix tablets.


137

Figure No 36.Diltiazem Hydrochloride release dissolution profile

comparison of HPMC SR matrix tablet & marketed product (DILZEM SR)

Matrix tablets containing 10,20, 40 and 60 % Eudragit showed fast

release of diltiazem hydrochloride because of disintegration (Figure

37).For the SR tablet containing 60% Eudragit, 73.2% of the diltiazem

hydrochloride was released within2 hours. The data thus suggests that

for the different levels of Eudragit L 100-55 alone in the tablets does not

promote sustained release of the diltiazem hydrochloride.


138

Figure No 37: Effect of Eudragit on Diltiazem Hydrochloride release from

SR matrix tablet

It was observed that the combination of HPMC at 5% and 10% and

Eudragit at 5% and 10% polymer levels did not retard the drug release.

The low HPMC level probably played an important role for the faster

release of diltiazem hydrochloride. The combination of HPMC at 20% and

30% and Eudragit at 20% and 30% level showed a slow release of drug

comparable to the formulations containing only HPMC at 40% and 60%

level (Figure 38).The release rates were found to be 28.10 and 18.25 %


139

h-1/2for the blends of HPMC/Eudragit at 20% and 30% levels each

respectively.

Dissolution profiles of the HPMC and Eudragit combination blends at

20% and 30% individual level SR matrix tablets were comparable to the

profile obtained by the marketed product. Figure 39 shows the

comparison profiles.

The FDA recommended f2 similarity test was then applied to compare

the HPMC and Eudragit combination blends at 20% and 30% individual

level SR matrix tablets to the marketed product as shown below.

a) HPMC 20% / Eudragit 20%, f2 value of 77.19

b) HPMC 30% / Eudragit 30%, f2 value of 38.04

The f2 values show formulation of the HPMC and Eudragit combination

blends at 20% level SR matrix tablets to be similar to the marketed product.


140

Figure No 38: Effect of HPMC/ Eudragit combination blend on Diltiazem

Hydrochloride release from SR matrix tablets.

Figure: No 39: Diltiazem Hydrochloride release profile comparison of

HPMC/Eudragit combination SR matrix tablet & Marketed Product

(DILZEM SR).


141

7.7.1.2. Dissolution Studies of matrix tablet of HPMC, Eudragit containing Metoprolol Succinate.

Table No. 26: Mean cumulative % drug release of all formulation of HPMC, Eudragit containing Metoprolol

Succinate

Time

(HRS)


Formulation

FM1 FM2 FM3 FM4 FM5 FM6 FM7 FM8 FM9 FM10 FM11 FM12 M k d

1 99.23±0.71 53.07±0.25 19.22±0.17 16.14±0.95 98.9±1.08 66.56±0.13 82.19±0.84 60.41±0.87 96.4±0.42 55.20±0.13 28.22±0.97 16.38±0.96 23.95±0.84

2 99.39±0.4 80.180.91 30.08±0.21 22.24±0.76 98.9±0.72 84.59±0.81 94.23±0.96 73.15±0.82 98.4±0.10 82.33±0.98 44.39±0.89 24.14±0.82 40.56±0.79

3 99.39±0.4 94.79±0.18 41.31±0.74 31.48±0.86 98.9±0.72 90.49±0.27 98.11±0.46 80.5±0.55 98.4±0.45 90.34±0.46 55.53±0.41 34.58±0.16 50.71±0.35

4 99.39±0.4 96.54±0.55 50.28±0.25 39.64±0.50 98.9±0.72 94.55±0.83 98.23±0.08 86.2±0.76 98.4±0.48 94.64±0.06 64.43±0.87 39.69±0.54 59.31±0.96

5 99.39±0.4 98.06±0.57 60.30 ±0.14 44.80 ±0.20 98.9±0.72 96.52 ±0.91 98.23±0.08 88.8 ±0.61 98.4 ±0.48 97.1 ±0.56 72.28 ±0.78 46.75 ±0.16 68.95 ±0.44

6 99.39±0.4 99.11±0.49 67.82±0.19 52.86±0.19 98.9±0.72 98.26±0.45 98.23±0.08 94.24±0.38 98.4±0.48 98.84±0.73 78.69±0.52 54.83±0.92 76.56±0.07

7 99.39±0.4 99.11±0.49 78.49±0.90 60.29±0.52 98.9±0.72 98.26±0.45 98.23±0.08 98.1±0.42 98.4±0.48 99.17±0.73 84.03±0.38 62.29±0.81 84.96±0.82

8 99.39±0.4 99.11±0.49 84.77±0.90 66.15±0.82 98.9±0.72 98.26±0.45 98.23±0.08 98.1±0.42 98.4±0.48 99.17±0.73 90.13±0.23 69.11±0.51 88.23±0.07

9 99.39±0.4 99.11±0.49 91.36±0.26 73.72±0.61 98.9±0.72 98.26±0.45 98.23±0.08 98.1±0.42 98.4±0.48 99.17±0.73 93.68±0.77 75.53±0.97 92.00±0.45

10 99.39±0.4 99.11±0.49 97.29±0.04 80.18±0.77 98.9±0.72 98.26±0.45 98.23±0.08 98.1±0.42 98.4±0.48 99.17±0.73 96.56±0.38 80.11±0.44 92.25±0.78

11 99.39±0.4 99.11±0.49 98.31±0.71 82.21±0.43 98.9±0.72 98.26±0.45 98.23±0.08 98.1±0.42 98.4±0.48 99.17±0.73 98.03±0.34 82.13±0.59 94.87±0.53

12 99.39±0.4 99.11±0.49 99.1±0.80 84.25±0.82 98.9±0.72 98.26±0.45 98.23±0.08 98.1±0.42 98.4±0.48 99.17±0.73 99.51±0.35 84.17±0.37 97.27±0.85


142

The effect of the amount of HPMC10, 20, 40 and 60% on the

metoprolol succinate release is shown in Figure 40. The Metoprolol

succinate release decreased as the percent amount of HPMC level in the

tablet increased. Drug release is controlled by the hydration of HPMC,

which forms a gelatinous barrier layer at the surface of the matrix. In

addition, the resistance of such a gel layer to erosion is controlled by the

viscosity grade of the HPMC. HPMC K100LV is a low viscosity polymer

(100cps), therefore, 10% and 20% polymer level showed a fast drug

release from the matrix. It was observed that for the 10% HPMC level,

within 1 hour, near about 100% of the Metoprolol succinate was released.

While for the 20% HPMC level after 3 hours, 94.79 % of the Metoprolol

succinate was released in the dissolution media. An increase in polymer

amount causes an increase in the viscosity of the gel as well as the

formation of a gel layer with a longer diffusional path. This could cause a

decrease in the effective diffusion coefficient of the drug and therefore a

reduction in the drug release rate. The results from the HPMC polymer

show this predictable behavior. The metoprolol succinate release from the

formulations containing 40% and 60% HPMC was found to be 99.10% and

84.25%, respectively at 12 hours. Release rate data from table 30 show a

very high r2 for the HPMC 40 and 60% formulations suggesting diffusion

release kinetics. The gel thickness might have prolonged the drug release

from the formulations. Table 30 (release kinetics) -shows the release rate

data.


143

Dissolution profiles of the HPMC alone SR matrix tablets showed

that at levels of 40% and 60%, the profiles were close to the profile

obtained by the marketed product.

The FDA recommended f2 similarity test was then applied to

compare the HPMC at 40% and 60% levels to the marketed product as

shown below.

a) HPMC 40%, f2 value of 58.27

b) HPMC 60%, f2 value of 36.37

The f2 values show that the HPMC SR matrix tablet with a level of 40%

was similar to the marketed product.

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM1

FM2

FM3

FM4

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 40: Effect of HPMC on Metoprolol succinate release from SR

matrix tablet.


144

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM3

FM4

Marketed(Meta XL)

Time(Hrs)

% C

um

ula

tiv

e D

rug

Re

lea

se

Figure No 41: Metoprolol Succinate release dissolution profile of HPMC

SR matrix tablets & Marketed product (Metal XL)

Matrix tablets containing 10%, 20%, 40% and 60 % Eudragit showed

fast release of metoprolol succinate because of disintegration (Figure No

41). For the SR tablet containing 60% Eudragit, 73.15% of the metoprolol

succinate was released within 2 hours. The data thus suggests that for

the different levels of EudragitL 100-55 alone in the tablets does not

promote sustained release of the metoprolol succinate.


145

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM5

FM6

FM7

FM8

Time(Hrs)

% C

umul

ativ

e D

rug

Rel

ease

Figure No 42: Effect of Eudragit on Metoprolol Succinate release from SR

matrix tablets.

It was observed that the combination of HPMC at 5% and10% and

Eudragit at 5% and 10% polymer levels did not retard the drug release.

The low HPMC level probably played an important role for the faster

release of metoprolol succinate. The combination of HPMC at 20% and 30%

and Eudragit at 20% and 30% level showed as low release of drug

comparable to the formulations containing only HPMC at 40% and 60%

level(Figure 43).The release rates were found to be 28.22 and 16.38 %

h-1/2for the blends of HPMC/Eudragit at 20% and 30% levels each

respectively .


146

Dissolution profiles of the HPMC and Eudragit combination blends at

20% and 30% individual level SR matrix tablets were comparable to the

profile obtained by the marketed product. Figure 44 shows the

comparison profiles.

The FDA recommended f2 similarity test was then applied to compare

the HPMC and Eudragit combination blends at 20% and 30% individual

level ER matrix tablets to the marketed product as shown below.

a) HPMC 20% / Eudragit 20%, f2 value of 72.52

b) HPMC 30% / Eudragit 30%, f2 value of 38.13

The f2 values show formulation of the HPMC and Eudragit combination

blends at 20% level SR matrix tablets to be similar to the marketed product.

