Design, Formulation and Evaluation of Controlled Release Tablets of Selected Non-Steroidal Anti-
inflammatory Drugs
DOCTOR OF PHILPSOPHY
(PHARMACEUTICS)
THESIS
(2006-2010)
By
MUHAMMAD AKHLAQ
SUPERVISED BY: Prof. Dr. Gul Majid Khan
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan
Design, Formulation and Evaluation Controlled Release Tablets of Selected Non-Steroidal Anti-
inflammatory Drugs
DOCTOR OF PHILPSOPHY
(PHARMACEUTICS)
THESIS
By
Muhammad Akhlaq
SUPERVISED BY: Prof. Dr. Gul Majid Khan
A thesis submitted in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan
Approval Certificate
The thesis entitled “Design, Formulation and Evaluation of Controlled Release Tablets of
Selected Non-Steroidal Anti-inflammatory Drugs” prepared by Muhammad Akhlaq under
my guidance in partial fulfillment of the requirement for the degree of Doctor of Philosophy
(Pharmaceutics) is hereby approved for submission.
Prof. Dr. Gul Majid Khan Research Supervisor
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan
Declaration
The work presented in this dissertation has been carried out by me at the Department of
Pharmaceutics, Faculty of Pharmacy, Gomal University, Dera Ismail Khan under supervision
of Prof. Dr. Gul Majid Khan.
Muhammad Akhlaq Ph.D. Scholar
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan
vi
Dedication
To
MY MOTHER
For
Leading me into intellectual pursuits and unconditional support in my studies
To
MY FATHER
For
The uncompromising principles that guided me throughout my student life
To
MY SISTERS
For
Their kindness and to create a friendly environment
To
MY TEACHERS
For
Their guidance and kind patronage throughout my research pursuits
Controlled Release Tablets of Selected NSAIDs Content
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. vii
Content
CHAPTER #
TOPIC PAGE
#
CERTIFICATE OF APPROVAL iv
DEDICATION vi
CONTENT vii
LIST OF FIGURES xii
LIST OF TABLES xvi
LIST OF ABBREVIATIONS xxi
ACKNOWLEDGEMENT xxiii
ABSTRACT xxiv
1 INTRODUCTION 1
1.1 Oral Drug Delivery Systems 1
1.2 Anatomical and Physiological Consideration of GIT 3
1.2.1 The Oesophagus 5
1.2.2 The Stomach 6
1.2.3 The Small Intestine 7
1.2.4 The Colon 9
1.3 Drug Absorption form GIT 10
1.4 Modified Drug Delivery System 12
1.4.1 Types of Modified Drug Delivery Systems 13
1.4.1.1 Delayed or Repeated Release Dosage Forms 13
1.4.1.2 Prolonged or Extended Release Dosage Forms 13
1.4.1.3 Targeted Release Dosage Forms 14
1.4.2 Requirements for Candidate for Oral Controlled Released Dosages Form
14
1.4.2.1 Drug Dissolution 14
1.4.2.2 Solubility and pKa 15
1.4.2.3 Absorption 16
1.4.2.4 Distribution 17
1.4.2.5 Elimination and Clearance 18
1.4.2.6 Routine Binding 19
1.4.2.7 Elimination Half-life 20
1.4.3 Oral Controlled Release Matrix Systems 21
1.4.3.1 Advantages and Disadvantages of Oral Controlled Released Matrix Systems
22
1.4.3.2 Controlled Released Matrix Tablets 24
1.4.3.3 Lipid Matrix Systems 27
1.4.3.4 Insoluble Polymer Matrix Systems 28
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. viii
1.4.4 Reservoir Systems 29
1.4.5 Other Technologies 30
1.4.5.1 Multi-Particulate Formulation 30
1.4.5.2 Phased Drug Delivery 30
1.4.5.3 Ion-Exchange Systems 31
1.4.5.4 Bioadhesive 32
1.4.5.5 Gastroretentive Systems 32
1.5 Model Drugs 33
1.5.1 Flurbiprophen 33
1.5.2 Dicolofenac Sodium 34
1.6 Controlled Released Polymers 35
1.6.1 Cellulose Derivative Polymers Used for Drug Delivery 36
1.7 Tablet Preparation 38
1.7.1 Direct Compression 38
1.7.2 Advantages of Direct Compression 39
1.7.3 Limitation of Direct Compression 39
1.8 In-Vitro Evaluation 39
1.8.1 Bioavailability-Bioequivalence Studies 40
1.8.2 Absolute Bioavailability 41
1.8.3 Relatives Bioavailability 41
1.8.4 Direct Method 42
1.8.5 In-Direct Method 42
1.9 High Performance Liquid Chromatographic Analysis 44
1.9.1 Method Validation 44
1.9.2 Linearity 45
1.9.3 Precision 45
1.9.4 Repeatability or Intra-day Precision 46
1.9.5 Intermediate Decision or Inter-day Precision 46
1.9.6 Reproducibility 46
1.9.7 Accuracy 46
1.9.8 Limit of Quantitation (LOQ) / Limit of Detection (LOD) 47
1.10 Aims of the Work 47
2 REVIEW OF LITERATURE 48
3 MATERIALS AND METHODS 64
3.1 Materials 64
3.2 Equipments 64
3.3 Methods 66
3.3.1 Particle Size Analysis 66
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. ix
3.3.2 Particle Size Distribution 66
3.3.3 UV Spectrophotometeric Analysis 66
3.3.3.1 Selection of Suitable Wavelength 66
3.3.3.2 Standard Curve of FLB and DCL –Na 67
3.3.4 Pre-Formulation Study 67
3.3.4.1 Equilibrium Solubility 67
3.3.4.2 Preparation of Solid Dispersion 67
3.3.4.3 Bulk Density 68
3.3.4.4 Tapped Density 68
3.3.4.5 Hausner’s Ratio 69
3.3.4.6 Angle of Repose 69
3.3.4.7 Compressibility Index 70
3.3.5 Differential Scanning Calorimetery 70
3.3.6 Infra-Red Absorption spectroscopy 71
3.3.7 Scanning Electron Microscopy 71
3.3.8 X-Ray Diffractometery 71
3.3.9 Preparation of Matrix Tablets 71
3.3.9.1 Preparation of 100 mg each of FLV and DCL-Na Tablets 71
3.3.9.2 Preparation of 100 mg each of FLV and DCL-Na Tablets without Polymer
76
3.3.9.3 Preparation of 200 mg each of FLV Tablets 77
3.3.10 Physical Characterises of Matrix Tablets 77
3.3.10.1 Thickness and Diameter 77
3.3.10.2 Hardness 78
3.3.10.3 Weight Variation 78
3.3.10.4 Friability Test 79
3.3.10.5 Content Uniformity Test 80
3.3.11 In-Vitro Drug Release Study 80
3.3.12 Drug Release Kinetics 81
3.3.12.1 Zero-Order Kinetics 82
3.3.12.2 First-Order Kinetics 82
3.3.12.3 Hixson Crowell’s Equation or Erosion Model 82
3.3.12.4 Higuchi’s Kinetics 83
3.3.12.5 Krosmeyer-Peppas Equation 83
3.3.13 Polymer Hydration or Water Uptake 84
3.3.14 Matrix Erosion 85
3.3.15 Testing Dissolution Equivalency 85
3.3.16 Effect of Aging on the Release of FLV and DCL-Na from Controlled Released Matrix Tablets
86
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. x
3.3.17 High Performance Liquid Chromatography (HPLC) Method Development
87
3.3.17.1 Preparation of HPLC analytical Method 87
3.3.17.2 Precision and Accuracy 87
3.3.17.3 Limit of Detection and Limit of Quantitation 88
3.3.17.4 Specificity 88
3.3.18 In-vivo Studies 89
3.3.18.1 Study Protocol and Design 89
3.3.18.2 Selection of Animals 89
3.3.18.3 Animal Housing and Maintaining 89
3.3.18.4 Dose Administration 90
3.3.18.5 Collection of Blood Samples 90
3.3.18.6 Extraction of Drug from Serum 90
3.3.18.7 Preparation of Standard Curve 91
3.3.18.8 Analysis of FLV and BCL-Na 92
3.3.18.9 Pharmacokinetic Analysis 92
3.3.19 In-Vitro In-vivo Co-Relation 92
3.3.20 Statistical Analysis 92
4 RESULTS AND DISCUSSION 93
4.1 Particle Size Analysis 93
4.2 Particle Size Distribution 94
4.3 UV Spectrophotometeric Analysis 98
4.3.1 Selection of Suitable Wavelength 98
4.3.2 Standard Curve of FLB and DCL –Na 100
4.4 Pre-Formulation Study 102
4.4.1 Equilibrium Solubility 102
4.4.2 Preparation of Solid Dispersion 103
4.4.3 Bulk Density 104
4.4.4 Tapped Density 104
4.4.5 Hausner’s Ratio 105
4.4.6 Angle of Repose 106
4.4.7 Compressibility Index 106
4.7 Differential Scanning Calorimetery 111
4.8 Infra-Red Absorption spectroscopy 112
4.9 Scanning Electron Microscopy 114
4.10 X-Ray Diffractometery 123
4.11 Preparation of Matrix Tablets 124
4.12 Physical Characterises of Matrix Tablets 125
4.12.1 Thinks and Diameter 126
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xi
4.12.2 Hardness 126
4.12.3 Friability 126
4.12.4 Weight Variation 127
4.12.5 Content Uniformity 127
4.13 In-Vitro Drug Release Study 131
4.13.1 Release of Drug from tablets prepared without polymer 131
4.13.2 Effect of Ethocel® Viscosity Grade 132
4.13.3 The Effect of Drug to Polymer Ratios 134
4.13.4 Ethocel® Std: Premium vs. Ethocel® Std: FP Premium 135
4.13.5 Effect of Partial Replacement of HPMC 136
4.13.6 Effect of Partial Replacement of CMC 139
4.13.7 Effect of Partial Replacement of Starch 141
4.13.8 Release of Drug from Solid dispersions Tablets 144
4.14 Drug Release Kinetics 146
4.15 Polymer Hydration or Water Uptake 156
4.16 Matrix Erosion 159
4.17 Testing Dissolution Equivalency 160
4.18 Effect of Aging on the Release of FLB and DCL-Na from Controlled Released Matrix Tablets
161
4.19 High Performance Liquid Chromatography (HPLC) Method Development 163
4.19.1 Preparation of HPLC analytical Method 163
4.19.2 Precision and Accuracy 163
4.19.3 Limit of Detection and Limit of Quantitation 164
4.19.4 Specificity 164
4.20 In-vivo Studies and Pharmacokinetics Analysis 169
4.21 In-vitro In-vivo Co-Relation 174
5 CONCLUSION 178
6 FUTURE PROSPECTS 179
7 LIST OF PUBLICATIONS 180
8 REFERENCES 182
Controlled Release Tablets of Selected NSAIDs List of Figures
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xii
ListofFiguresFigure 1.1: The gross anatomy of the anterior segment of human small intestine….…..008
Figure 1.2: Physiological consideration and pH range along gastrointestinal tract……..011
Figure 1.3: Drug dissolution and absorption into the systemic circulation……………..014
Figure 1.4: A physiological sketch of hepatic clearance…………………………….….018
Figure 1.5: A schematic diagram of drug release by diffusion from controlled release
matrix tablest in stomach…………………………………………………...025
