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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
Diltiazem Hydrochloride
78
6.6.3.2. Drug Content of Matrix Tablet Containing
Metoprolol Succinate
79
6.6.4. In vitro dissolution study of matrix tablet 80
6.6.4.1. Dissolution Studies of matrix tablet containing
Diltiazem Hydrochloride
80
6.6.4.2. Dissolution Studies of matrix tablet containing
Metoprolol Succinate
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
Diltiazem Hydrochloride.
118
7.5.1.2 Evaluation of pre-compression parameters of
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
7.5.2.2 Evaluation of pre-compression parameters of
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
Diltiazem Hydrochloride.
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
7.10.2. SEM study of selected optimized formulation
containing HPMC and Eudragit with Metoprolol
Succinate (FM11)
174
7.10.3. SEM study of selected optimized formulation
containing PVAP with Diltiazem Hydrochloride (FD17)
176
7.10.4. SEM study of selected optimized formulation
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
7.13.2. Effect of stability conditions on physical
characteristics and release of Metoprolol Succinate
from optimized formulation (FM11).
201
7.13.3. Effect of stability conditions on physical
characteristics and release of Diltiazem Hydrochloride
from optimized formulation (FD17).
203
7.13.4. Effect of stability conditions on physical
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
21 IR spectra of pure diltiazem hydrochloride 100
22 IR spectra of mixture of optimized formulation (FD11) 101
23 IR spectra of pure Metoprolol Succinate 103
24 IR spectra of mixture of drug (Metoprolol Succinate) and
polymer- FM11
104
25 IR spectra of pure diltiazem hydrochloride 106
26 IR spectra of mixture of drug (Diltiazem Hydrochloride) and
polymers-FD17
107
27 IR spectra of pure Metoprolol Succinate 109
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
58 SEM photomicrographs of optimized matrix tablet (batch
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 hours (F, 500×) of dissolution study
174
59 SEM photomicrographs of optimized matrix tablet (batch
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 hours (F, 500×) of dissolution study
176
60 SEM photomicrographs of optimized matrix tablet (batch
FM17)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
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
Diltiazem Hydrochloride
68
10 Composition of PVAP Matrix Tablet Containing
Metoprolol Succinate
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
26 Mean cumulative % drug release of all formulation of
HPMC, Eudragit containing Metoprolol Succinate
141
27 Mean cumulative % drug release of all formulation of
PVAP containing Diltiazem Hydrochloride
148
28 Mean cumulative % drug release of all formulation of
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
30 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 metoprolol succinate
164
31 Correlation coefficient [R], Constant [k], and Diffusion
exponent [n] after fitting of dissolution data into various
release kinetic models of all formulation of PVPA
containing Diltiazem Hydrochloride
166
32 Correlation coefficient [R], Constant [k], and Diffusion
exponent [n] after fitting of dissolution data into various
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
38 Effect of long term stability storage on the physical
properties of HPMC/Eudragit tablets (FM11 Batch)
202
39 Effect of long term stability storage on the physical
properties of PVAP tablets (FD 17 Batch)
204
40 Effect of long term stability storage on the physical
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
INTRODUCTION TO MATERIALS
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
.
INTRODUCTION TO MATERIALS
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.
INTRODUCTION TO MATERIALS
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
INTRODUCTION TO MATERIALS
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
INTRODUCTION TO MATERIALS
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.
INTRODUCTION TO MATERIALS
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
INTRODUCTION TO MATERIALS
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.
INTRODUCTION TO MATERIALS
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.
INTRODUCTION TO MATERIALS
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.
INTRODUCTION TO MATERIALS
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
INTRODUCTION TO MATERIALS
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
INTRODUCTION TO MATERIALS
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.
INTRODUCTION TO MATERIALS
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
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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:
Standard Solution: Accurately weighed 100 mg of diltiazem hydrochloride
was dissolved in 100 ml of 0.1 N HCl to give a concentration of 1 mg/ ml.
MATERIALS AND METHODS
62
Stock Solution: From the standard solution, a stock solution was
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
hydrochloride respectively. The absorbance of prepared solutions of
diltiazem hydrochloride in 0.1 N HCl 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-12. 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 pH 7.4 phosphate buffer :
The standard curve of diltiazem hydrochloride was prepared in pH 7.4
phosphate buffer.