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM9

FM10

FM11

FM12

Time(Hrs)

% C

umul

ativ

e D

rug

Rele

ase

Figure No 43: Effect of HPMC/Eudragit combination blends on Metoprolol



147

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM11

FM12

Marketed(Meta XL)

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 44: Metoprolol Succinate release profile comparison of

HPMC/Eudragit combination SR matrix tablets & marketed product

(Meta XL)


148

7.7.2 Dissolution Studies of matrix tablet containing PVAP.

7.7.2.1 Dissolution Studies of matrix tablet of PVAP containing Diltiazem Hydrochloride

Table No.27:Mean cumulative % drug release of all formulation of PVAP containing Diltiazem Hydrochloride

Time

(HRS)


Formulation

FD13 FD14 FD15 FD16 FD17 FD18 FD19 FD20 FD21 FD22 M k d

1 17.24±0.33 96.12±0.24 98.1±0.44 20.3±0.79 24.58±0.05 98.2±0.64 11.63±0.26 65.22±0.32 98.15±0.09 60.2±0.50 26.25±0.35

2 25.25±0.05 98.80±0.18 98.8±0.77 35.5±0.08 40.3±0.34 98.8±0.31 20.18±0.94 86.3±0.90 98.9±0.11 84.3±0.59 38.12±0.19

3 31.67±0.32 99.11±0.13 99.1±0.08 44.53±0.93 49.82±0.36 98.8±0.49 22.90±0.55 92.8±0.08 99.2±0.85 92.8±0.10 48.26±0.71

4 35.60±0.58 99.11±0.13 99.1±0.08 51.8±0.11 59.78±0.15 98.8±0.49 25.30±0.15 99.1±0.14 99.2±0.85 96.1±0.87 58.16±0.87

5 39.81±0.28 99.11±0.13 99.1±0.08 59.1±0.13 69.58±0.88 98.8±0.49 27.66±0.33 99.1±0.14 99.2±0.85 96.1±0.87 68.22±0.62

6 42.92±0.22 99.11±0.13 99.1±0.08 65.1±0.09 75.6±0.89 98.8±0.49 28.38±0.19 99.1±0.14 99.2±0.85 96.1±0.87 76.95±0.46

7 46.30±0.44 99.11±0.13 99.1±0.08 70.964±0.85 82.53±0.27 98.8±0.49 29.93±0.45 99.1±0.14 99.2±0.85 96.1±0.87 84.40±0.70

8 48.11±0.63 99.11±0.13 99.1±0.08 77.51±0.27 88.54±0.78 98.8±0.49 31.1±0.40 99.1±0.14 99.2±0.85 96.1±0.87 90.79±0.39

9 49.63±0.42 99.11±0.13 99.1±0.08 83.2±0.85 92.99±0.79 98.8±0.49 31.77±0.06 99.1±0.14 99.2±0.85 96.1±0.87 94.44±0.32

10 51.15±0.82 99.11±0.13 99.1±0.08 87.55±0.19 95.23±0.37 98.8±0.49 32.45±0.08 99.1±0.14 99.2±0.85 96.1±0.87 96.38±0.73

11 53.12±0.05 99.11±0.13 99.1±0.08 92.28±0.77 97.77±0.80 98.8±0.49 33.74±0.85 99.1±0.14 99.2±0.85 96.1±0.87 98.46±0.34

12 54.14±0.15 99.11±0.13 99.1±0.08 95.68±0.25 98.24±0.35 98.8±0.49 34.44±0.35 99.1±0.14 99.2±0.85 96.1±0.87 99.17±0.92


149

The matrix tablet formulation with high levels, greater than 50% of

polyvinylacetate/ Povidone polymer, formulation variable FD13 and FD19,

showed a low drug release (Figure No 45). Where it was found that the

higher the percent polymer level in the tablet matrix, the slower the drug

release rate. This slowed drug diffusion can be explained by the reduction

in the porosity and higher tortuosity of matrix. Thus PVAP, which is a very

plastic material, produces a coherent matrix, sustaining the drug release

from the matrix tablet. The matrix remained intact during the dissolution

test due to the water-insoluble polyvinyl acetate. The f2 similarity number

when compared to the marketed product for FD13 was 23.01 and for FD19

was also 15.35. So, while FD13 and FD19 do show sustained release in

vitro of the diltiazem hydrochloride from the matrix tablets, the similarity

factor tells us that the set of formulations are not similar to the marketed

product.

The matrix tablet formulation with high levels, greater than 50%, of

microcrystalline cellulose, formulation variable FD14 and FD20, showed

high drug release rate (Figure No 46) as the level of PVAP polymer in

FD14 was 0% while in FD20, it was 13.16%. Microcrystalline cellulose

allows water to enter the tablet matrix by means of capillary pores,

resulting in disruption of the hydrogen bonding between adjacent bundles

of the cellulose microcrystals Therefore, at a higher rate of incorporation,

79% for FD14 and 52.66% for FD20, microcrystalline cellulose acted as a


150

disintegrant, destroying matrix cohesion, and in essence, producing an

immediate release tablet.


dibasic calcium phosphate, formulation variable FD15 and FD21, showed

high drug release rate (Figure No 47). This can be explained by the fact

that dibasic calcium phosphate on its own at high levels of 79% w/w of

tablet does not compress well, as was the case for FD15, and produced a

tablet whose hardness was only 2.2 kg/cm2 and which when tested by the

friability test failed miserably as all tablets capped.FD21 also showed a

very fast in vitro drug release.

0 1 2 3 4 5 6 7 8 9 10 11 12 130

10

20

30

40

50

60

FD13

FD19

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 45: Effect of high level PVAP polymer (>50%) on Diltiazem

Hydrochloride release from SR matrix tablet


151

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FD14

FD20

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 46: Effect of high level microcrystalline cellulose excipient

(>50% ) on Diltiazem Hydrochloride release from SR matrix tablet.

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FD15

FD21

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 47: Effect of high level Dicalcium Phosphate (>50%) excipient

on Diltiazem Hydrochloride release from SR matrix tablet


152

Figure 48,49 shows the drug release profiles of theformulation

variables, FD16 and FD17 and comparison to the marketed product.FD16

and FD17 both have a high level (39.5%) of PVAP in their formulations and

as such exhibit low diltiazem hydrochloride release in vitro. FD16 has high

level of microcrystalline cellulose which as we haveseen can act as a

disintegrant.In this instance however, the level of PVAP overrides this

property, hence the extended release of the diltiazem hydrochloride in

vitro.FD17 has a high level of dibasic calcium phosphate which combines

well with the PVAP to give an sustained release of diltiazem hydrochloride

in vitro.The f2 value for FD16 is 52.61 whencalculated in comparison to the

marketed product while the f2 value for FD17 is 86.50 thus suggesting that

FD17 is similar to the marketed product in diltiazem hydrochloriderelease

over 12 hours.Figure 50 shows the drug release profiles of the formulation

variables,FD18, FD22.FD18 has no PVAP polymer incorporated into the

formulation and the in vitro drug release results show a tablet the behaved

like an immediate release.FD22 had PVAP levels of 26.33% and has

minimum drug retarding properties unless it is in levels of greater than 40%

in a tablet matrix.


153

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FD16

FD17

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 48: Effect of PVAP on diltiazem Hydrochloride release from SR

matrix tablet

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FD16

FD17

Marketed(DILZEM SR)

Time(Hrs)

% C

um

ula

tiv

e D

rug

Re

lea

se

Figure No 49: Diltiazem Hydrochloride release dissolution profile

comparison of FD16 & FD17 SR tablet & marketed product (DILZEM SR)


154

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FD18

FD22

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 50: Effect of PVPA on Diltiazem Hydrochloride release from SR

matrix tablet


155

7.7.2.2. Dissolution Studies of matrix tablet of PVAP containing Metoprolol Succinate.

Table No.28 Mean cumulative % drug release of all formulation of PVAP containing Metoprolol Succinate

Time

(HRS)


Formulation

FM13 FM14 FM15 FM16 FM17 FM18 FM19 FM20 FM21 FM22 M k d

1 18.27±0.84 97.34±0.79 98.53±0.88 22.3±0.87 24.19±0.44 98.3±0.08 12.59±0.25 64.44±0.56 98.05±0.17 64.2±0.04 23.95±0.84

2 26.53±0.15 98.9±0.25 99.15±0.84 34.86±0.26 38.66±0.98 98.8±0.24 20.07±0.94 86.22±0.50 98.90±0.25 84.32±0.30 40.56±0.79

3 31.55±0.88 99.04±0.11 99.15±0.84 42.11±0.48 47.38±0.44 98.8±0.85 24.79±0.24 93.79±0.30 99.28±0.68 95.91±0.60 50.71±0.35

4 35.68±0.56 99.04±0.11 99.15±0.84 48.96±0.90 56.89±0.03 98.8±0.85 26.48±0.75 99.1±0.77 99.28±0.68 98.14±0.36 59.31±0.96

5 39.86±0.93 99.04±0.11 99.15±0.84 54.46±0.80 64.61±0.83 98.8±0.85 27.72±0.17 99.1±0.77 99.28±0.68 99.19±0.52 68.95±0.44

6 42.89±0.94 99.04±0.11 99.15±0.84 61.91±0.76 73.36±0.20 98.8±0.85 29.19±.78 99.1±0.77 99.28±0.68 99.19±0.52 76.56±0.07

7 46.19±0.96 99.04±0.11 99.15±0.84 68.26±0.95 81.96±0.79 98.8±0.85 29.98±0.54 99.1±0.77 99.28±0.68 99.19±0.52 84.96±0.82

8 48.10±0.29 99.04±0.11 99.15±0.84 75.61±0.97 88.28±0.93 98.8±0.85 31.01±0.25 99.1±0.77 99.28±0.68 99.19±0.52 88.23±0.07