Figure 1.6: Molecular Structure of Flurbiprofen………………………………………...033
Figure 1.7: Molecular Structure of Diclofenc Sodium…………………………………..034
Figure 3.1: Schematic presentation of angle of repose……………………………….....070
Figure 3.2: A brief sketch of Pharma test dissolution apparatus PTWS-11/P, TPT
(Hamburg, Germany)………………………………………………………081
Figure 3.3: Blood sampling from rabbit marginal ear vein after dosing………….. …...091
Figure 4.1: Particle size distribution of FLB and DCL-Na powders: Differential percent
through sieving……………………………………………………………...093
Figure 4.2: Flurbiprofen particle size distribution though laser scattering……………...094
Figure 4.3: Diclofenac Sodium particle size distribution though laser scattering………095
Figure 4.4: Ethocel® 7 FP particle size distribution though laser scattering……………095
Figure 4.5: Ethocel® 7 Simple particle size distribution though laser scattering………..096
Figure 4.6: Ethocel® 10 FP particle size distribution though laser scattering…………...096
Figure 4.7: Ethocel® 10 Simple particle size distribution though laser scattering……....097
Figure 4.8: Ethocel® 100 FP particle size distribution though laser scattering………….097
Figure 4.9: Ethocel® 100 Simple particle size distribution though laser scattering……..098
Figure 4.10: UV spectrum of FLB in 0.1 N HCl…………………………………………098
Figure 4.11: UV spectrum of FLB in pH 7.4 phosphate buffer solution…………………099
Figure 4.12: UV spectrum of FLB in 0.1 N NaOH………………………………………099
Figure 4.13: UV spectrum of DCL-Na in 0.1 N HCl…………………………………….099
Figure 4.14: UV spectrum of FLB in pH 7.4 phosphate buffer solution…………………100
Figure 4.15: UV spectrum of DCL-Na in 0.1 N NaOH…………………………………..100
Figure 4.16: Standard curve for FLB in pH 7.4 phosphate buffer solution at 247 nm…...101
Figure 4.17: Standard curve for FLB in pH 7.4 phosphate buffer solution at 247 nm…...101
Figure 4.18: Solubility FLB in different pH media……………………………………....102
Figure 4.19: Solubility DCl-Na in different pH media…………………………………...103
Controlled Release Tablets of Selected NSAIDs List of Figures
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xiii
Figure 4.20: Differential Scanning Calorimetric Thermograms of FLB (A), FLB Physical
mixture (B), FLB Solid Dispersions (C)…………………………………... 111
Figure 4.21: Differential Scanning Calorimetric Thermograms of DCL-Na (A), DCL-Na
Physical mixture (B) and DCL-Na Solid Dispersions (C)………………….112
Figure 4.22: FTIR Spectroscopy of FLB (A), EC (B), FLB-EC (C), FLB-EC-HPMC (D),
FLB-EC-Starch (E), FLB-EC-CMC (F) and FLB Solid Dispersions (G)…..113
Figure 4.23: FTIR Spectroscopy of DCL-Na (A), EC (B), DCL-Na-EC (C), DCL-Na-EC-
HPMC (D), DCL-Na-EC-Starch (E), DCL-Na-EC-CMC (F) and DCL-Na
Solid Dispersions (G)…………………………………………………….....114
Figure 4.24: Scanning Electron Micrographs of FLB (A), FLB Physical Mixture (B), FLB
Solid Dispersions (C), DCL-Na (D), DCL-Na Physical Mixture (E) and DCL-
Na Solid Dispersions (F)……………………………………………..……..122
Figure 4.25: X-Ray Diffraction Pattern of FLB (A), FLB-EC Physical mixture (C) & FLB
Solid Dispersions (C)…………………………………………………….....123
Figure 4.26: X-Ray Diffraction Pattern of DCL-Na (A), DCL-Na-EC Physical mixture (C)
& DCL-Na Solid Dispersions (C)………………………………………..…124
Figure 4.27: FLB release profile from matrix tablets prepared without polymer....……...132
Figure 4.28: DCL-Na release profile from matrix tablets prepared without polymer.…...132
Figure 4.29: FLB release profiles from matrix tablets containing Ethocel® 7 FP and simple standard premium…………………………………………………………...133
Figure 4.30: DCL-Na release profiles from matrix tablets containing Ethocel® 7 FP and simple standard premium…………………………………………………...134
Figure 4.31: FLB release profiles from matrix tablets containing Eethocel® 7 FP and simple standard premium with partial replacement of HPMC……………………..138
Figure 4.32: DCL-Na release profiles from matrix tablets containing Eethocel® 7 FP and simple standard premium with partial replacement of HPMC……………...139
Figure 4.33: FLB release profiles from matrix tablets containing Eethocel® 7 FP and simple standard premium with partial replacement of CMC……………………….140
Figure 4.34: DCL-Na release profiles from matrix tablets containing Eethocel® 7 FP and simple standard premium with partial replacement of CMC……………….141
Figure 4.35: FLB release profiles from matrix tablets containing Eethocel® 7 FP and simple standard premium with partial replacement of Starch………………………143
Controlled Release Tablets of Selected NSAIDs List of Figures
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xiv
Figure 4.36: DCL-Na release profiles from matrix tablets containing Eethocel® 7 FP and simple standard premium with partial replacement of Starch………………144
Figure 4.37: FLB release profiles of tablets prepared with polymer and solid dispersions tablet…………………………………………………………………..…….145
Figure 4.38: DCL-Na release profiles of tablets prepared with polymer and solid dispersions tablets………………………………………… ….....……..…...145
Figure 4.39: Plot of % swelling by FLB controlled release tablets as a function of time..157
Figure 4.40: Plot of % swelling of DCL-Na controlled release tablets as a function of time …………………………………….…………………..………………….....157
Figure 4.41: Morphology of FLB (A, C, E, and G) and DCL-Na (B, D, F and H) matrix tablets swelling……………………………………………………………...158
Figure 4.42: Plot of FLB controlled release matrix erosion……………………………...159
Figure 4.43: Plot of DCL-Na controlled release matrix erosion………………………….160
Figure 4.44: FLB dissolution equivalency………………………………………………..161
Figure 4.45: DCL-Na dissolution equivalency…………………………………………...161
Figure 4.46: FLB Representative HPLC chromatograms for FLB at three different concentrations in mobile phase……………………………………………..166
Figure 4.47: DCL-Na Representative HPLC chromatograms for DCL-Na at three different concentrations in mobile phase……………………………………………..166
Figure 4.48: PDA- absorption spectra of the FLB peak from a standard solution……….167
Figure 4.49: UV- absorption spectra of the DCL-Na peak from a standard solution…….167
Figure 4.50: Mean standard HPLC-Calibration Curve for FLB (n=5)…………………...168
Figure 4.51: Mean standard HPLC-Calibration Curve for DCL-Na……………………..168
Figure 4.52 A representative curve of FLB extracted from rabbit plasma withdrawn 4 hours after oral administration of FLB test tablets……………………………….. 170
Figure 4.53 A representative curve of FLB extracted from rabbit plasma withdrawn 4 hours after oral administration of FLB test tablets………………………………..170
Figure 4.54: FLB standard curve in plasma………………………………………………170
Figure 4.55: DCL-Na standard curve in plasma………………………………………….171
Controlled Release Tablets of Selected NSAIDs List of Figures
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xv
Figure 4.56: Comparative serum concentration-time profiles of FLB test and reference
tablets, following oral administration to rabbit……………………………..172
Figure 4.57: Comparative serum concentration-time profiles of DCL-Na test and reference
tablets, following oral administration to rabbit…………………………….174
Figure 4.58: Percent drug absorbed (Pa) plotted against percent drug released (Pa) to show
in-vitro in-vivo correlation of FLB test formulation………………………..175
Figure 4.59: Percent drug absorbed (Pa) plotted against percent drug released (Pa) to show
in-vitro in-vivo correlation of FLB market formulation…………………….175
Figure 4.60: Percent drug absorbed (Pa) plotted against percent drug released (Pa) to show
in-vitro in-vivo correlation of DCL-Na test formulation……………………176
Figure 4.61: Percent drug absorbed (Pa) plotted against percent drug released (Pa) to show in-vitro in-vivo correlation of DCL-Na market formulation………………..176
Controlled Release Tablets of Selected NSAIDs List of Tables
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xvi
ListofTables
Table 3.1: Composition of each of FLB and DCL-Na 100 mg tablets containing without
polymer……………………………………………………………………..072
Table 3.2: Composition of each FLB and DCL-Na 100 mg matrix tablets containing
Ethocel® FP standard premium polymer……………………………………072
Table 3.3: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel®
simple standard premium polymer………………………………………….073
Table 3.4: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel® FP
standard premium polymer and HPMC……………………………………..073
Table 3.5: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel®
simple standard premium polymer and HPMC……………………………..074
Table 3.6: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel® FP
standard premium polymer and CMC………………………………………074
Table 3.7: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel®
simple standard premium polymer and CMC………………………………075
Table 3.8: Composition of each of FLB/DCL-Na 100 mg matrix tablets containing
Ethocel® FP standard premium polymer and starch………………………..075
Table 3.9: Composition of each of FLB and DCL-Na 100 mg matrix tablets containing
Ethocel® simple standard premium polymer and starch……………………076
Table 3.10: Composition of each of FLB and DCL-Na 100 mg solid dispersions tablets
containing Ethocel® FP standard premium polymer………………………..076