Procedure:
Standard Solution: Accurately weighed 100 mg of diltiazem hydrochloride
was dissolved in 100 ml of 7.4 phosphate buffer 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 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
MATERIALS AND METHODS
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.
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
MATERIALS AND METHODS
64
diltiazem hydrochloride in distilled water 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-14. 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.
c) In 0.1 N HCl
The standard curve of metoprolol succinate was prepared in 0.1 N HCl.
Procedure:
Standard Solution: Accurately weighed 100 mg of metoprolol succinate
was dissolved in 100 ml of 0.1 N HCl 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 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.
MATERIALS AND METHODS
65
c) In pH 7.4 phosphate buffer
The standard curve of metoprolol succinate was prepared in pH 7.4
phosphate buffer.
Procedure:
Standard Solution: Accurately weighed 100 mg of metoprolol succinate
was dissolved in 100 ml of 7.4 phosphate buffer 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 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.
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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)
All batches quantity in mg/tablet
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
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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)
All batches quantity in mg/tablet
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
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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:
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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.
MATERIALS AND METHODS
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.
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
92
Figure 13: IR spectra of HPMCK 100LV
OHstr. 3240.76
CH2 str. 2865.54
C-O-C str 1056.76
RESULTS AND DISCUSSION
93
Figure 14: IR spectra of Eudragit L100-55
CH2 str. 2711.42
C=O str. 1727.91
C-O-C str. 1022.09
RESULTS AND DISCUSSION
94
Figure 15: IR spectra of Microcrystalline Cellulose
OH str 3289.96
CH2 str. 2904.27
C-O-C str. 1041.37
RESULTS AND DISCUSSION
95
Figure 16: IR spectra of Lactose
OH str. 3252.16
CH2 str. 2900.41
C-O-C str. 1037.52
RESULTS AND DISCUSSION
96
Figure 17: IR spectra of magnesium stearate
CH2 str. 2867.99
C=O str. 1720.19
C-O-C str. 1029.8
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
98
Figure 19: IR spectra of dibasic calcium phosphate
OH str. 3270.68
RESULTS AND DISCUSSION
99
Figure 20: IR spectra of colloidal silicon dioxide
RESULTS AND DISCUSSION
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)
Figure 21: 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
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
103
7.2.1.2. Compatibility Study of HPMC, Eudragit matrix tablets
Containing Metoprolol Succinate (FM11).
Figure 23: 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
RESULTS AND DISCUSSION
104
Figure 24: IR spectra of mixture of drug (Metoprolol Succinate) and
polymer- FM11
NH str 3252.65cm-1
Ar-CH str. 3008.52cm-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.
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
106
7.2.2. Compatibility Study of matrix tablet containing PVAP.
7.2.2.1. Compatibility Study of PVAP matrix tablet containing
Diltiazem Hydrochloride.
Figure 25: 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
RESULTS AND DISCUSSION
107
Figure 26: IR spectra of mixture of drug (Diltiazem Hydrochloride) and
polymers-FD17
Ar-CH str. 3004.56cm-1
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
109
7.2.2.2. Compatibility Study of PVAP matrix tablet containing
Metoprolol Succinate.
Figure 27: 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
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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
Standard deviation n=3
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
RESULTS AND DISCUSSION
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
Standard deviation n=3
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
RESULTS AND DISCUSSION
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
Standard deviation n=3
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
RESULTS AND DISCUSSION
116
b) In 0.1 N HCls
Table No 15: Absorbance values of Metoprolol Succinate in0.1 N HCl
Sr. No. Concentration in mcg/ml Absorbance mean ± SD*
(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
Standard deviation n=3
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
RESULTS AND DISCUSSION
117
c) In pH 7.4 phosphate buffer
Table No 16: Standard graph of Metoprolol Succinate in pH 7.4 phosphate
buffer
Sr. No. Concentration in mcg/ml Absorbance mean ± SD*
(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
Standard deviation n=3
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
RESULTS AND DISCUSSION
118
7.5. EVALUATION OF MATRIX TABLETS:
7.5.1 Evaluation of pre-compression parameters of HPMC and
Eudragit Matrix Tablet
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)
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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 ±
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
123
Results of the pre-compression parameters performed on the blend
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
RESULTS AND DISCUSSION
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)
Results of the pre-compression parameters performed on the blend
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%,
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
126
7.6. POST-COMPRESSIONAL STUDIES
7.6.1. Evaluation of Post-compression parameters of HPMC and
Eudragit Matrix Tablet
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)
RESULTS AND DISCUSSION
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%.