9 50.50±0.61 99.04±0.11 99.15±0.84 82.09±0.35 92.76±0.96 98.8±0.85 31.81±0.98 99.1±0.77 99.28±0.68 99.19±0.52 92.00±0.45

10 52.21±0.27 99.04±0.11 99.15±0.84 86.04±0.01 94.44±0.88 98.8±0.85 32.61±0.91 99.1±0.77 99.28±0.68 99.19±0.52 92.25±0.78

11 53.22±0.92 99.04±0.11 99.15±0.84 91.19±0.91 97.79±0.47 98.8±0.85 33.65±0.76 99.1±0.77 99.28±0.68 99.19±0.52 94.87±0.53

12 54.00±0.97 99.04±0.11 99.15±0.84 94.74±0.43 98.33±0.18 98.8±0.85 34.47±0.95 99.1±0.77 99.28±0.68 99.19±0.52 97.27±0.85


156

The matrix tablet formulation with high levels ,greater than 50% of

poly vinyl acetate /povidone polymer,formulation variableFM13 and FM19,

showed a low drug release (Figure 51).Where it was found that the higher

the percent polymer level in the tablet matrix, the slower the drug release

rate.This slowed drug diffusion can be explained by the reduction in the

porosity and higher tortuosity of matrix.Thus PVAP, which is a very

plastic material, produces a coherent matrix, sustaining the drug release

from the matrix tablet.The matrix remained intact during the dissolution test

due to the water-insoluble poly vinyl acetate. The f2 similarity number when

compared to the marketed product for FM13 was 23.97 and for FM19 was

also 16.03.So, while FM13 and FM19 do show sustained release in vitro

of the metoprolol succinate from the matrix tablets, the similarity factor tells

us that these two formulations are not similar to the marketed product.

The matrix tablet formulation with high levels,greaterthan 50%,of micro

crystalline cellulose,formulation variable FM14andFM20, showed high

drug release rate(Figure52) as the level of PVAP polymer in FM14 was

0% while in FM20, it was 13.19%. Microcrystalline cellulose allows water

to enter the tablet matrix by means of capillary pores,resulting in a

disruption of the hydrogen bonding between adjacent bundles of the

cellulose microcrystals.Therefore, at a higher rate of incorporation, 79.16%

for FM14 and 52.77% for FM20,micro crystalline cellulose acted asa


157

disintegrant, destroying matrix cohesion,and in essence, producing an

immediate release tablet.


dibasic calcium phosphate, formulation variable FM15 and FM21, showed

high drug release rate (Figure 53).This can be explained by the fact that

dibasic calcium phosphate on its own at high levels of 78.91% w/w of tablet

does not compress well, as was the case for FM15, and produced a tablet

whose hardness was only 1.8 kg/cm2 and which when tested by the

friability test failed miserably as all tablets capped.FM 21 also showed a very

fast in vitro drug release.

0 1 2 3 4 5 6 7 8 9 10 11 12 130

10

20

30

40

50

60

FM13

FM19

Time(Hrs)

% C

umul

ativ

e D

rug

Rel

ease

Figure No 51: Effect of high level of PVAP polymer (>50%) on Metoprolol



158

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM14

FM20

Time(Hrs)

% C

umul

ativ

e D

rug

Rel

ease

Figure No 52: Effect of high level of microcrystalline cellulose (>50%)

excipient on Metoprolol succinate release from SR matrix tablets

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM15

FM21

Time(Hrs)

% C

umul

ativ

e D

rug

Rele

ase

Figure No 53: Effect of high level of Dicalcium phosphate excipient

(>50%) on Metoprolol Succinate release from SR matrix tablets


159

Figure 54, 55 shows the drug release profiles of the formulation

variables, FM16 and FM17 and comparison to the marketed product.FM16

and FM17 both have a high level (39.5%) of PVAP intheir formulations and

as such exhibit low metoprolol succinate release in-vitro.FM16 has high

level of microcrystalline cellulose which as we have seen can act as a

disintegrant.In this instance however, the level of PVAP overrides this

property,hence the extended release of the metoprolol succinate in

vitro.FM17 has a high level of dibasic calcium phosphate which combines

well with the PVAP to givea sustained release of metoprolol succinate

vitro.The f2 value for FM16 is 49.58 when calculated in comparison to the

marketed product while the f2 value for FM 17 is 78.65 thus suggesting

that FM17 is similar to the markete dproduct in metoprolol succinate release

over 12 hours.

Figure 56 shows the drug release profiles of the formulation

variables, FM18, FM22.FM18 has no PVAP polymer incorporated into the

formulation and the in vitro drug release results show a tablet the behaved

like an immediate release.FM22 had PVAP levels of 26.33% and has

minimum drug retarding properties unless it is in levels of greater than 40%

in a tablet matrix.


160

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM16

FM17

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 54: Effect of PVAP on Metoprolol Succinate release from SR

matrix tablets

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM16

FM17Marketed(Meta XL)

Time(Hrs)

% C

um

ula

tiv

e D

ru

g R

ele

as

e

Figure No 55: Metoprolol Succinate release dissolution profile comparison

of FM16 & FM17 SR tablets & marketed product (Meta XL)


161

0 1 2 3 4 5 6 7 8 9 10 11 12 130

20

40

60

80

100

120

FM18

FM22

Time(Hrs)

% C

um

ula

tive

Dru

g R

elea

se

Figure No 56: Effect of PVAP on Metoprolol Succinate release from SR

Matrix tablets


162

7.8. RELEASE KINETIC STUDY

7.8.1 Release Kinetic Study of All Formulation of HPMC, Eudragit


Table No 29: Correlation coefficient [R], Constant [k], and Diffusion

exponent [n] after fitting of dissolution data into various release kinetic

models of all formulation of HPMC, Eudragit containing Diltiazem

Hydrochloride

Formu-

Lation

Correlation Coefficient [R] For Krosmeyer-

Peppas Equation

Zero

Order

1st

Order

Matirx

(Higuchi)

Korsmeyer

Peppas

Hix.

Crow.

Release

Exponent [N]

Rate

Constant [K]

FD1 0.6720 0.8072 0.9134 0.9065 0.7425 0.0197 96.5946

FD2 0.6795 0.9614 0.9557 0.9384 0.9561 0.3440 57.6164

FD3 0.9509 0.8803 0.9795 0.9918 0.9728 0.6892 19.3749

FD4 0.9711 0.9842 0.9730 0.9953 0.9940 0.7142 14.9072

FD5 0.8367 0.8574 0.9562 0.3333 0.8432 0.0002 98.0932

FD6 0.5091 0.9132 0.9203 0.9524 0.8763 0.2211 68.7400

FD7 0.8117 0.9695 0.9686 0.9840 0.9600 0.1979 78.9213

FD8 0.5217 0.9200 0.9335 0.9896 0.9072 0.2416 61.1373

FD9 0.6892 0.9028 0.9203 0.8790 0.8259 0.0369 94.2938

FD10 0.3066 0.9617 0.8810 0.9694 0.8432 0.1519 77.1085

FD11 0.8303 0.9363 0.9927 0.9906 0.9919 0.5208 29.6589

FD12 0.9481 0.9875 0.9823 0.9911 0.9907 0.6514 17.3922

Marketed

DILZEM SR 0.8763 0.9126 0.9910 0.9901 0.9888 0.5675 26.4660

The in-vitro release data was treated according to zero order,first

order,Higuchi’s,Hixson-Crowell cube root law and Korsmeyer. The


163

release rate kinetic data for all the models can be seen in Table 29. In the

present study, the in vitro release profiles of drug from FD11 and

Marketed formulation could be best expressed by Higuchi’s equation,as

correlation coefficient value (r2): 0.9927 and 0.9910 shows high linearity

respectively. The high correlation coefficient (above 0.99) obtained

indicates a square root of time dependent release kinetics. Thus, as the

data fitted the Higuchi model,itconfirmeda diffusion drug release

mechanism. To confirm the diffusion mechanism, the data were fit into

Korsmeyer equation. The n value of 0.5208 for FD11and n value of 0.5675

for marketed formulation shows a coupling of diffusion and erosion

mechanisms so-called anomalous (non-fickian) diffusion. It is suggested

that the main driving force for the drug release in case of water soluble drug

like diltiazem hydrochloride from the matrix tablets is the infiltration of

release medium. Also, as observed in, as the polymer level in the

formulationis increased, drug diffusion is slowed due to the lower porosity

and higher tortuosity ofthe matrix.


164

7.8.2. Release Kinetic Study of All Formulation of HPMC, Eudragit

Containing Metoprolol Succinate.



models of all formulation of HPMC, Eudragit containing metoprolol succinate

Formu-

Lation


Peppas Equation

Zero

Order

1st

Order

MATIRX

(Higuchi)

Korsm

Eyer

Peppas

HIX.

CROW.

Release

Exponent [n]

Rate

Constant [k]

FM1 0.8375 0.7778 0.9565 0.3333 0.8305 0.0023 99.2347

FM2 0.6754 0.9818 0.9538 0.9360 0.9297 0.3455 58.2583

FM3 0.9485 0.8912 0.9810 0.9944 0.9787 0.6964 19.2318

FM4 0.9709 0.9836 0.9716 0.9895 0.9932 0.7188 14.7064

FM5 0.8362 0.7483 0.9559 0.3333 0.8165 -0.0012 98.9980

FM6 0.4965 0.9616 0.9184 0.9635 0.8797 0.2129 69.5004

FM7 0.6255 0.9118 0.9222 0.9393 0.8453 0.1345 83.5423

FM8 0.5232 0.9508 0.9349 0.9939 0.9089 0.2433 61.0969

FM9 0.4369 0.5579 0.8591 0.4725 0.5330 0.0150 96.7259

FM10 0.5080 0.9852 0.9265 0.9299 0.9115 0.2860 61.2470

FM11 0.8079 0.9376 0.9916 0.9891 0.9911 0.5082 30.6630

FM12 0.9599 0.9879 0.9766 0.9908 0.9927 0.6975 15.6761

Marketed

(MetaXL 50) 0.8450 0.9535 0.9905 0.9871 0.9887 0.5631 26.5455


165

The release rate kinetic data for all the models can be seen in Table

30. In the present study, the in vitro release profiles of drug from FM11 and

Marketed formulation could be best expressed by Higuchi’s equation, as

correlation coefficient value (r2): 0.9916 and 0.9905 shows high linearity

respectively. The high correlation coefficient (above 0.99) obtained

indicates a square root of time dependent release kinetics. When data is

fitted to higuchi model, it showed diffusion release mechanism. To confirm

the diffusion mechanism, the data was fit into Korsmeyer equation. The ‘n’

value of 0.5082 for FM11 and n value of 0.5631 for marketed formulation

shows a combination of diffusion and erosion mechanisms (anomalous

non-fickian) diffusion.