Table 3.11: Composition of FLB 200 mg matrix tablets containing Ethocel® FP standard
premium polymer…………………………………………………………...077
Table 3.12: Weight variation tolerance for controlled release matrix tablets………….079
Table 3.13: Release exponent and mechanism of diffusional release from various
controlled release matrix tablets…………………………………………….084
Table 4.1: Physical evaluation of starting material…………………………………….107
Controlled Release Tablets of Selected NSAIDs List of Tables
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xvii
Table 4.2: Physical evaluation of starting material…………………………………….107
Table 4.3: Physical evaluation of starting material…………………………………….108
Table 4.4: Physical evaluation of starting material…………………………………….108
Table 4.5: Physical evaluation of starting material…………………………………….109
Table 4.6: Physical evaluation of starting material…………………………………….109
Table 4.7: Physical evaluation of starting material…………………………………….110
Table 4.8: Physical evaluation of starting material…………………………………….110
Table 4.9: Hardness, Friability, Weight variation, Drug content Thickness and Diameter
of the prepared tablets expressed as Mean ± SD…………………………..127
Table 4.10: Hardness, Friability, Weight variation, Drug content Thickness and Diameter
of the prepared tablets expressed as Mean ± SD…………………………..128
Table 4.11: Hardness, Friability, Weight variation, Drug content Thickness and Diameter
of the prepared tablets expressed as Mean ± SD…………………………..128
Table 4.12: Hardness, Friability, Weight variation, Drug content Thickness and Diameter
of the prepared tablets expressed as Mean ± SD…………………………..129
Table 4.13: Hardness, Friability, Weight variation, Drug content Thickness and Diameter
of the prepared tablets expressed as Mean ± SD…………………………..129
Table 4.14: Hardness, Friability, Weight variation, Drug content Thickness and Diameter
of the prepared tablets expressed as Mean ± SD…………………………..130
Table 4.15: Hardness, Friability, Weight variation, Drug content Thickness and Diameter
of the prepared tablets expressed as Mean ± SD…………………………..130
Table 4.16: Hardness, Friability, Weight variation, Drug content Thickness and Diameter
of the prepared tablets expressed as Mean ± SD…………………………..131
Table 4.17: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Flurbiprofen consisting of Ethocel® Standard FP Polymer
of Different viscosity grades. (Mean ± SD of three determinations)……….148
Controlled Release Tablets of Selected NSAIDs List of Tables
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xviii
Table 4.18: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple
Polymer. (Mean ± SD of three determinations)…………………………….148
Table 4.19: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Flurbiprofen consisting of Ethocel® Standard FP Polymer
of Different viscosity grades. (Mean ± SD of three determinations) and co-
excipient Starch…………………………………………………..…………149
Table 4.20: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple
Polymer of Different viscosity grades. (Mean ± SD of three determinations)
and co-excipient Starch……………………………………………………..149
Table 4.21: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Flurbiprofen consisting of Ethocel® Standard FP Polymer
of Different viscosity grades. (Mean ± SD of three determinations) and co-
excipient CMC. …………………………………………………….………150
Table 4.22: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple
Polymer of Different viscosity grades. (Mean ± SD of three determinations)
and co-excipient CMC…………………………………………….………..150
Table 4.23: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Flurbiprofen consisting of Ethocel® Standard FP Polymer
of Different viscosity grades. (Mean ± SD of three determinations) and co-
excipient HPMC…………………………………………………………….151
Table 4.24: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple
Polymer of Different viscosity grades. (Mean ± SD of three determinations)
and coexcipient HPMC……………………………………………………..151
Table 4.25: Different kinetic models applied to determine the release profile of Controlled
Release Flurbiprofen 200 mg simple and 100 mg solid dispersion tablets
consisting of Ethocel® Standard 7 FP Polymer……………………………..152
Controlled Release Tablets of Selected NSAIDs List of Tables
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xix
Table 4.26: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP
Polymer. (Mean ± SD of three determinations) ……………………………152
Table 4.27: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium consisting of Ethocel® Standard
Simple Polymer of Different viscosity grades. (Mean ± SD of three
determinations) …………………………………………………….……….152
Table 4.28: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP
Polymer of Different viscosity grades. (Mean ± SD of three determinations)
and co-excipient Starch …………………………………………………….153
Table 4.29: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium consisting of Ethocel® Standard
Simple Polymer of Different viscosity grades. (Mean ± SD of three
determinations) and co-excipient Starch……………………………………153
Table 4.30: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP
Polymer of Different viscosity grades. (Mean ± SD of three determinations)
and co-excipient CMC ……………………………………………………..154
Table 4.31: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium consisting of Ethocel® Standard
Simple Polymer of Different viscosity grades. (Mean ± SD of three
determinations) and co-excipient CMC……………………………………154
Table 4.32: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP
Polymer of Different viscosity grades. (Mean ± SD of three determinations)
and co-excipient HPMC…………………………………………………….155
Controlled Release Tablets of Selected NSAIDs List of Tables
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xx
Table 4.33: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium consisting of Ethocel® Standard
Simple Polymer of Different viscosity grades. (Mean ± SD of three
determinations) and coexcipient HPMC……………………………………155
Table 4.34: Different kinetic models applied to determine the release profile of Controlled
Release matrices of Diclofenac Sodium solid dispersions consisting of
Ethocel® Standard 7 FP Polymer …………………………………………..156
Table 4.35: FLB Reverse predicted concentrations, % recovery and regression coefficient
(R2) …………………………………………………………………………164
Table 4.36: DCL-Na Reverse predicted concentrations, % recovery and regression
coefficient (R2)……………………………………………………………...165
Table 4.37: FLB Precision and accuracy data of the QC samples (Results were expressed
as mean values, n = 5) …………………………………………………...…165
Table 4.38: DCL-Na Precision and accuracy data of the QC samples (Results were
expressed as mean values, n = 5) …………………………………………..165
Table 4.39: Various pharmacokinetic parameters determined for 200 mg FLB and 100 mg
DCL-Na controlled release matrix tablets, following oral administration to
rabbits……………………………………………………………………….177
Controlled Release Tablets of Selected NSAIDs List of Abbreviation
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xxi
ListofAbbreviation
CR Controlled release
FLB Flurbiprofen
DCL-Na Diclofenac Sodium
SD Solid Dispersions
DC Direct compression
GIT Gastrointestinal tract
LOQ Limit of quantization
NSAIDs Non-steroidal anti-inflammatory drugs
USP United States Pharmacopeia
BP British pharmacopeia
DSC Differential scanning calorimeter
LOD Limit of detection
cGMP Current good manufacturing practice
IVIVC In-vitro and in-vivo correlation
HPMC Hydroxypropylmethylcellulose
CMC Corboxymethylcellulose
HPLC High performance liquid chromatography
MDT Mean dissolution time
XRD X-ray diffraction
ICH International Commission on Harmonization
SEM Scanning electron microscopy
pKa Ionization constant
Controlled Release Tablets of Selected NSAIDs List of Abbreviation
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xxii
UV Ultra violet
AUC Area under curve
Cltotal Total clearance
Cmax Maximum plasma concentration
Tmax Time to maximum plasma concentration
MRT Mean residence time
Kel Elimination rate constant
t1/2 Half-life
Vd Volume of distribution
hr hour
gm gram
µg microgram
µL microliter
kg kilogram
L Liter
mg Milligram
mL Milliliter
µm Micrometer
GIT Gastrointestinal tract
NSAIDs Non-steroidal anti-inflammatory drugs
FDA Food and drug administration
Controlled Release Tablets of Selected NSAIDs Acknowledgement
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xxiii
AcknowledgementForemost I bow to ALLAH ALMIGHTY, Who has enlightened our minds and hearts with
faith and guided us to the right path, the path of wisdom, perspicacity and sophistication.
I would like to express my gratitude to my supervisor Professor Dr. Gul Majid Khan for his
overall direction and ongoing support. Prof. Dr. Gul Majid’s door is always open for
discussions. I am greatly appreciative of his expertise and guidance without which this
project would not have been possible. He has a sound, critical and healthy research attitude
towards the controlled release formulations. I deem it a great honor and no word is too
eloquent to express my sense of gratitude to him.