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
129
Matrix tablets of Metoprolol succinate were prepared by the dry
granulation method and subjected to different evaluation tests reported in
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.
For all the prepared formulations, friability percentage was less than
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.
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
131
Matrix tablets of diltiazem hydrochloride were prepared by the dry
granulation method and subjected to different evaluation tests reported in
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
For all the prepared formulations, friability percentage was less than
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%.
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
133
Matrix tablets of Metoprolol succinate were prepared by the dry
granulation method and subjected to different evaluation tests reported in
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.
For all the prepared formulations, friability percentage was less than
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
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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 %
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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).
RESULTS AND DISCUSSION
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)
Mean Cumulative % Drug Release of all Formulation (Mean SD, n=3)
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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 .
RESULTS AND DISCUSSION
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
Succinate release from SR matrix tablets
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
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)
Mean Cumulative % Drug Release of all Formulation (Mean SD, n=3)
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
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
150
disintegrant, destroying matrix cohesion, and in essence, producing an
immediate release tablet.
The matrix tablet formulation with high levels, greater than 50%, of
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
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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)
Mean Cumulative % Drug Release of all Formulation (Mean SD, n=3)
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
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
157
disintegrant, destroying matrix cohesion,and in essence, producing an
immediate release tablet.
The matrix tablet formulation with high levels, greater than 50%, of
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
Succinate release from SR matrix tablets
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
162
7.8. RELEASE KINETIC STUDY
7.8.1 Release Kinetic Study of All Formulation of HPMC, Eudragit
Containing Diltiazem Hydrochloride.
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
164
7.8.2. Release Kinetic Study of All Formulation of HPMC, Eudragit
Containing Metoprolol Succinate.
Table No 30: 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 metoprolol succinate
Formu-
Lation
Correlation Coefficient [R] For Krosmeyer-
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
166
7.8.3. Release Kinetic Study of All Formulation of PVAP Containing
Diltiazem Hydrochloride.
Table No 31: Correlation coefficient [R], Constant [k], and Diffusion
exponent [n] after fitting of dissolution data into various release kinetic
models of all formulation of PVPA containing Diltiazem Hydrochloride
Formu-
Lation
Correlation Coefficient [R] For Krosmeyer-
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
RESULTS AND DISCUSSION
167
The release rate kinetic data for all the models can be seen in Table
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
mechanism. To confirm the diffusion mechanism, the data were fit into
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.
RESULTS AND DISCUSSION
168
7.8.4 Release Kinetic Study of All Formulation of PVAP Containing
Metoprolol Succinate.
Table No 32: Correlation coefficient [R], Constant [k], and Diffusion
exponent [n] after fitting of dissolution data into various release kinetic
models of all formulation of PVAP containing Metoprolol succinate
Formu-
Lation
Correlation Coefficient [R] For Krosmeyer-
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
RESULTS AND DISCUSSION
169
The release rate kinetic data for all the models can be seen in Table
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
mechanism. To confirm the diffusion mechanism, the data were fit into
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.
RESULTS AND DISCUSSION
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
dataset of marketed formulation (Standard). From statistical test (ANOVA)
its observed that all the sample batches are statistically different except
Batch FM11. It reflects that batch FM11 resembles batch M (standard
batch/marketed preparation). Concluding that batch FM11 is better
amongst rest of the batches.
7.9.3 Statistical analysis of diltiazem hydrochloride with PVAP matrix
tablet.
All date 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
RESULTS AND DISCUSSION
171
Batch FD17. It reflects that batch FD17 resembles batch M (standard
batch/marketed preparation). Concluding that batch FD17 is better
amongst rest of the batches.
7.9.4 Statistical analysis of Metoprolol succinate with PVAP matrix
tablet.
All data set obtained from all the sample batches are compared with
dataset of marketed formulation (Standard). From statistical test (ANOVA)
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
amongst rest of the batches.
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
174
7.10.2. SEM study of selected optimized formulation containing HPMC
and Eudragit with Metoprolol Succinate (FM11)
Figure No 58: SEM photomicrographs of optimized matrix tablet (batch
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
hours (F, 500×) of dissolution study.