166

7.8.3. Release Kinetic Study of All Formulation of PVAP Containing




models of all formulation of PVPA containing Diltiazem Hydrochloride

Formu-

Lation


Peppas Equation

Zero

Order

1st

Order

Matrix

(Higuchi)

Korsm

Eyer

Peppas

Hix.

Crow.

Release

Exponent

[n]

Rate

Constant

[k]

FD13 0.7385 0.8725 0.9825 0.9875 0.8360 0.4587 18.4191

FD14 0.6806 0.9073 0.9171 0.9617 0.7991 0.0293 96.3129

FD15 0.6633 0.7893 0.9095 0.8830 0.7219 0.0093 98.1200

FD16 0.9165 0.9630 0.9931 0.9927 0.9914 0.6072 21.9132

FD17 0.8627 0.9651 0.9928 0.9891 0.9927 0.5651 26.4844

FD18 0.6602 0.7683 0.9081 0.9339 0.7033 0.0060 98.2509

FD19 0.5494 0.6870 0.9560 0.9641 0.6472 0.3988 13.7884

FD20 0.7977 0.9611 0.9762 0.9811 0.9782 0.3014 66.7768

FD21 0.6638 0.8053 0.9097 0.9453 0.7281 0.0098 98.1710

FD22 0.7239 0.9842 0.9635 0.9609 0.9589 0.3084 63.4358

Marketed

DILZEM SR 0.8763 0.9126 0.9910 0.9901 0.9888 0.5675 26.4660


167


31. In the present study, the in vitro release profiles of drug from FD17

and Marketed formulation could be best expressed by Higuchi’s

equation, as correlation coefficient value (r2): 0.9928 and 0.9910 shows

high linearity respectively. The high correlation coefficient (above 0.99)

obtained indicates a square root of time dependent release kinetics. After

fitting the data to Higuchi model, it confirmed diffusion drug release


Korsmeyer equation. The ‘n’ value of 0.5651 for FD 17 and n value of

0.5675 for marketed formulation shows a combination of diffusion and

erosion mechanisms (anomalous non-fickian). As the tablet is introduced

into the medium, water penetrates into the matrix and Povidone leaches

out to form pores through which the drug may diffuse out. Thus polyvinyl

acetate, which is a very plastic material, produces a coherent matrix,

sustaining the drug release from the tablet matrix.


168

7.8.4 Release Kinetic Study of All Formulation of PVAP Containing




models of all formulation of PVAP containing Metoprolol succinate

Formu-

Lation


Peppas Equation

Zero

Order

1st

Order

Matrix

(Higuchi)

Korsm

Eyer

Peppas

Hix.

Crow.

Release

Exponent

[n]

Rate

Constant

[k]

FM13 0.7465 0.8828 0.9856 0.9849 0.8456 0.4393 19.1290

FM14 0.6694 0.8185 0.9122 0.7500 0.7534 0.0165 97.4572

FM15 0.8400 0.8238 0.9578 0.3333 0.8456 0.0092 98.5245

FM16 0.9222 0.9553 0.9881 0.9878 0.9845 0.5832 22.2252

FM17 0.8872 0.9383 0.9902 0.9833 0.9897 0.5881 24.9566

FM18 0.6592 0.7136 0.9078 0.6937 0.6855 0.0053 98.3572

FM19 0.4358 0.6062 0.9369 0.9482 0.5587 0.3691 14.6429

FM20 0.8051 0.9740 0.9781 0.9800 0.9807 0.3132 66.1028

FM21 0.6653 0.7546 0.9103 0.4778 0.7277 0.0115 98.0721

FM22 0.6947 0.9801 0.9566 0.9645 0.9476 0.2795 66.8160

Marketed

(MetaXL 50) 0.8450 0.9535 0.9905 0.9871 0.9887 0.5631 26.5455


169


32. In the present study, the in vitro release profiles of drug from FM17

and Marketed formulation could be best expressed by Higuchi’s

equation, as correlation coefficient value (r2): 0.9902 and 0.9905 shows

high linearity respectively. The high correlation coefficient (above 0.99)

obtained indicates a square root of time dependent release kinetics. After

fitting the data to Higuchi model, it confirmed a diffusion drug release


Korsmeyer equation. The ‘n’ value of 0.5881 for FM17 and n value of

0.5631 for marketed formulation shows a combination of diffusion and

erosion mechanisms (anomalous non-fickian). As the tablet is introduced

into the medium, water penetrates into the matrix and Povidone leaches

out to form pores through which the drug may diffuse out.


170

7.9 STATISTICAL ANALYSIS

7.9.1 Statistical analysis of diltiazem hydrochloride with HPMC:

Eudragit matrix tablet.

All data set obtained from all the sample batches are compared with

dataset of marketed formulation (Standard). From statistical test (ANOVA)

its observed that all the sample batches are statistically different except

Batch FD11. It reflects that batch FD11 resembles batch M (standard

batch/Marketed Preparation). Concluding that batch FD11 is better

amongst rest of the batches.

7.9.2 Statistical analysis of Metoprolol succinate with HPMC: Eudragit

matrix tablet.

All date set obtained from all the sample batches are compared with



Batch FM11. It reflects that batch FM11 resembles batch M (standard

batch/marketed preparation). Concluding that batch FM11 is better


7.9.3 Statistical analysis of diltiazem hydrochloride with PVAP matrix

tablet.

All date set obtained from all the sample batches are compared with




171

Batch FD17. It reflects that batch FD17 resembles batch M (standard

batch/marketed preparation). Concluding that batch FD17 is better


7.9.4 Statistical analysis of Metoprolol succinate with PVAP matrix

tablet.

All data set obtained from all the sample batches are compared with


it is observed that all the sample batches are statistically different except

Batch FM17. It reflects that batch FM17 resembles batch M (standard

batch/marketed preparation). Concluding that batch FM17is better



172

7.10. SCANNING ELECTRON MICROSCOPY (SEM):

7.10.1. SEM study of selected optimized formulation containing HPMC

and Eudragit with Diltiazem Hydrochloride (FD11)

Figure No 57: SEM photomicrographs of optimized matrix tablet (batch

FD11) showing surface morphology after 0 hours (A, 500×), 1 hours (B,

500×), 3 hours (C, 500×), 6 hours (D, 500×), 9 hours (E, 500×), and 12

hours (F, 500×) of dissolution study.


173

SEM photomicrograph of the matrix tablet taken at different time

intervals during dissolution study. It showed that matrix was intact with

formation of pores throughout the matrix (Figure 57-F). SEM study

confirmed that drug is release by both diffusion and erosion mechanisms.

The tablet shows erosion after 1 hour on their surface early in the process,

so the active agent placed in this area is immediately released (Figure57-B).

SEM photomicrograph of the surface of fresh tablet (Figure 57-A) did not

show any pores while erosion is increased with time. The

photomicrographs also revealed formation of gelling structure indicating

the possibility of swelling of matrix tablets (Figure 57-D). Thus both above

mechanisms are involved in sustaining drug release from tablets.


174

7.10.2. SEM study of selected optimized formulation containing HPMC

and Eudragit with Metoprolol Succinate (FM11)


FM11) showing, surface morphology after 0 hours (A, 500×), 1 hours (B,

500×), 3 hours (C,500×),6 hours (D, 500×), 9 hours (E, 500×), and 12



175






so the active agent placed in this area is immediately released (Figure58-B).

SEM photomicrograph of the surface of fresh tablet (Figure 58-A) did not

show any pores while erosion is increased with time. The photo

micrographs also revealed formation of gelling structure indicating the

possibility of swelling of matrix tablets (Figure 58-D). Thus both above

mechanisms are involved in sustaining drug release from tablets.


176

7.10.3. SEM study of selected optimized formulation containing PVAP

with Diltiazem Hydrochloride (FD17)


FD17) showing surface morphology after 0 hour (A, 500×), 1 hour (B,

500×), 3 hours (C, 500×), 6 hours (D, 500×), 9 hours (E, 500×), and 12


A B

C D

E F


177






so the drug in this area is released immediately (Figure 59-B). SEM photo

micrograph of the surface of fresh tablet (Figure 59-A) did not show any

pores while erosion is increased with time. Hence, the formation of pores

on the tablet surface was responsible for sustaining the release of

diltiazem hydrochloride from formulated matrix tablets.


178

7.10.4. SEM study of selected optimized formulation containing PVAP

with Metoprolol Succinate (FM17)

Figure No 60: SEM photomicrographs of optimized matrix tablet

(batchFM17)showing surface morphology after 0 hours (A, 500×), 1

hours (B, 500×), 3 hours (C, 500×), 6 hours (D, 500×), 9 hours (E, 500×),

and 12 hours (F, 500×) of dissolution study


179






so the active agent placed in this area is immediately released (Figure 60-

B).SEM photomicrographs of the tablet surface at different time intervals

also showed that erosion of matrix increased with respect to time. SEM

photomicrograph of the surface of fresh tablet (Figure 60-A) did not show

any pores. The pore size has increased with time. Hence, the formation of

pores on the tablet surface is responsible for sustaining the release of

Metoprolol Succinate from formulated matrix tablets.