Special thanks to Higher Education Commission (HEC) of Pakistan for financial support
throughout my PhD project, including six months research support to conduct a part of my
research at The School of Pharmacy, University of Auckland, New Zealand, under the kind
supervision of Professor Doctor Raid Alany. Thanks to Dr Zaheer-ud-Din Babar, Hamdy
Abdelkader, Ali Saifuddin and Imtiaz Nadeem, who helped me during my stay at New
Zealand. Thanks to British Council (BC) for a special grant to visit UK universities. I highly
appreciate and acknowledge the help extended by Dr. Nadeem Irfan Bukhari and Syed
Mubashir Ali Abid during the in-vivo studies of my project. Also, Many thanks to Dr Nisar-
u-Rehman, Dr Jamshed Ali Bangash and Dr Abdullah Dayo for their help and guidance.
Special thanks to all my teachers at Faculty of Pharmacy, Gomal University, D.I.Khan,
especially Prof. Dr. Muhammad Farid Khan, Malik Satar Bakhsh Awan, Hameedullah Khan,
Tahir Salim Faiz, Fayyaz Ahmed, Hafiz Ramzan, Nusratullah, Sheikh Rahseed, Fazal-ur-
Rehman and Junaid Asghar, for their encouragement. Thanks to my friends at Faculty of
Pharmacy, especially Abdul Wahab, Waqas Rabbani, Abid Hussain, Asif Nawaz, Abdul
Shakoor, Nauman Rahim Khan, Dr. Arshad Khan, Alam Zeb, Ehsanullah Khan, Haroon
Khan, Kamran Ahmed, Asim Khan, Nasim Khan, Shifatullah Shah, Kifayatullah Shah,
Anjum Niaz, Asif Javed and Kifayatullah Shah for their valuable suggestions and critical
discussions. I am also grateful to the office and laboratory staff for their cooperation and
friendly attitude. I pay special gratitude to Ajab Khan (Artist) for his calligraphy, made
especially for my thesis.
Muhammad Akhlaq
Controlled Release Tablets of Selected NSAIDs Abstract
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xxiv
AbstractThe present study aims to design, formulate and evaluate Flurbiprofen (FLB) and Diclofenac
Sodium (DCL-Na) once-daily controlled release 100 mg tablets, using various grades of
Ethocel® ethylcellulose ether derivative polymer both in-vitro and iv-vivo. FLB and DCL-Na
are widely used non-steroidal anti-inflammatory drugs, usually recommended in steroid
therapy, and for symptomatic relief of dysmenorrhoea.
Optimization of drug substances throughout the determination of some physical and chemical
properties is authoritatively ordered in the development of a stable, effective, safe, and
reproducible dosage form. The bioavailability of these drugs in gastrointestinal tract is
dissolution rate limited. Therefore, during our preformulation work, our efforts encompassed
the detailed study of parameters such as particle size, particle size distribution, pH solubility
profiles and dissolution behavior of FLB and DCL-Na powders. Differential scanning
calorimetery (DSC), Fourier transform infra-red absorption spectroscopy (FTIR), Scanning
electron microscopy (SEM), and X-ray diffractomertery (XRD) were exploited as the
characterization and evaluation techniques. Solid dispersions of each of FLB and DCL-Na
drugs were prepared by solvent evaporation technique. Drug powders, physical mixtures and
solid dispersions of each of the drugs were evaluated by different physical methods, including
bulk density, tapped density, hausner’s ratio, angle of repose and compressibility index.
Different bio-polymeric approaches have been used to the drug release rate and to maintain a
steady state plasma concentration throughout the treatment time. Ethylcellulose ether
derivative polymers were used to design and formulate oral controlled release hydrophobic
matrix tablets prepared by direct compression technique, using a single punch machine.
Tablets were subjected to various physical and quality control tests, including thickness,
diameter, weight variation, hardness, friability and content uniformity. Tablets were
subjected to dissolution test for in-vitro release studies. Later, different kinetic parameters
were applied to investigate the drug release mechanism from the polymer based matrix
tablets. Diffusion controlled pH independent release with desired zero order kinetics for both
the FLB and DCL-Na drugs was an important achievement planned into once-daily
controlled released matrix tablets. The controlled released matrix tablets, each of FLB and
DCL-Na, containing 30% Ethocel® Standard 7 FP Premium were selected as optimized
Controlled Release Tablets of Selected NSAIDs Abstract
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xxv
tablets for further pharmacokinetic studies. Stability of the selected tablets of both FLB and
DCL-Na drugs was observed during the short term accelerated stability studies. After
selecting optimized test tablets of both FLB and DCL-Na drugs, in-vivo studies were
conducted using albino rabbits, using HPLC-based simple, rapid and validated methods. The
test ad market formulation were given to the rabbits already fasted for 24 hours. Blood
samples were collected from marginal ear vein at predetermined time intervals for 42 hours,
and were analyzed by HPLC developed method. In order to investigate the release
mechanism in-vivo, various pharmacokinetic parameters, including Cmax, Tmax, AUC0-24,
AUC0-inf, MRT, t1/2 and Cltotal for test and reference tablets, were obtained using kinetica
software.
The best mode of particle size distribution (80-100 µm) of both FLB and DCL-Na was best
dissolved in the pH 7.4 phosphate buffer solution and gave maximum absorbance at 247 and
276 nm, respectively. Physical evaluation of the starting materials, including bulk density
ranged from 0.250±0.09 to 0.3880.02, tapped density from 0.250±0.09 to 0.398±0.07,
hausner’s ratio from 1.01±0.01 to 1.34±0.08, angle of repose from 11.53˚±0.09 to
29.88±0.01, and percent compressibility ranged from 11.21±0.02 to 28.55±0.01%, which
were found to be in the best acceptable range, reported in literature. These results showed
Ethocel® standard 7 FP premium alone sequentially extended the release of drugs up to 24
hours. Ethocel® helped in maintaining the drugs knotted in its viscous gel layer. The drug
release rate could be altered by polymer concentration and particle size. The inclusion of
HPMC likely caused slow hydration leading to erosion and drug release by diffusion. While,
CMC and Starch-based formulation showed the burst release and completely disintegrated
within two hours.
Simple and rapid HPLC methods were developed both for FLB and DCL-Na drugs with short
retention time of 3.2 and 5.9 minutes, respectively. Optimum levels of both the FLB and
DCL-Na Serum concentrations (Cmax) were observed forecasting minimum chances of
adverse effects. Significantly prolonged tmax of the test tablets of both FLB and DCL-Na
indicated smooth and extended absorption phase of the drugs under study. A good co-relation
between the in-vitro drug release and in-vivo drug absorption of the drugs was observed. It
was also observed that the area under curves (AUCs) of test tablets and reference tablets were
not significantly different (p<0.05) from each other in case of both FLB and DCL-Na drugs.
Controlled Release Tablets of Selected NSAIDs Abstract
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xxvi
It was concluded that (Ethocel®) ethycellulose ether derivative polymer could be used to prepare once-daily controlled release matrix tablets of FLB and DCL-Na non-steroidal anti-inflammatory drugs.
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 1
1. INTRODUCTION
1.1. Oral Drug Delivery Systems
Oral dosage forms are increasing exponentially on pharmacy shelves, and this growth is
expected to continue in the years to come. The growth is due to many factors including
patient convenience and compliance, reduced health care cost, unmet medical needs, market
exclusivisity and the large scale at which these drugs are manufactured. All those products
that can reduce dosing frequency provide convenience and satisfaction that can have a
positive impact on patient fidelity and more positive outcomes (Lizheng et al., 2007). It could
be observed that the management of some diseases, that have historically been difficult to
treat, is now possible because a proper amount of drug can now be delivered to the right site
at the right time, using different controlled release polymeric approaches (Sabel et al., 1989).
Pharmaceutical advancements have made it possible to develop more sophisticated and
intricate oral drug delivery systems to manufacture them on a large scale and to meet the
modern day challenges all over the world (Mittra, 2008). The oral route is considered to be
the most convenient, safe and widely accepted means of administering drugs (Francis et al.,
2004). Oral route of administration is preferred for the drugs that are not marked for life-
threatening emergency situations and are considered safe. Oral Modified-release delivery
systems provide market exclusivisity and extend a product’s life cycle, which is of
commercial interest of pharmaceutical firms and promotes product innovation (Santos, 2003).
The disadvantages to this route may include a slower onset of response as compared to the
intravenous route (Chan et al., 1995), and the possibility of irregular and unpredictable
absorption depending upon the physiological properties of the drug and the anatomic (i.e,
vascularity, epithelial thickness, and surface area) and biological features of the
gastrointestinal tract (GIT) (Body, 2001) for example environmental fluctuations (i.e. pH
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 2
changes along the tract) (Tengjaroenkul et al., 2000), biochemical variances (presence or
absence of enzymes, transport proteins and cofactors) (Tengjaroenkul et al., 2000, Jamei et
al., 2009). It could be observed that pH of the gastric content and pKa of the drug play
important role in absorption of drugs from the stomach, hence it could be postulated that the
pH and pKa regulates the rate of dissolution and ionization of an administered drug (Charman
et al., 1997, Avdeef, 2003).
The pH of the stomach is strongly acidic. It ranges between 1 and 3 for fasted and fed sates,
respectively (Schoen and Vender, 1989). Chemicals undergo degradation in the highly acidic
gastric environment (Erah et al., 1997). The passage of drugs across the membrane is also
slow due to the impaired absorption by the thick layer of the mucous on the gastric lining of
the stomach (MacAdam, 1993), which limits drug absorption from stomach. Gastric
emptying is the absorption rate-limiting step because most of the drugs are absorbed more
quickly and effectively from small intestine than from the stomach (Willems et al., 2001).