RESULTS AND DISCUSSION
175
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 58-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 (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.
RESULTS AND DISCUSSION
176
7.10.3. SEM study of selected optimized formulation containing PVAP
with Diltiazem Hydrochloride (FD17)
Figure No 59: SEM photomicrographs of optimized matrix tablet (batch
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
hours (F, 500×) of dissolution study.
A B
C D
E F
RESULTS AND DISCUSSION
177
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 59-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 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.
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
179
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 60-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 (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.
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
184
Figure No 66: DSC thermogram of Metoprolol Succinate+
HPMCK100LV+Eudragit L100-55
Figure No 67: DSC thermogram of optimized formulation (FM11)
RESULTS AND DISCUSSION
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
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 1400C in
thermograms of DSC and optimized formulation (FM11) at 136.590C. 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 34 and DSC thermograms are
shown in Figure 64 to Figure 67. After the compatibility study, it was
revealed that there was no interaction between the drug and the polymers
were selected.
RESULTS AND DISCUSSION
186
7.11.3. Diltiazem Hydrochloride, PVAP.
Figure No 68: DSC thermogram of Diltiazem Hydrochloride
Figure No 69: DSC thermogram of PVAP+DCP
RESULTS AND DISCUSSION
187
Figure No 70: DSC thermogram of Diltiazem hydrochloride+PVAP+DCP
Figure No 71: DSC thermogram of optimized formulation (FD17)
RESULTS AND DISCUSSION
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
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 219.10 C in
thermograms of DSC and optimized formulation (FD17) at 218.50 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 35 and DSC thermograms are
shown in Figure 68 to Figure71. After the compatibility study, it was
revealed that there was no interaction between the drug and the polymers
were selected.
RESULTS AND DISCUSSION
189
7.11.4. Metoprolol Succinate, PVAP
Figure No 72: DSC thermogram of Metoprolol Succinate
Figure No73: DSC thermogram of PVAP+DCP
RESULTS AND DISCUSSION
190
Figure No 74: DSC thermogram of Metoprolol Succinate+ PVAP+DCP
Figure No 75: DSC thermogram of optimized formulation (FM17)
RESULTS AND DISCUSSION
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
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 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
shown in Figure 72 to Figure 75. After the compatibility study, it was
revealed that there was no interaction between the drug and the polymers
were selected.
RESULTS AND DISCUSSION
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.
RESULTS AND DISCUSSION
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).
RESULTS AND DISCUSSION
194
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. FM11 formulation showed sustained effect for
12 hr as shown in Figure 77.
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
196
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. FD17 formulation showed sustained effect for 12
hr as shown in Figure 78.
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
198
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. FM17 formulation showed sustained effect for 12
hr as shown in Figure 79.
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
Containing Diltiazem Hydrochloride.
B) Optimized Matrix Tablet formulation (FM11)of HPMC, Eudragit
Containing metoprolol succinate.
C) Optimized Matrix Tablet formulation (FD17) of PVAP containing
Diltiazem Hydrochloride.
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:
RESULTS AND DISCUSSION
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)
RESULTS AND DISCUSSION
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
RESULTS AND DISCUSSION
201
7.13.2. Effect of stability conditions on physical characteristics and
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)
RESULTS AND DISCUSSION
202
Table No 38: Effect of long term stability storage on the physical properties
of HPMC/Eudragit tablets (FM11 Batch)
Physical
Property Initial 1 month 3 months 6 months 9 months
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
(*) significantly different from initial at 0.05 level
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
RESULTS AND DISCUSSION
203
7.13.3. Effect of stability conditions on physical characteristics and
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.
RESULTS AND DISCUSSION
204
Table No 39: Effect of long term stability storage on the physical properties
of PVAP tablets (FD 17 Batch)
Physical
Property Initial 1 month 3 months 6 months 9 months
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
(*) significantly different from initial at 0.05 level
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
RESULTS AND DISCUSSION
205
7.13.4. Effect of stability conditions on physical characteristics and
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.
RESULTS AND DISCUSSION
206
Table No 40. Effect of long term stability storage on the physical properties
of PVAP tablets (FM17 Batch)
Physical
Property Initial 1 month 3 months 6 months 9 months
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*
(*) significantly different from initial at 0.05 level
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
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