180

7.11. DIFFERENTIAL SCANNING CALORIMETRY (DSC)

7.11.1 Diltiazem hydrochloride, HPMC: Eudragit

Figure No 61: DSC thermogram of Diltiazem Hydrochloride

Figure No 62: DSC thermogram of HPMCK100LV+Eudragit L100-55


181

Figure No 63: DSC thermogram of optimized formulation (FD11)

Table: No 33: DSC data of physical mixtures of Diltiazem Hydrochloride,

excipients & Optimized Formulation (FD11)

Sr. No. Contents of the

physical mixture

Peaks ofexcipient

and drug

1 Diltiazem Hydrochloride 219.1 oC

2 HPMC K100LV + Eudragit L100-55 229.1oC

3 Optimized Formulation (FD11) 222.4oC


182

The physical incompatibility study was done by DSC. Thermograms

were generated for both pure drug and drug excipients mixtures. From the

DSC analysis, it was observed that there is no interaction between drug

and polymers. Endothermic peak of pure drug was found at 219.1oC

inthermograms of DSC and optimized formulation (FD11) at 222.4oC.it was

found that there was no significant deviation in melting endotherms of the

physical mixture of drug with all polymers. The results indicated that the

selected drug was physically compatible with the selected polymers. The

DSC results are represented in Table 33 and DSC thermograms are

shown in Figure 61 to Figure 63. After the compatibility study, it was

revealed that there was no interaction between the drug and the polymers

were selected.


183

7.11.2. Metoprolol Succinate, HPMC –Eudragit.

Figure No 64: DSC thermogram of Metoprolol Succinate

Figure No 65: DSC thermogram of HPMCK100LV+Eudragit L100-55


184

Figure No 66: DSC thermogram of Metoprolol Succinate+

HPMCK100LV+Eudragit L100-55

Figure No 67: DSC thermogram of optimized formulation (FM11)


185

Table No 34: DSC data of physical mixtures of Metoprolol Succinate,

excipients & Optimized Formulation (FM11).

Sr. No. Contents of the physical mixture Peaks of excipient

and drug

1 Metoprolol Succinate 1400 C

2 HPMC K100LV+Eudragit L100-55 229.10C

3 Metoprolol Succinate+ HPMC K

100LV + Eudragit L100-55

137.420 C

4 Optimized Formulation (FM11) 136.590 C




and polymers. Endothermic peak of pure drug was found at 1400C in

thermograms of DSC and optimized formulation (FM11) at 136.590C. It was







were selected.


186

7.11.3. Diltiazem Hydrochloride, PVAP.

Figure No 68: DSC thermogram of Diltiazem Hydrochloride

Figure No 69: DSC thermogram of PVAP+DCP


187

Figure No 70: DSC thermogram of Diltiazem hydrochloride+PVAP+DCP

Figure No 71: DSC thermogram of optimized formulation (FD17)


188

Table No 35: DSC data of physical mixtures of Diltiazem Hydrochloride,

excipients & Optimized Formulation (FD17)

S.No. Contents of the physical mixture Peaks of excipient and

drug

1 Diltiazem Hydrochloride 219.1 oC

2 PVAP+DCP 157.63oC

3 Diltiazem Hydrochloride+ PVAP+ DCP 218.5oC

4 Optimized Formulation (FD17) 218.5oC




and polymers. Endothermic peak of pure drug was found at 219.10 C in

thermograms of DSC and optimized formulation (FD17) at 218.50 C. it was





shown in Figure 68 to Figure71. After the compatibility study, it was


were selected.


189

7.11.4. Metoprolol Succinate, PVAP

Figure No 72: DSC thermogram of Metoprolol Succinate

Figure No73: DSC thermogram of PVAP+DCP


190

Figure No 74: DSC thermogram of Metoprolol Succinate+ PVAP+DCP

Figure No 75: DSC thermogram of optimized formulation (FM17)


191

Table No 36: DSC data of physical mixtures of Metoprolol Succinate,

excipients & Optimized Formulation (FM17)

Sr.

No.

Contents of the

physical mixture

Peaks of excipient and

drug

1 Metoprolol Succinate 1400C

2 PVAP+DCP 157.630C

3 Metoprolol Succinate + PVAP+DCP 137.860C

4 Optimized Formulation (FM17) 139.930C




and polymers. Endothermic peak of pure drug was found at 1400 C in

thermograms of DSC and optimized formulation (FM17) at 139.930 C. It

was found that there was no significant deviation in melting endotherms of

the physical mixture of drug with all polymers. The results indicated that

the selected drug was physically compatible with the selected polymers.

The DSC results are represented in Table 36 and DSC thermograms are



were selected.


192

7.12 IN VIVO X-RAY STUDIES:

7.12.1 In vivo X-ray Studies of selected optimized matrix tablet

containing Barium sulphate (FD11)

Figure No 76: X-Ray photographs taken at 0, 1, 3, 6, 9 and 12 hr after oral

administration of matrix tablets of barium sulphate similar to FD11

The in vivo X-ray studies were carried out in New Zealand rabbit

using soft X-ray analysis. The result has showed adhesion and resident

time of formulation in GIT. FD11 formulation showed sustained effect for 12

hr as shown in Figure 76.


193

7.12.2. In vivo X-ray Studies of matrix tablet containing Barium

sulphate with HPMC (FM11)

Figure No77: X-Ray photographs taken at 0 (Control), 1, 3 , 6, 9 and 12 hr

after oral administration of matrix tablets of barium sulphate similar in

composition to diltiazem hydrochloride optimized formulation (FM11).


194



time of formulation in GIT. FM11 formulation showed sustained effect for

12 hr as shown in Figure 77.


195

7.12.3. In vivo X-ray Studies of matrix tablet containing Barium

sulphate with PVAP (FD17)

Figure No 78: X-Ray photographs taken at 0 (Control), 1, 3 , 6, 9 and 12hr

after oral administration of matrix tablets of barium sulphate similar in

composition to diltiazem hydrochloride optimized formulation (FD17)


196



time of formulation in GIT. FD17 formulation showed sustained effect for 12



197

7.12.4 In vivo X-ray Studies of matrix tablet containingBarium

sulphate with PVAP (FM17)

Figure No 79: X-Ray photographs taken at 0 hr (control), 1hr, 3 hr, 6hr,

9hr and 12 hr after oral administration of matrix tablets of barium sulphate

similar in composition to diltiazem hydrochloride optimized formulation

(FM17)


198



time of formulation in GIT. FM17 formulation showed sustained effect for 12


7.13 STABILITY STUDY

Effect of stability conditions on physical characteristic & release of

drug from optimized formulations

A) Optimized Matrix Tablet formulation (FD11) of HPMC, Eudragit


B) Optimized Matrix Tablet formulation (FM11)of HPMC, Eudragit

Containing metoprolol succinate.

C) Optimized Matrix Tablet formulation (FD17) of PVAP containing


D) Optimized Matrix Tablet formulation (FM17) of PVAP containing

metoprolol succinate.

7.13.1. Effect of stability conditions on physical characteristics and

release of Diltiazem Hydrochloride from optimized formulation (FD11)

Results of physical properties of the HPMC/Eudragit matrix tablets

are shown in Table 37, the conditions for the long term storage were based

on the ICH guidelines:


199

Long term stability study (FDA, 2001 ICH Q1A, FDA, 1997 ICH Q1C):

Storage: 25 ± 2oC / 60 ± 5% Relative humidity

Frequency of testing: Initial, 1, 3, 6, and 9 months

Tests performed: Appearance, weight, hardness, drug release

Optimized formulation (FD11) stability data:

Table 37- shows the effect of long term stability storage on the physical

properties of HPMC, Eudragit.

Result shows no change in the dissolution profile for tablets stored under

long term stability conditions for up to 9 months. (Figure 80)


200

Table No 37: Effect of long term stability storage on the physical properties

of HPMC/Eudragit tablets (FD11 Batch)

Physical

Property Initial 1 month 3 months 6 months 9 months

Weight 450±2.4767 449±2.5726 450±2.5726 451±2.2820 451±3.5703

Hardness 5.2±0.07071 5.2±0.0836 5.3±0.0894 5.4 ± 0.0447 5.5±0.0894

(*) significantly different from initial at 0.05 level

Figure No 80: Effect of storage on Diltiazem Hydrochloride release from

HPMC/Eudragit matrix tablets under long term stability conditions (FD11

Batch) (Plotted values are average values, n=3)

FD11

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13

% C

um

ula

tive

Dru

g R

ele

ase

Time (Hrs)

FD11

1 month

3 month

6 months

9 months


201


release of Metoprolol Succinate from optimized formulation (FM11).

Results of physical properties of the HPMC/Eudragit matrix tablets

are shown in Table 38, the conditions for the long term storage were based

on the ICH guidelines:

Long term stability study (FDA, 2001 ICH Q1A, FDA, 1997 ICH Q1C):

Storage: 25 ± 2oC / 60 ± 5% Relative humidity

Frequency of testing: Initial, 1, 3, 6, and 9 months

Tests performed: Appearance, weight, hardness, drug release

Optimized formulation (FM11) stability data:

Table 38- shows the effect of long term stability storage on the physical

properties of HPMC, Eudragit.