The small intestine is the drug primary absorption site, due to its extraordinary huge
absorption area available, favorable membrane permeability and wider pH range. The pH in
the proximal portion of the small intestine is roughly 5, whereas, in the distal region it is
roughly 7 to 8, thus, makes the environment favorable for drug absorption (Glass, 1968). The
stability of drugs is dependent on the surrounding pH. Many drugs have unstable due to the
environment of the stomach and usually degrade when they are exposed to the acidic pH
(Taneja and Gupta, 2003).
Before reaching body blood circulating system, a drug may undergo degradation in the GIT
or biotransformation in the intestinal mucosa or in the liver (Werle et al., 2006). The ideal
dosage regimen is that which provides a desired therapeutic amount of a drug at the site (s) of
action is achieved promptly after the drug administration. Few limitations are associated with
the immediate release dosage forms. A constant therapeutic concentration of drug is usually
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 3
difficult to maintain at a desired site (where needed) for an intended period. It has been
evaluated that the mean plasma concentration almost remains constant at the site of action for
the whole treatment time (Sandberg et al., 1988, Birns et al., 2000). If Cssmax and Css
min
increase or decrease, it results in inexorable fluctuations of drug concentrations (Verbeeck,
2000, Capone et al., 2007). Drugs with shorter half-lives require frequent doses to maintain a
constant remedial concentration at the site of action (Henry et al., 2002). In case of drug
requiring frequent administration, lack of patient compliance is often an important reason for
therapeutic insufficiency or failure. Clearly, not even a peroral dosage regimen has been
designed to achieve and maintain clinically effective therapeutic amount of a drug at a
desired site if the patient does not comply with it (Langer, 1999). Pharmaceutical scientists
have designed and developed, patented, and commercialized a number of modified drug
delivery technologies, which provide safe and effective therapeutic level and will be
discussed later in section 1.4 (Sastry et al., 2000). Before we proceed to the oral drug delivery
systems in detail, the anatomical and physiological aspects of oral drug delivery are discussed
in detail.
1.2. Anatomical and Physiological Consideration of GIT
Gastrointestinal tract is a hollow muscular tube stretching from mouth to anus. It consists of
four main physiological/anatomical areas including oesophagus, stomach, small intestine and
large intestine or colon. It is a hollow muscular tube, approximately six meters long with
varying diameters at different parts, starting from mouth and ending at anus (Zhan et al.,
2004a). The inner surface of the tube is rough, increasing the surface area for absorption. The
wall of the intestinal tract is essentially similar in structure in all parts consisting of four
principal histological layers (Von et al., 2001).
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 4
o An outer layer of epithelium usually supporting connective tissue called serosa
(Tortora and Derrickson, 2008)
o The second layer containing two adjacent layers of smooth muscle tissue, a thinner
outer layer which is longitudinal in orientation, and a thicker inner layer, whose fibres
are oriented in a circular pattern called muscularis externa. Contractional behaviour of
these muscles causes the movement of gastrointestinal contents.
o The third layer is composed of epithelium and supporting connective tissue having
richly supplied with the blood and lymphatic vessels. A network of nerve cells,
known as sub-mucous plexus are located in this layer.
o The mucosa is composed of three layers including muscularis mucosa, that have the
ability to alter the local conformation of mucosa, a layer of connective tissue called
the lamina propria, and the epithelium (Tortora and Derrickson, 2008).
A protective layer and a mechanical barrier of mucous covers the majority of the
gastrointestinal epithelium, which is a vesoelastic translucent aqueous gel secreted
throughout the gastrointestinal tract and is composed of a complex mixture of secretions and
exfoliated epithelial cells which changes constantly, containing a large water component of
95%. Other primary components includes large glycoproteins called mucins which are
responsible for physical and functional properties (Atuma et al., 2001). Thickness of mucous
layer ranges from 5μm to 500 μm along the length of the gastrointestinal tract, with average
values of around 80 μm. The layer is thought to be continuous in the stomach and duodenum,
but may not be so in the rest of the small and large intestine (Lai et al., 2009). Mucous layer
is constantly being removed from the luminal surface of the gastrointestinal tract through
abrasion and acidic and enzymatic breakdown, and is continually replaced from beneath
(Atuma et al., 2001).
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 5
1.2.1. The oesophagus
The oesophagus is the tube that carries food, liquids and saliva from mouth to the stomach. It
actually links the oral cavity with the stomach at the gastroesophageal junction, or cardiac
orifice and is composed of a thick muscular layer approximately 250 mm long and 20 mm in
diameter, with a pH range of 5 to 6 (Meyer et al., 1986). The oesophagus apart from the
lowest 20 mm, which is similar to the gastric mucosa, contains a well differentiated
squamous epithelium of non-proliferative cells. The function epithelial cells are protective,
secretary mucous glands secret mucus into the narrow lumen to lubricate food and protect the
lower part of the oesophagus from gastric acid. Act of swallowing causes the materials to
move down the oesophagus. After swallowing, a single peristaltic wave of contraction,
depending on the size of the material being swallowed; pass down the length of the
oesophagus at the rate of 20 to 60 mm per second, speeding up as it progresses (Amft and
Troster, 2006). Quick repetition swallowing interrupts the initial peristaltic wave and only the
final wave proceeds down the length of the oesophagus to the gastrointestinal junction,
carrying material to the lumen with it. Secondary peristaltic waves occur involuntarily in
response to any distension of the oesophagus and serve to move sticky lumps of material or
refluxed material to the stomach. In the upright position the transit of materials through the
oesophagus is assisted by gravity. The oesophagus transit of dosage forms is extremely rapid,
usually of the order of 10-14 seconds (Kramer and Ingelfinger, 1949).
1.2.2. The stomach
The stomach is an organ of digestion. It has a sac-like shape containing different food
digesting enzymes. The four major functions of the stomach are
o To act as temporary reservoir for ingested food.
o To deliver food to the duodenum at a controlled rate.
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 6
o To reduce ingested solid to a uniform mass, called chime, by the action of acid and
enzymatic digestion. This process enables the chime to better contact with the mucous
membrane of the intestines and hence facilitates absorption.
o To reduce the risk of unhealthy/harmful agents reaching the intestine.
The stomach is considered the most detailed part of the GI tract. It has a capacity of
approximately 1.5 L, although under fasting conditions it usually contains no more than 50
mL of fluid, which is mostly gastric secretions, including (Cox, 1945)
o The gastric acid secreted by the parietal cells, which maintains the pH of the stomach
between 1 and 3.5 in the fasted state (Lindström et al., 2001).
o The hormones gastrin, is simulated by peptides, amino acids and distension of the
stomach. It is a potent stimulator of gastric acid production (Barbezt and Grossman,
1971).
o Pepsin secreted by the peptic cells, break down the proteins to peptides at low pH. At
above pH 6, pepsin is denatured (Kronman and Holmes, 1971, Lanas et al., 1994).
o Mucus is secreted by the surface mucosal cells and lines the gastric mucosa, and
protects the gastric mucosa from auto-digestion by the pepsin-acid
combination(Hollander, 1954). The rate of gastric emptying is a controlling factor in
the onset of drug absorption from the major absorptive site in the small intestine
(Heading et al., 1973). It is believed that very little drug absorption occurs in the
stomach owing to its small surface area as compared to the small intestine (Oberle and
Amidon, 1987).
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 7
1.2.3. The small intestine
The small intestine is the longest (Xu, 1996) (5-6 m) (Zhan et al., 2004b) and the most
convoluted part, extending from stomach pyloric sphincter to the ileocaecal junction where it
joins the large intestine. Its main functions includes (Lavender et al., 1969):
o Storing the food.
o To break down the food.
o Enzymatic digestion, which begins in the stomach and is completed in the small
intestine.
o Absorption of most of the nutrients and other material.
o Emptying the liquidly mixture into small intestine.
The small intestine can be divided into duodenum, which is approximately 250 m (Zhan
et al., 2004b) in length, the jejunum, which is approximately 1.5 m in length, and the ileum,
which is approximately 2.6 m in length (S Santoro et al., 2004).
The gastrointestinal circulation is largest systematic regional vasculature and nearly a third of
the cardiac output flows through the gastrointestinal viscera. A rich network of both blood
and lymphatic vessels are present in the wall of the small intestine (Schacht et al., 2003). The
blood vessels of small intestine receive blood from the superior mesenteric artery via
branched arterioles. The blood leaving the small intestine flows into the hepatic portal vein,
which carries it via the liver to the systemic circulation (Kvietys, 2010). Drugs that are
metabolized by the liver are degraded before they reach the systemic circulation which is
termed hepatic pre-systemic clearance, or first-pass metabolism (Lin et al., 1999).
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 8
Figure 1.1. The gross anatomy of the anterior segment of human small intestine
The wall of the small intestine also contains lacteals containing lymph which is the part of the
lymphatic system. The lymphatic system is important in the fast absorption of fast from the
gastrointestinal tract (DeSesso and Jacobson, 2001). In the ileum having lymphoid tissue
close to epithelial surface which are known as payer’s patches. These patches play an
important role in the immune response as they transport macromolecules and are also
involved in antigen uptake (Momotani et al., 1988). The surface area of the small intestine is
increased enormously, consisting of villi, microvilli and folds of kercking, which makes the
small intestine a good absorption site (Wilson, 1967).
o Villi are finger-like projections into the lumen and are well supplied with blood
vessels. Each villus contains an arteriole, a venule and a blind-ending lymphatic
vessel (lacteal). The structure of the villus is shown in the figure 1.1.
o Folds of kerckring are well developed sub mucosal folds which extend circularly most
of the way around the intestine.
o Microvilli are brush-like structures (1µm in length and 0.1µm in width), providing the
largest increase in surface area. These are covered by a fibrous substance known as
glycocalyx (Laster et al., 1961).