Results show no change in the dissolution profile for tablets stored under

long term stability conditions for up to 9 months. (Figure 81)


202


of HPMC/Eudragit tablets (FM11 Batch)

Physical


Weight 240±0.053 239±0.071 240±0.192 241±0.057 241±0.066

Hardness 4.6 ±0.102 4.6 ±0.114 4.8 ±0.312 4.8 ±0.158 4.8 ±0.214


Figure No 81: Effect of storage on Metoprolol Succinate release from

HPMC/Eudragit matrix tablets under long term stability conditions (FM11

Batch) (Plotted values are average values, n=3)

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13

% C

um

ula

tive

Dru

g R

ele

ase

Time(Hrs)

FM11

1 month

3 month

6 months

9 months


203


release of Diltiazem Hydrochloride from optimized formulation (FD17).

Table 39- shows the effect of long term stability storage on the

physical properties of PVAP tablets.

Result shows a significant change in hardness at the 3 month, 6

month and 9 month period. However, there was no significant change in

the dissolution profile (Figure 82) for tablets stored under long term stability

conditions for up to 9 months.


204


of PVAP tablets (FD 17 Batch)

Physical


Weight 449 ± 2.5808 449 ± 2.5726 450 ± 2.5726 450± 3.5703 450 ± 2.2820

Hardness 5.4 ± 0.08944 5.6 ± 0.0894 6.2 ± 0.0836 6.8± 0.0447 7.4 ± 0.0894


Figure No 82: Effect of storage on Diltiazem Hydrochloride release from

PVAP matrix tablets under long term stability conditions (FD17 Batch)

(Plotted values are average values, n=3)

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13

% C

um

ula

tive

Dru

g R

ele

ase

Time(Hrs)

FD17

1 month

3 month

6 months

9 months


205


release of Metoprolol Succinate from optimized formulation (FM17).

Table 40- shows the effect of long term stability storage on the

physical properties of PVAP tablets.

Result shows a significant change in hardness at the 3 month, 6

month and 9 month period. However, there was no significant change in

the dissolution profile (Figure83) for tablets stored under long term stability

conditions for up to 9 months.


206

Table No 40. Effect of long term stability storage on the physical properties

of PVAP tablets (FM17 Batch)

Physical


Weight 240±0.053 239±0.057 240±0.071 241±0.045 241±0.173

Hardness 4.2 ±0.132 4.8 ±0.156 5.4 ±0.114 6 ±0.214* 6.8 ±0.158*


Figure No 83 Effect of storage on Metoprolol Succinate release from

PVAP matrix tablets under long term stability conditions(FM17 Batch)

(Plotted values are average values, n=3)

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13

% C

um

ula

tive

Dru

g R

ele

ase

Time(Hrs)

FM17

1 month

3 month

6 months

9 months

CONCLUSION

207

CONCLUSION

From the complete study, it is concluded that, HPMC K100LV &

Eudragit® L100-55 at a concentration of 20% respectively produced

sustained release Diltiazem hydrochloride/ Metoprolol Succinate matrix

tablets that are similar to the marketed product (Dilzem SR/MetaXL50)

in-vitro according to the f2 similarity factor.

PVAP & dibasic calcium phosphate at a concentration of 39.5%

respectively, produced sustained release Diltiazem hydrochloride/

Metoprolol Succinate matrix tablets that are similar to the marketed

product (Dilzem SR/MetaXL50) in vitro according the f2 similarity factor.

Optimized sustained release Diltiazem hydrochloride/ Metoprolol

Succinate matrix tablets, showed square root of time dependent kinetics of

drug release indicating a dissolution and diffusion controlled release

mechanism.

Selected polymers and their concentrations are also capable of

sustaining the release of drug Diltiazem hydrochloride/ Metoprolol

Succinate beside drug concentration.

The in-vivo X-ray study of selected sustained release HPMC and

Eudragit and PVAP Diltiazem hydrochloride/Metoprolol Succinate matrix

Tablets proved that the polymer utilized for the optimization of the

CONCLUSION

208

formulation showed the sustaining activity in-vivo in rabbit by sticking to

various sites in the GIT.

Under long term storage conditions at 25oC and 60% RH, stability

testing performed on the selected HPMC/Eudragit and PVAP tablets

showed no significant change in the dissolution rates. Based on this

finding, the recommended storage conditions are 25oC and 60% RH.

Based on the above, it is concluded that sustained release Diltiazem

hydrochloride/Metoprolol Succinate matrix tablets was developed using

HPMC and Eudragit combination and PVAP as the release sustaining

excipients. In vitro testing indicated that sustained release Diltiazem

hydrochloride/Metoprolol Succinate matrix tablets had similar dissolution

behavior to the marketed product according to the model independent

FDA guideline (f2 factor).

209

REFERENCES

1. Oral controlled release matrix tablets: concept and literature

review. 2005:5-30.

2. Applied Biopharmaceutics & Pharmacokinetics. Modified-Release

Drug Products. 2004:515-16.

3. Committee for veterinary medicinal products (CVMP). Note for

guidance on, the quality of modified release dosage forms for

veterinary use. European agency. 2003;(2): 1-10.

4. Ratnaparkhi MP, Gupta Jyoti P. Sustained Release Oral Drug

Delivery System - An Overview. International Journal of Pharma

Research & Review, 2013; 2(3): 11-21.

5. Niraj VK, Srivastava N, Singh T, Gupta U. Sustained and controlled

drug delivery system - as a part of modified release dosage form.

International Journal of Research in Pharmaceutical and Nano

Sciences.2015; 4(3):347 - 364.

6. Ansel HC, Allen LV, Popovich NC. Pharmaceutical dosage forms

and drug delivery systems. Lippincott Williams and Wilkins;

Baltimore 7th ed. 2000:231-75.

7. Lachman L, Liberman AH, Kanig LJ. “The Theory and Practice of

IndustriesPharmacy”, 3rd ed. Lea & Febiger, 1986:430-56.317-24.

210

8. James S, James C: Boylan encyclopedia of Pharmaceutical

technology, 4th ed.Marcel Dekker; 1997:304-07.

9. Popli H, Sharma SN. Trend in oral sustained release formulation.

Dept. of pharmaceutics, Hamdard College of Pharmacy. NewDelhi-

110062. The Eastern Pharmacist August 1989:99.

10. Thomas WY, Joseph L, Robinson R. Sustained and Controlled

release drug delivery system , Marcel Dekker; 1978 (6):132- 34.

11. Chien YW. Rate controlled drug delivery systems; 2nd ed.; Marcel

Dekker; New york, Revised and expanded. 2005;(2):1-10.

12. Brahmankar HA, Jaiswal SB, Biopharmaceutics and

Pharmacokinetics A Treatise, Vallabh Prakashan, 2000:337,348-

357.

13. Shargel L, Yu ABC. Modified release drug products. In: Applied

Biopharmaceutics and Pharmacokinetics. 4th ed. McGraw Hill.

1999:169-171.

14. Sustained Release dosage form in Pharmaceutics and

pharmaceutical jurisprudence, 3rded.; Piyush Publications:3.111-

3.112.

15. Sathish UB, Shravani NG, Rao R, Reddy M, Sanjeev B. Overview

on Controlled Release Dosage Form. International Journal of

Pharma Sciences.2013:3(4):258-269.

16. Lloyd NS. Oral extended-release products. [Internet].1999; 22:88-90.

211

Available from: www.australianprescriber.com/magazine/22/4/88/90/-

Australia.

17. Sayed I, Abdel-Rahman, Gamal MM, El-Badry M, Preparation and

comparative evaluation of sustained release metoclopramide

hydrochloride matrix tablets, Saudi Pharmaceutical

Journal.2009;17:283-288.

18. Chandran S, Laila FA and Mantha N, Design and evaluation of Ethyl

Cellulose Based Matrix Tablets of Ibuprofen with pH Modulated

Release Kinetics, Indian Journal of Pharmaceutical Sciences,

2008;42(5):234-240.

19. Gothi GD, Parinh BN, Patel TD, Prajapati ST, Patel DM, Patel CN.

Study on Design and Development Of Sustained Release Tablets of

Metoprolol Succinate, Journal of Global Pharma Technology,

2010:2(2):69-74.

20. Basak SC, Reddy JBM, Lucas Mani KP. Formulation and release

behavior of sustained release ambroxol hydrochloride HPMC Matrix

tablet, Indian Journal of Pharmaceutical Sciences, 2006:68(5):594-

598.

21. Varshosaz J, Tavakoli N, Kheirolahi. Use of hydrophilic natural gums

in formulation of sustained-release matrix tablets of tramadol

hydrochloride.AAPS PharmSciTech. 2006;7(1):E168–E174.

212

22. Raghvengra Rao NG, Gandhi S, Patel T. Formulation and

Evaluation Of Sustained Release Matrix Tablets Of Tramadol

Hydrochloride. International Journal of Pharmacy and

Pharmaceutical Sciences.2009; 1(1):124-130.

23. Shivhare UD, Adhao ND, Bhusari KP, Mathur VB, Ambulkar

UD.Formulation development, evaluation and validation of sustained

release tablets of Aceclofenac. Int J Pharm Pharmaceu Sci. 2009;

1:74-80.

24. Vyas SP, Khar RK. Controlled Drug Delivery: Concepts and

Advances. 1st ed. vallabh prakashan, 2002: 156-189.

25. Borguist P, Korner A, Larsson A. A model for the drug release from a

polymeric matrix tablets-effect of swelling and dissolution, J

Controlled Release; 2006: 113(3):216-225.

26. Nishihata T, Tahara K, Yamamoto K. Overall mechanisms behind

matrix sustained release (SR) tablets prepared with hydroxypropyl

cellulose 2910, J Controlled Release.1995;35:59-66.

27. Siepmann J, Peppas NA, HPMC matrices for controlled drug

delivery: new model combining diffusion, swelling and dissolution

mechanisms and predicting the release kinetics, Pharm

Research.2000;16:1748-1756.

213

28. Chobanian AV. The Seventh Report of the Joint National Committee

on Prevention, Detection, Evaluation, and Treatment of High Blood

Pressure: the JNC 7 report. JAMA. 289:2560-72.