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 9
The luminal pH of the small intestine ranges between about 5.5 and 7.5 (NUGENT et al.,
2001). The sources of the secretions that produce these pH values in the small intestine are
o Bile, which is secreted by hepatocytes in the liver into bile canaliculi, concentrated in
the gallbladder and hepatic biliary system by the removal of sodium ions, chlorides
and water, and delivered to the duodenum (Coleman, 1987).
o Intestinal cells, which are present throughout the small intestine and are involved in
the secretion of mucus and enzymes. The enzymes, hydrolases and proteases,
continue the digestive process (Specian and Neutra, 1980).
o Burnner’s glands are located in the duodenum and are responsible for the secretion of
bicarbonate having the function to neutralize the acid emptied from the stomach
(Patrick et al., 1974);
o Pancreatic secretions is produced by the pancreas which is the large gland having the
ability to secretes about 1-2 L of pancreatic juice per day in to the small intestine via a
duct. The components of the pancreatic juice include sodium bicarbonates and
enzymes. The enzymes consist of proteases, principally trypsin, chymotrypsin and
carboxypeptidase, which are secreted as inactive precursors or zymogens and
converted to their active forms in the lumen by the enzyme enterokinase (Grønborg et
al., 2004).
1.2.4. The colon
The colon is the final portion of the gastrointestinal tract. It stretches from the ileocaecal
junction to the anus (Kellow et al., 1986). Colon plays a significant homeostatic role in the
body. The main functions of the colon are (Salminen et al., 1998).
o Storing waste
o The absorption of sodium ion, chloride ions
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 10
o Reclaiming water from the lumen, to maintain water balance.
o Absorbing some vitamins such as vitamin K.
o The storage and compaction of faeces.
Drug absorption in the gastrointestinal tract is influenced by number of factors, including
mainly the route through which the drug is given, various physicochemical characteristics of
drug and formulation factors.
1.3. Drug Absorption from GIT
The absorption of the oral dosage forms may begin in mouth provided the drug is present in
solution form. The drug is administered as an orally disintegrating tablet, or is retained in the
oral cavity for an extended period. Most orally administered products (i.e. tablets, capsules,
clear liquids, suspensions) are swallowed too quickly to allow any drug absorption through
the mucous membranes in the mouth. On the other hand, products that are held under the
tongue (sublingual) or between the cheek and gum (buccal) are retained longer at the
absorption site (Pather et al., 2008). Oral administration of a drug provides the opportunity
for the drug to be absorbed at various points in the alimentary tract, extending from the
mouth to the rectum (Tobío et al., 2000). Thin mucous membranes in these regions present a
low barrier for the drugs to entr the systemic circulation. The rate and extent of drug
absorption varies substantially throughout the GIT due to environmental fluctuations (i.e. pH
changes along the tract ranging from 1 to 8 as shown in the figure 1.2 (Kobayashi et al.,
2001), biochemical variances (i.e. presence or absence of enzymes (Custodio et al., 2008),
transport proteins (Rogers et al., 2002), cofactors (Bernkop-Schnürch and Krajicek, 1998),
and anatomic differences (i.e. vascularity, epithelial thickness, and surface area) (Charman et
al., 1997, Senel and Hincal, 2001).
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 11
Figure 1.2. Physiological consideration and pH range along gastrointestinal tract
Oral route is considered the most convenient route for the drugs which can remain stable in
the gastric enzymes (Xing et al., 2003). Main role of the gastrointestinal tract is to digest and
absorb food, and it is not easy to separate these two functions from that of the drug delivery
(Rowland, 1972). No doubt, the absorption of the drugs is greatly influenced by the natural
processes in the gut (Levine, 1970), but the gut pH (Amidon et al., 1995) and munerous
enzymes (Rowland, 1972), bile (Welling, 1977), the microbes also play an important role in
overall drug absorption from the GIT (Levine, 1970). Passive diffusion is the main process to
absorb most of the drugs (Stenberg et al., 2000) while those drug molecule which are closely
similar to natural molecules are actively moved across the membrane by special processes
(Bartley et al., 1954). Rate of diffusion is proportional to concentration gradient. Ionization
of molecules, molecular size and the solubility also plays a role in the drug diffusion (Kansy
et al., 1998, Schanker, 1960). Drug penetration across the epithelium occurs via the
paracellular route or transcellular route (i.e. between the epithelial cells). The absorption
across this route is limited because of the presence of tight junctions between the cells
(Anderberg et al., 1993). Absorption across the epithelial cells can occur by passive
diffusion, carrier-mediated transport (Meunier et al., 1995), or pinocytosis (Siccardi et al.,
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 12
2005). As the name suggests, carrier mediated transport requires the use of specialized carries
to transport drug molecules across the membrane (Hidalgo and Li, 1996). It is called ‘active
transport’ if the movement is against the concentration gradient and requires energy (Gill et
al., 1992) and ‘facilitated diffusion’ if the movement is in the direction of concentration
gradient and does not require energy (Banks and Kastin, 1990). Pinocytosis plays a very
small role in drug transport. Pinocytosis is the process in which molecules are engulfed. It is
the outer membrane of the cell that inveginates and contracts and moves to cell interior,
where it releases its contents (Yewdell et al., 1999).
1.4. Modified Drug Delivery Systems
Technologic advancements in the pharmaceutical research, an enhanced understanding of
disease patho-physiology, increased size of aging populations, heightened awareness of many
diseases and a need to develop safer and more effective pharmaceutical treatments, have
revolutionized the way many drugs are delivered to the body (Zeller, 2002). Modified release
drug delivery technology provides insight and critical assessment of the many available and
emerging drug delivery systems for their current and future value. These are sophisticated
systems and take into account pharmacokinetics principals, specific drug characteristics, and
variability of response among individual with different medical conditions (Cardinal, 2001).
In 1950s, Smith kline and French introduced Spansule℗ capsules. The Spansule℗ contained
drug dispersed among many small coated pellets. The drug was liberated from the pellets as a
result of coating erosion fat wax and other natural material such as shellac were used as
coating material to prolong drug release (Blythe, 1956). The initial goal in developing such
products was to achieve a zero-order release of active ingredient from the product (Sastry et
al., 2000). The idea was to mimic pharmacokinetic profile observed with a continuous
intravenous infusion, with maintained a constant plasma drug concentration as a function of
time. This is a highly desirable therapeutic feature, especially for drugs with low therapeutics
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 13
index, because it eliminated significant fluctuations in peak and trough plasma concentrations
(Vaughan and Tucker, 1976). Over the last few decades, pharmaceutical research has become
more sophisticated and structured. As a result, delivery of drug can now be precisely
controlled with respect to the time and interval of oral doses (Thatte et al., 2005). Based on
the mechanism of drug release, oral modified delivery systems can be broadly categorized
into two classes, matrix systems and reservoir systems. It could be observed that the drugs
with some specific properties are considered suitable candidates to be manufactured as
controlled release dosage forms. The ideal drug delivery to the specific site of action should
be bio-compatible, non-reactive, mechanically strong, comfortable for the patient and capable
of achieving high drug loading. Here we discuss few requirements for a drug to be the best
candidate to once-daily CR matrix tablets.
1.4.1. Types Modified Release Drug Delivery Systems
1.4.1.1. Delayed or Repeated Release Dosage Forms
A Delayed- or repeated-release dosage form is the one that releases a specific amount of drug
at a specified time interval. These products could also be named as modified release, but
usually they are known as extended release dosage forms. They are usually thought to release
different amounts of drugs soon after the administration or after sometime. For example,
enteric-coated tablets release a drug after sometime.
1.4.1.2. Prolonged or Extended Release Dosage Forms
Prolonged or extended release dosage forms are those which release the therapeutic entity
slowly after administration. In this case the release may prolong for sometimes but the time
and concentration of the drugs are not determined.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 14
1.4.1.3. Targeted-Release Dosage Forms
The dosage forms which release the specified amount of drugs exactly at or near by the
desired site in the body. These dosage forms may have either immediate or extended release
properties (2).
1.4.2. Requirements for candidate drug in oral controlled release dosage form
1.4.2.1. Drug Dissolution
The dissolution is considered as a technique used for the in-vitro evaluation of a drug release
mechanism of a dosage form. The dissolution method is considered the best approach and is
mostly used at different stages of a dosage form preparation. Drug dissolution process in the
liquids is usually composed of two sequential phases. During the first phase, interfacial
reaction works leading to the release of a solid/solute particle from the solid phase. This
process of release of solute molecule leads to a phase change. So, the molecules of solid
become molecules of solute in the solution in contact with the solid will be saturated
(Mosharraf and Nyström, 1995). During the second phase, the solute molecule must migrate
across the outer layer encompassing the crystal to the solution bulk, leading to the movement
of molecules usually away from the solid liquid interface. The whole process is influenced by
the process of diffusion. Boundary layers are static or slow moving layers of liquid that
surround all wetted solid surfaces. The process of mass transfer is considered rather slow
through the outer static layer, inhibiting the movement of solute molecules from surface of
solid to bulk of solution (Lachman et al., 1987).
Figure 1.3. Drug dissolution and absorption into the systemic circulation
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1.4.2.2. Solubility and pKa
The absorption of a drug can be affected by its solubility. Therefore, equilibrium solubility of
a the drug in given medium is of practical pharmaceutical interest which indicates the rate of
dissolution. The higher the solubility, the rapid is rate of solution, provided that no chemical
reaction is involved. The pH which is one of the primary factors that influences the solubility
of drugs containing unionisable groups (Chen and Venkatesh, 2004, Jorgensen and Duffy,
2002). The drug should be in the form of solution while absorbed. Before manufacturing a
dosag form, solubility of the active moiety should be considered first, depending upon
anticipated route of administration (Perumal and Podaralla, 2007). Usaually the pH
dependant solubility will cover the pH values 1.5-3 (stomach), 6.5 (duodenum, jejunum), 7.4
(ileum) and 7.8 (colon, rectum) as shown in the figure 1.2. The aqueous and pH dependant
solubility is of importance in drug release from different dosage forms (Dressman et al.,
1990).
In order to utilize the concentration gradient as the deriving force for drug release one would
select the limit of solubility (Colombo et al., 1996). Solubility is a prerequisite for a drug to
be absorbed and transported in the body (Wasan, 2001). For weak electrolytes, solubility is a
function of pH (Serajuddin, 2007). Majority of drugs are organic electrolytes and therefore,
four parameters determine their solubility, including degree of ionization (Kallinteri and G.
Antimisiaris, 2001), molecular size (Leuner and Dressman, 2000), interaction of substituent
groups with solvent (Mura et al., 1998) and crystalline properties (Streng et al., 1984). Drugs
usually belong to the group of week electrolytes. The non-ionized moiety is usually lipid
soluble, hence therefore, may dissolve in the lipid material of a membrane and may be
transported by passive diffusion, whereas the ionized moiety is mostly lipid insoluble to the
extent to permit permeation (Baggot, 1978). A considerable change in degree of ionization
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 16
can be expected with change of pH for acidic drugs having a pKa value between 3 and 7.5
(Neuhoff et al., 2005) and for basic drugs having a pKa between 7 and 11 (Neuhoff et al.,
2003).
Acidic drugs, such as flurbiprofen and diclofenac sodium are less soluble in acidic solutions
because the predominant undissociated species are unable to interact with water molecules to
the same extent as the ionized form which is readily hydrated (Florence and Attwood, 1998).
Diclofenac sodium and flurbiprofen due to their pKa values (pKa = 4.0, 4.2), respectively,
have an extreme solubility in acidic media (Velasco et al., 1999, Tang-Liu and Liu, 1987).
1.4.2.3. Absorption
It is the primary accession in designing and manufacturing a dosage form. Absorption is the
movement of an active therapeutic moiety into the bloodstream. It is also considered the
process by which a drug proceed from the site of administarion to site of measurement within
the body. Since the drug cannot be generally measured directly at site of action, its
concentration is mesured at an alternative site, the plasma. Apart from being a more accesible
site for measurement, quantity of drug in plasma also reflects the concentration of drug at the
site of action (Artursson and Karlsson, 1991). The rate of absorption is then measured as the
rate of disappearnace of drug in plasma. It cannot be measured as the rate of disapearnce
from an extravascular site of adiministarion as the integrity of the drug moiety may be
affected during absorption (Nelson, 1961) by one of the several mechanisms described below,
such as degradation which is catalyzed by acid in the stomach e.g. erythromycin
(Hassanzadeh et al., 2007) and sulfasalazine (Corpet, 1993). Extensive metabolism by the
liver (first pass effect) e.g. propranolol, morphine, aspirine (von Bahr et al., 1980).
Metabolism in the lung e.g Xenobiotics (De Kanter et al., 1999).
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The time required for 50% unchanged drug to be absorbed is called the half-life. The fraction
of the percentage of the administered dose that is altimately absorbed intact is called the
bioavailablity and is proportional to the total area under the plasma concnetration-time curve
(AUC), irrespective of its shape. Rate and extent of absorption is also reflected in the
maximum drug concentrations attained (Cmax) and the time required to achieve these
concentrations (tmax). It has been observed that the most of the pharmacokinetic parameters a
drug depend upon its ability to cross the cell membrane (Chillistone and Hardman, 2008).
1.4.2.4. Distribution
It refers to the reversible tranfer of a drug from one site to another site after administration in
the general circulation (Molimard et al., 2004). A drug circulates in the systemic circulation
after administration. The average blood circulation time is considered to be 1 minute. The
drug moves from the blood in to the body tissues during the circulation. Distribution occurs
at various rates and to variuous extents (Tabrizi et al., 2010). Several factors determine the
distribution of drug, including rate of delivery of drug to the tissues by the circulation
(Collins, 1984, Gillette, 1971), drug capability to pass through tissue membranes (Harris and
Robinson, 1992) and binding affinity of drug to plasma protein (Meyer and Guttman, 1968,
Kratochwil et al., 2002).
It is difficult to ascertain exact transportation of a drug in various tissues in-vivo, the extent of
distribution is determined as a proportionality constant i.e. the volume of distribution (Vd),
which correlates observed amount of drug in the plasma with the maximum/total qauntity of
drug in body. The volume of distribution is thus a hypothetical space into which the drug is
distributed at equilibrium. A high Vd generally implies graeter exposure of the body to the
drug. In general for drugs those do not bind to protein or tissue, the volume of distribution
varies between the extracellular fluid volume (16 L) (Kaltreider et al., 1941) and the total
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 18
body water (34.4 L) (Steele et al., 1950) depending on the extent to which the drug gains
access to the intercellular fluids. Digoxin is extensively taken up by extravascular tissue and
has Vd of 3 L (Reuning et al., 1973).
1.4.2.5. Elimination and clearnace
Removal of a drug from the body by metabolism and/or excretion is called drug elimination.
The kidneys, hepatobiliary system and the lungs are the main routes for drug excretion.
Elimination of drugs mainly comprises of biotransformation or metabolism primarily by the
liver (Zanger et al., 2008) and renal excrection of both the unchanched drug and its
metabolites (Fliser et al., 1999, Prescott and Wright, 1973). Metabolism by the gut
epithelium, lungs, blood, kidneys, other organs and tissues, biliary excretion and excretion
through sweat, saliva and breast milk are some of the other modes of elimination (Doherty
and Charman, 2002).
Figure 1.4. A physiological sketch of hepatic clearance
Elimination half-life (t ½) is usually considered as the time taken for qauntity of a therpeutic
moiety to fall by one half. On the bases of the linear kinetic assumption, elimination is a first
order process and consequently it takes three half-lives for approximately 90% of the drug to
be eliminated from the body (Greenblatt, 1985). The rate at which the active drug is removed
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 19
from the body is called as the drug clearance. This can also be assumed as the loss of drug
across organ of elimination is viewed as clearance (CL), while physiologically, it is defined as
blood volume cleared of drug per unit time (Rowland et al., 1973). Mathematically, it relates
the rate of elimination to the plasma concentration. Clearance can be described in terms of the
eliminating organ e.g. hapatic clearanace (Wilkinson and Shand, 1975), renal clearance
(Andrew et al., 1990), pulmonary clearance (Kilburn, 1968) etc. Hepatic clearance by liver is
due to biotransformation of the drug by enzymes via phase I and phase II metabolic reactions.
Drugs with high hepatic clearanace have low oral bioavailability (Schmucker, 2001). The
sum of the individual clearances i.e. both renal and external is termed as total body clearance
(Chiou, 1980). CL has unti of volume per time (i.e. liters per hour, or mililiters per minute per
kilogram) (Rolan and Molnar, 2007). It is used to determine the amount of drug that could be
administered per day to attain desried average serum drug concentrations (Willis et al., 1979).
1.4.2.6. Protien binding
The effectiveness of a therapeutic entity is determined by the amount of drug which usually
bound to plasma protein. This Binding of drug to plasma protien is cosidered one of the main
cause which affetcs drug disposion in the small intestine (Greenblatt et al., 1982, Maruyama
et al., 1992). The complexes made from the drug and protein serves as reservoir of drug
concntration. Thus, the physicochemical properties, the most suitable drug amount to be
delivered at the desired site and potential side effects, influence how much binding to
prtoteins (plasma) can still be undergon and how this approach could be used to design a new
drug molecule (Kratochwil et al., 2002). The fact is usually admitted that the therapeutic
action of a drug depends upon patient exposure to free/unbound drug (Benet et al., 1996).
Unbound fraction may be metabolized and/or excreted. It has been observed that the affinity
of a drug to protiens (plasma) is smaller than that for receptors or the enzyme targets
(Goodman and Gillman, 1996). Human serum ablumin has multiple binding sites for neutral
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 20
and negatively charged drug molecules (Benet et al., 1996, Kratochwil et al., 2002).
Diclofenac sodium [O-(2,6-dichloroanilino) phenyl] acetate) protein binding affinity has been
investigated by (Chan et al., 1987) in two different body fluids by equilibrium dialysis. It has
been observed that diclofenac sodium was highly protein bound (99.5%). It has also been
observed that the amount of drug binding was constant between the concentrations of 2-10
µg/ml.
1.4.2.7. Elimination half-life
The time required for the srum drug concentration to decrease to one half of its origional
quantity is called half-life and is abberiviated as (t ½) (Gibaldi, 1991). While selecting a drug
to be incorporated into controlled release dosage forms it is important to consider its t½.