29. Oater JA. Antihypertensive agents and the drug therapy of

hypertension “Goodman and Gillman’s ‘the pharmacological basis of

Therapeutics”9thEdition, McGrew Hill, NewYork: 1996:780-981.

30. Encyclopedia of controlled drug delivery. Benjamin A Hertzog,Chris

Thanos. Cardiovascular drug delivery systems. 30th Edi

Mathiowitz.New York: A Wiley- Interscience Publication; 1999:169.

31. Ford JL, Rubinstein MH, Mccaul F,Hogan JE & Edgar PJ.

Importance of drug type, tablet shape and added diluents on drug

release kinetics from hydroxy propyl methylcellulose matrix tablets.

International Journal of Pharmaceutics;1987 : 40: 223-234.

32. Feely LC, Davis SS. Influence of polymeric excipients on drug

release from hydroxy propyl methylcellulose matrices. Int. J.

Pharm.1998; 41:83-90.

33. Wan LSC, Heng PWS, Wong LF.The effect of hydroxy propyl

methylcellulose on water penetration into a matrix system.

International Journal of Pharmaceutics.1991; 73:111- 116.

34. Mitchell K., Ford JL, Armstrong DJ, Elliott PNC, Rostron C, Hogan

JE. The influence of concentration on the release of drugs from gels

214

and matrices containing Cellulose ethers. International Journal of

Pharmaceutics.1993; 100: 155-163.

35. Rajabi-Siahboomi AR, Bowtell RW, Mansfield P,Davies MC, Melia,

CD.Structure and behavior in hydrophilic matrix sustained release

dosage forms: 4. Studies of water mobility and diffusion coefficients

in the gel layer of HPMC tablets using NMR imaging.

Pharmaceutical Research.1996; 13:376-380.

36. Gao P, Skoug JW, Nixon PR, Robert JU, Stemm NL, Sung KC.

Swelling of Hydroxypropyl methylcellulose matrix tablets. 2.

Mechanistic study of the influence of formulation variables on matrix

performance and drug release. Journal of Pharmaceutical

Sciences.1996; 85:732-740.

37. Sung KC,Nixon PR, Skoug JW, Ju TR, Patel MV.Effect of

formulation variables on drug and polymer release from HPMC

based matrix tablets. Int. J. Pharm. 1996; 142:53-60.

38. Formulating for controlled release with Methocel Premium cellulose

ethers. The Dow Chemical Company, Midland, Michigan. Dow

Pharmaceutical Excipients, 1996.

39. Campos-Aldrete ME, Villafuerte-Robles L. Influence of the viscosity

grade and the particle size of HPMC on metronidazole release from

matrix tablets. European Journal of Pharmaceutics and

Biopharmaceutics.1997:43; 173-178.

215

40. Nellore RV, Singh Rekhi G, Hussain AS, Tillman LG, Augsburger,

LL. Developmentof metoprolol tartrate extended-release matrix

tablet formulations for regulatory policy consideration. Journal of

Controlled Release: 1998: 50;247-256.

41. Colombo P, Bettini R., Peppas NA. Observation of swelling process

and diffusion front position during swelling in hydroxy propyl methyl

cellulose (HPMC) matrices containing a soluble drug. Journal of

Controlled Release : 1999;61:.83-91.

42. Velasco MV, Rowe JLFP, Rajabi-Siahboomi AR. Influence of drug:

hydroxy propyl mmethylcellulose ratio, drug and polymer particle

size and compression force on the release of diclofenac sodium from

HPMC tablets. Journal of Controlled release.1999:57;75–85.

43. Rekhi GS, Nellore RV, Hussain AS, Tillman L, Augsburger L.

Identification of critical formulation and processing variables for

metoprolol tartrate extended-release (ER) matrix tablets. J. Contr.

Rel. 1996; 59:327-342.

44. Siepmann J,Lecomte F, Bodmeier R. Diffusion-controlled drug

delivery systems: calculation of the required composition to achieve

desired release profiles. J. Contr. Rel.1996; 60:379-389.

45. Colombo P,Bettini R,Santi P, Peppas N. Swellable matrices for

controlled drug delivery: gel-layer behaviour, mechanisms and

216

optimal performance. Pharmaceutical Science and Technology

Today; 2000:3:198-204.

46. Siepmann J, Peppas NA. Modeling of drug release from delivery

systems based on hydroxypropyl methylcellulose (HPMC).Adv Drug

Deliv Rev.2011:11;139-57.

47. Bettini R, Catellani PL, Santi P, Massimo G, Peppas NA, Colombo

P.Translocation of drug particles in HPMC matrix gel layer: Effect of

drug solubility and influence on release rate. Journal of Controlled

Release.2001; 70:383-391.

48. Tiwari SB, Murthy TK, Pai MR, Mehta PR, Chowdary PB.Controlled

release formulation of tramadol hydrochloride using hydrophilic and

hydrophobic matrix system. AAPS Pharm Sci Tech.2003; 4:18-23..

49. Li Martini , Ford JL, Roberts M.The use of hypromellose in oral drug

delivery. Journal of Pharmacy and Pharmacology.2005:57;533-546.

50. Conti S, Maggi L, Segale L, Ochoa Machiste E, Conte U, Grenier

P, Vergnault G. Matrices containing NaCMC and HPMC 2. Swelling

and release mechanism study.Int J Pharm.2007;21:143-51.

51. Miranda A,Millan M, Caraballo I. Investigation of the influence of

particle size on the excipientpercolation thresholds of HPMC

hydrophilic matrix tablets. Journal of Pharmaceutical Sciences.2007;

96:10:2746-2756.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Siepmann%20J%5BAuthor%5D&cauthor=true&cauthor_uid=11369079

http://www.ncbi.nlm.nih.gov/pubmed/?term=Peppas%20NA%5BAuthor%5D&cauthor=true&cauthor_uid=11369079

http://www.ncbi.nlm.nih.gov/pubmed/11369079


http://www.ncbi.nlm.nih.gov/pubmed/?term=Conti%20S%5BAuthor%5D&cauthor=true&cauthor_uid=17240091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Maggi%20L%5BAuthor%5D&cauthor=true&cauthor_uid=17240091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Segale%20L%5BAuthor%5D&cauthor=true&cauthor_uid=17240091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Ochoa%20Machiste%20E%5BAuthor%5D&cauthor=true&cauthor_uid=17240091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Conte%20U%5BAuthor%5D&cauthor=true&cauthor_uid=17240091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Grenier%20P%5BAuthor%5D&cauthor=true&cauthor_uid=17240091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Grenier%20P%5BAuthor%5D&cauthor=true&cauthor_uid=17240091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Vergnault%20G%5BAuthor%5D&cauthor=true&cauthor_uid=17240091


217

52. Tamer B, Evren algin,ozge inal. The effects of polymer type and ratio

on the extended release of atenolol from hydrophilic matrices.

Turkish J. Pharm. Sci. 2007;4(1):41 – 52.

53. Ravi PR, Kotreka UK, Saha, RN.Controlled release matrix tablets of

Zidovudine: effect of formulation variables on the in vitro drug

release kinetics. AAPS Pharm. Sci. Tech.2008;9(1):302-313.

54. Barhate SD, Patel MP, Patil AB, Pawar SR, Rathi SR. Formulation

and optimization of controlled released floating tablets of

clarithromycin. Journal of Pharmacy Research .2009;2(3):445-448.

55. Chaudhary A, Pacharane S, Jadhav KR, Kadam VJ. Formulation

and Development of Extended Released Tablet of Lamotrigine.

International Journal of Pharma and Bio Sciences; 2011: 2(1):198-

210.

56. Gunjal PT, Shinde MB, Gharge VS, Pimple SV, Gurjar MK, Shah

MN. Design, Development and Optimization of S (-) AtenololFloating

Sustained Release Matrix Tablets Using Surface Response

Methodology. Indian J Pharm Sci 2015; 77(5):563-572.

57. McGinity JW, Cameron CG., Controlled release theophylline tablet

formulations containing acrylic resins II.Combination resin

formulations. Drug Dev. Ind.Pharm. 1987; 13(8):1409-1427.

58. Vela MT, Fernandez-Hervas MJ, Fernandez-Arevalo M, Rabasco A

M, Effect of acrylic resins on the rheological and compressibility

218

properties of paracetamol: Formulation of directly compressible

matrix systems. Farmaco 1995; 50; 201-215.

59. Khopade AJ, Jain NK. Self assembling nanostructures for sustained

ophthalmic drug delivery. Pharmazie. 1995; 50(12):812-814.

60. Takka S, Rajbhandari S, Sakr A. Effect of anionic polymerws on the

release of propranolol hydrochloride from matrix tablets. Eur. J.

Pharm. Biopharm. 2001; 52: 75-82.

61. Pignatello R. Bucolo C, Puglisi G. Ocular tolerability of Eudragit

RS100 and RL100 nanosuspensions as carriers for ophthalmic

controlled drug delivery. J Pharm Sci. 2002; 91(12):2636-41.

62. Matolepsza-Jarmotowska K, Kubis AA, Hirnle L. Studies on

gynaecological hydrophilic lactic acid preparations, part 6: use of

Eudragit E-100 as lactic acid carrier in intravaginal tablets.

Pharmazie. 2003; 58(5):334-6.

63. Bucolo C, Maltese A, Maugeri F, Busa B, Puglisi G, Pignatello R.

Preparation and characterization of Eudragit Retard

nanosuspensions for the ocular delivery of cloricromene. J.

Pharm.Pharmacol. 2004, 56: 841-846

64. Kale RD, Tayade PT. A multiple unit floating drug delivery system of

piroxicam using eudragit polymer. Ind. J. Pharm. Sci., 2007; 69:120-

123.

219

65. Duarte AR, Roy C, Vega-González A, Duarte CM, Subra-Paternault

P. Preparation of acetazolamide composite microparticles by

supercritical anti-solvent techniques. Int J Pharm. 2007:6;332(1-

2):132-9.

66. Semalty M, Semalty A, Kumar G. Formulation and Characterization

of Mucoadhesive Buccal Films of Glipizide. Ind. J. Pharm. sci. 2008;

70. 43-48.

67. Rahman Md A, Ali J. Development and in vitro Evaluation of Enteric

Coated Multiparticulate System for Resistant Tuberculosis. Ind. J.

Pharm. Sci., 2008; 70: 477-481.

68. Degim IT, Tugcu-Demiroz F, Tamer-Ilbasmis S, Acarturk F.

Development of controlled release sildenafil formulations for vaginal

administration. Drug Deliv. 2008; 15(4):259-65.

69. Nagasamy VD, Reddy AK, Samanta MK, Suresh B. Development

and in vitro evaluation of colonic drug delivery systems for tegaserod

maleate.Asian J. Pharm. 2009; 3: 50-53.

70. Walid S, Fars A, Adel S. Effect of Kollidon® SR on the release of

Albuterol Sulphate from matrix tablets. Saudi Pharmaceutical

Journal.2011; 19: 19–27.

71. Shah P, Naik B, Zalak C. Optimization of Formulation Variables of

Ranolazine Extended-Release Tablets by 32 Full Factorial Designs.

Pharmagene 2013: 1(2); 1-9.

220

72. BASF, 1999. Technical information for Kollidon® SR, BASF AG,

Ludwigshafen/Rh., Germany.

73. Kolter K, Fraunhofer W, Ruchatz F. Properties of Kollidon SR as a

new excipient for sustained release dosage forms. BASF ExAct.

2000:5-6.

74. Draganoiu E, Andheria M, Sakr. A. Evaluation of the new

polyvinylacetate/ povidone excipient for matrix sustained release

dosage forms. J. Pharm. Ind. 2001; 63:624–629.

75. Shao ZJ, Farooqi MI, Diaz S, Krishna AK, Muhammad NA. Effects of

formulation variables and postcompression curing on drug release

from a new sustained release matrix material: polyvinylacetate

povidone. Pharm. Dev. Techol.2001; 6:247-254.

76. Siepmann F, Eckart K, Maschke A, Kolter K, Siepmann J. Modeling

drug release from PVAC/PVP matrix tablets. J. Control.

Release.2010; 141:216–222.

77. Mulani HT, Patel B, Shah NH. Formulation and Evaluation of

Kollidon® SR for PH-Independent Extended Release Matrix

Systems for Propranolol Hydrochloride .J. Pharm. Sci. & Res. 2011;

3(5):1233-1244.

78. USP35, diltiazem hydrochloride, 2916.

79. Indian Pharmacopoeia. Delhi: The Controller of Publications; 2007;

2:423-425.

221

80. Sweetman SC, editor. Martine Dale: the complete drug reference.

33rd ed. London: Pharmaceutical Press; 2002.

81. Tripathi KD. Essentials of medical pharmacology. 5th ed. New Delhi:

Jaypee Brothers Medical Publishers (P) Ltd; 2003.

82. Satoskar RS, Bhandarkar SD, Rege NN. In: Satoskar RR, editor.

Pharmacology and pharmacotherapeutics. 19th ed. Mumbai: Popular

Prakashan Private Limited; 2005.

83. USP31, metoprolol succinate, 2695.

84. Indian Pharmacopoeia. Delhi: The Controller of Publications; 2007;

2:423-425.

85. Wikstrand J, Andersson B, Kendall MJ, Stanbrook H and Klibaner M.

Pharmacokinetic considerations of formulation: extended-release

metoprolol succinate in the treatment of heart failure. J. Cardiovasc.

Pharmacol. 2003; 41: 151-157.

86. Falkner B, Kushner H. Treatment with metoprolol succinate, a

selective beta adrenergic blocker, lowers blood pressure without

altering insulin sensitivity in diabetic patients. J. Clin. Hypertens.

2008;10: 51-57.

87. Rowe RC, Sheskey PJ, Quinn ME. Handbook of pharmaceutical

excipients 6th edition.2009:326-329


excipients 6th edition.2009.525-533.

222


excipients 6th edition.2009.562-563

90. Rowe RC, Sheskey PJ, Quinn ME.. Handbook of pharmaceutical









excipients 6th edition. 2009. 359-369.

95. Banker GS, Anderson NR. Tablets. In: Lachman L, Lieberman HA,

Kanig JL. The theory and practice of industrial pharmacy. 3rd ed.

Mumbai: Varghese Publishing House. 2003; 182-84:296-303,311-

12.

96. Subramanyam CVS. Textbook of Physical Pharmaceutics, Vallabh

Prakashan. 2nded; 2001:315.

97. Pharmacopoeia of India. New Delhi: Ministry of Health and Family

Welfare, Government of India, Controller of Publications.1996;2:

555-56.

223

98. Mohammad SI, Selim R,Habibur R. In vitro Release Kinetics Study

of Diltiazem Hydrochloride from Wax and Kollidon SR Based Matrix

Tablets. Iranian Journal of Pharmaceutical Research. 2008; 7 (2):

101-108.

99. Reza S, Quadir MA, Syed SH. Comparative evaluation of plastic,

hydrophobic and hydrophilic polymers as matrices for controlled-

release drug delivery. J Pharm Pharmaceut Sci ,2003;6(2):282-291.

100. United State Pharmacopoeia 30 NF 25, 2648.

101. Deshmukh VN, Singh SP, Sakarkar DM. Formulation and Evaluation

of Sustained Release Metoprolol Succinate Tablet using Hydrophilic

gums as Release modifiers. International Journal of Pharm Tech

Research.2009; 1(2):159-163.

102. Chandana C, Ganesh Kumar Y, Vamshi Vishnu Y, Minnu Madhuri

M. Metoprolol Succinate Sustained Release Matrix Tablets-

Formulation Development and In-vitro Evaluation. International

Journal of Pharmacy and Pharmaceutical Sciences.2014; 6(7).

103. FDA’S Draft Guidance on Metoprolol Succinate. Recommended Jan

2008; Revised Apr 2008, Feb 2014.

104. FDA, 1997a. Modified Release Solid Oral Dosage Forms. Scale-Up

and Post approval Changes: Chemistry, Manufacturing, and

Controls, In Vitro Dissolution Testing and In Vivo Bioequivalence

Documentation. Guidance for Industry. US Department of Health and

224

Human Services Food and Drug Administration Center for Drug

Evaluation and Research, Center for Biologics Evaluation and

Research.

105. FDA, 1997b. Extended Release Solid Oral Dosage Forms

Development, Evaluation and Application Of In Vitro-In Vivo

Correlation. Guidance for Industry. US Department of Health and

Human Services, Food and Drug Administration, Center for Drug

Evaluation and Research.

106. Gohel MC, Panchal MK. Novel use of similarity factors f2 and SD for

the development of diltiazem HCl modified-release tablets using a

3(2) factorial design. Drug Dev. Ind. Pharm. 2002; 28(1): 77-87.

107. Suvakanta Dash, Padala Narasimha Murthy, Lilakanta Nath,

Prasanta Chowdhury. Kinetic Modeling on Drug Release From

Controlled Drug Delivery Systems. Acta Poloniae Pharmaceutica -

Drug Research.2003; 67(3):217-223.

108. Modeling and data treatment in the pharmaceutical sciences,

Cartensen J.T. Ed., Technomic Publishing Co. Inc., New York, Basel

1996.

109. Ozturk SS, Palsson BO, Dressman JB. Kinetics of release from

enteric-coated tablets. Pharm. Res.1988; 5:550.

110. Dressman JB, Fleisher D, Amidon GL. Physicochemical model for

dose-dependent drug absorption. J. Pharm. Sci.1984; 73:1274.

225

111. Lich BH, Des Rosiers L, Elands J, Tinke AP. Sub Micron Particle

Size and Shape Characterization by SEM.2012; 122-145.

112. Internal standard method for size calibration of sub-micrometer

spherical particles by electron microscope, Technical Note 010B,

Duke Scientific corporation.2003.

113. Gregorova A. Application of Differential Scanning Calorimetry to the

Characterization of Biopolymers. http://dx.doi.org/10.5772/ 53822.

114. Interpreting DSC curves; part 1 dynamic measurements. Usercom

1/2000.

115. Chowdary KPR, Suresh B, Sangeeta B and Reddy BK. Design and

Evaluation of Diltiazem Mucoadhesive Tablets for Oral Controlled

Release. Saudi Pharmaceutical Journal.2003; 11(4):201-205.

116. Senthil V, Sureshkumar R, Lavanya K, Rathi V, Venkatesh DN,

Ganesh GNK, Jawahar N, Gowth K. In vitro and in vivo evaluations

of Theophylline Gastroretentive Mucoadhesive tablets prepared by

using natural gums. Journal of Pharmacy Research .2010;3(8):1961-

1966.

117. Ige PP, Gattani SG. In vivo radio imaging studies on designed

swelling gastro retentive drug delivery system. African Journal of

Pharmacy and Pharmacology.2013; 7(43):2846-2848.

226

118. Dinesh Kumar P, Rathnam G, Prakash GR, Saravanan G, Karthick

V , Selvam PT. Formulation and Characterizatioin of Bilayer Floating

Tablets of Ranitidine. Rasayan J.Chem.2010; 3(2):368-374.

119. ICH Q1A Stability Testing of New Drug Substances and Products

Guidance for Industry. US Department of Health and Human

Services Food and Drug Administration Center for Drug Evaluation

and Research, Center for Biologics Evaluation and Research,

ICH,FDA;2001.

Formulation and Evaluation of Sustained Release …Formulation and Evaluation of Sustained Release...

Documents

Transcript of Formulation and Evaluation of Sustained Release …Formulation and Evaluation of Sustained Release...