Shorter the t½, the greater will be the quantity of drug to add into the controlled delivery
systems (Ritschel, 1989). The t ½ has unit of time (Aarons et al., 1986) (i.e. hours, minutes),
drugs levels will gradually accumulate after initiation of a dosage regimen untill the serum
drug concentraion reachs a plateau or a steady rate. This occurs after five t½s for intravenous
or rapidly absorbed extravascular drug formulations. Five t½s are also required to get
complete rid of drug from the body (MacKichan and Comstock, 1986). The half-life of drug
is also determined both by Vd and CL. Drugs that are inefficiently cleared (low CL) are
inaccessible to blood (large Vd), or both will persist in the body longer and have prolonged
half-lives. Those which are efficiently cleared and have relatively small Vds will have short
half-lives (Rowland, 1972). Only drugs whose t½ can be correlated with the pharmacologic
response are candidates for controlled delivery systems. The different pharmacokinetics
parameters of oral and interavenous diclofenac sodium have been investigated by (Willis et
al., 1979, Willis et al., 1980) and found that the time between the dose and appearnace of
diclfenac sodium in plasma and time to achieve the peak plasma concentration tmax 0.1 to 4.5
hours while Cmax was found to be in the range of 1.4 to 3.0 μg/ml.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 21
1.4.3. Oral controlled release matrix systems
Biopolymers are widely used in the pharmaceutical industry to achieve the controlled and
targeted drug delivery now-a-days. On the basis of drug carriers and matrix forming agents
oral prolonged drug release systems can be categorized into two groups.
o The systems containing drug particles dispersed in a soluble matrix. The drug
becomes bio-available as it comes in contact with the dissolution medium
(hydrophilic matrix) (Varshosaz et al., 2006, Dürig and Fassihi, 2002).
o The systems containing drug particles dispersed in an insoluble matrix. The drug
becomes bio-available as a solvent enters the matrix and dissolves the drug particles
(hydrophobic matrices) (Pohja et al., 2004, Crowley et al., 2004).
Hydrophilic matrix systems in which drug is dispersed in a soluble matrix or hydrophilic-
polymer carrier usually undergo a slow dissolution and erosion of the matrix to provide
extended release of drug (Sinha Roy and Rohera, 2002). Synthetic polymers such as
polyorthoesters and polyanhydrides have been used to design drug delivery devices to make
the drug bio-available to the desired site for a desired period of time (Hossainy, 2003). These
undergo erosion of the surface and ultimate diffusion of drug from the matrix. If the matrix is
presented with conventional tablet geometry, then on contact with dissolution media, release
of the drug from the polymer matrix also decreases (Nair and Laurencin, 2007, Rothstein et
al., 2009). Hydrophobic matrix systems containing drug particles incorporated into an
insoluble carrier have different mechanism of drug release from the controlled release
devices. Drug releases from these tablets undergo penetration of dissolution medium,
followed by dissolution and finally the diffusion. It is considered that these dosage forms are
not suitable for the release of compounds that are insoluble or which have low aqueous
solubility. Excipients used in the preparation of insoluble matrices include hydrophobic
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 22
polymers such as polyvinyl acetate (Strübing et al., 2008), ethylcellulose (Crowley et al.,
2004, Kuksal et al., 2006), and some waxes (Zhang et al., 2001).
1.4.3.1. Advantages and disadvantages of oral controlled release matrix systems
The main aim to formulate a controlled release dosage form is to deliver a therapeutic entity
to the desired site, to improve drug efficacy and to achieve patient satisfaction. However, the
advantages of this system are discussed in detail:
o It is very easy to understand the concept of controlled release dosage forms.
o Easy to manufacture using commonly available equipment, by direct compression,
wet granulation or roller compaction.
o Maintenance of therapeutic plasma drug concentration (Sandberg et al., 1988).
o Improved treatment of many chronic illnesses where symptoms breakthrough occurs
if the plasma concentration of drugs drops below the minimum effective
concentration, e.g. in treatment of asthma (Goldenheim et al., 1987), and in
depressive illness (Bielski and Ventura, 2004).
o Maintenance of therapeutic action of a drug during over-night no dose periods, e.g.
overnight management of pain in terminally ill patients permits improved sleep
(Bruera et al., 1998).
o To reduce unwanted systemic side effects related to high peak plasma drug
concentrations, usually in case of conventional dosage forms (Anderson et al., 1999).
o Improved patient compliance resulting from the reduction in the number and
frequency of doses required maintaining the desired therapeutic response (Uhrich et
al., 1999).
o To reduce localized Gastrointestinal side effects produced by conventional dosage
forms (Capuzzi et al., 1998) e.g. potassium chloride. The more controlled, slower
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 23
release of potassium chloride from its peroral modified release formulations
minimizes the build-up of localized irritant concentrations in the gastrointestinal tract
(Paradissis et al., 1992).
o It is also claimed that most savings are made from the better disease management and
patient recovery that can be achieved with modified release products (Brouwers,
1996).
o Conrolled release system is capable of sustaining high drug loading.
o Possible to maintain different types of release profile: zero order, first order, biomodal
etc.
o Excipients are generally cheap and safe, usualy erodible exciepients are used, so
reducing the possibility of “ghost” matrices.
o Provide a constant relief for a desired period of time.
Although oral controlled release dosage forms have number of advantages as discussed above
but there also exists a few disadvantages, as discussed below.
Disadvantages related to oral controlled release dosage forms may include:
o Impossibality of sudden stoppage of pharmacologic action of drug whenever required
due to some poising.
o Gastric emptying usually affects the reproducibility of the actions.
o Bigger size of a dosage form.
o Relatively reduced bioavailability
o More cost.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 24
1.4.3.2. Controlled release matrix tablets
Matrix tablet is a unit dosage form that contains hydrophilic or hydrophobic polymer
uniformly mixed with a selected model drug and other excipients such as matrix former
agent, filler, binder and lubricant (Siepmann and Peppas, 2001, Tiwari et al., 2003b), while
manufacturing these systems, a selected drug is properly distributed and embedded
throughout the polymer matrix. The designed matrix can then be compressed into tablets and
subjected to a uniform rate by dissolution, diffusion or combination of both (Abdelbary and
Tadros, 2008). It could be observed that when a controlled release NSAID tablet is ingested,
the drug is released slowly as a result of slow dissolution of matrix and erosion of the
polymer (Bravo et al., 2002, Bravo et al., 2004). A desired plasma profile can generally be
achieved by using different release controlling polymers such as ethylcellulose,
hydroxypropylmethylcellulose etc. Usually the free drug is released promptly and serves as
the loading dose. The entrapped drug is released gradually over a certain period of time
providing a constant plasma level of therapeutic entity (Roy and Shahiwala, 2009).
Hydrophilic and hydrophobic cellulose polymers such as hydroxylpropylmethyl cellulose,
carboxymethylcellulose (Khan and Zhu, 1998) and ethylcellulose ether derivative polymers
(Crowley et al., 2004) are commonly used in the pharmaceutical industries to design and
formulate a controlled release matrix tablet. Release of a drug from a dosage form usually
depends upon the rate of water uptake and water penetration into the matrix, polymer
solubility and erosion, the porosity of matrix (how deeply the water penetrates) and amount
of water needed to release the drug (Sinha Roy and Rohera, 2002). Now-a-days there is an
increased awareness of the potential relevance of modified-release matrix of water soluble
drugs. These can be prepared by mixing the drug with hydrophobic matrices. These
hydrophobic matrices help slow the rate of drug dissolution and hence, prolong the release of
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 25
drug (Streubel et al., 2000a, Khan, 2001). When a tablet is ingested the dissolution medium
penetrates and hydrates the polymer matrix, causing it to swell and forms a viscous gel layer.
The viscous gel layer controls the penetration of water into tablet and finally the diffusion. As
the water layer begins to break down and dissolve, water penetrates deeper in to the tablets
matrix, forming a viscous gel layer. This process continues until the entire hydrophilic
polymer has gelled and dissolved and the drug has been released (Amabile and Bowman,
2006). Using hydrophobic material like ethylcellulose (Crowley et al., 2004), glyceryl
monostrearate (Playfair, 1964) and glyceryl behenate (Obaidat and Obaidat, 2001), slow
release particles are prepared and are compressed into tablets. In some matrix systems drug
release is controlled mainly by diffusion through matrix pores and by the erosion of the
polymer. The concentration gradient (different amount of drug present in the delivery system
and concentration of drug in the GIT environment) drives drug release (Costa et al., 2001)
shown in the figure 1.5.
Figure 1.5. A schematic diagram of drug release by diffusion from controlled release matrix
tablet in stomach
These systems may be either hydrophilic or hydrophobic depending upon the drug carriers.
Role of ethylcellulose ether derivative polymer has been evaluated by (Katikaneni et al.,
Controlled Release Tablets of Selected NSAIDs Chapter 1….Introduction
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 26
1995), to control the release of pseudophenadrine matrices. Direct compression was found to
be the best method to sustain the release rate effectively (Varshosaz et al., 2006).
Ethylcellulose (low viscosity grades) were more compressible resulting in stronger tablets
(Katikaneni et al., 1995). (Dabbagh et al., 1996) investigated propranolol from a controlled
release matrix tablet formulated with Ethocel® polymer and was observed that the release rate
of propranolol could be modified from ethylcellulose matrix tablets by altering particle size
and polymer viscosity grades. Lower polymer viscosity grades and smaller particle size
controlled the drug release efficiently (Khan and Meidan, 2007). Matrix tablets containing
HPMC K4 with Ethocel® polymer increased the release rate gradually (Rani and Mishra,
2004). And the similar behaviour was observed for the matrix containing CMC with
ethulcellulose, where the burst release of the drug was observed with starch-based matrix
tablets.
Using different hydrophilic hydrophobic drug carriers, matrix tablets can be broadly
classified into various types.
o Controlled release tablets usually release the required amount of drug for a prolong time
steadily during the whole treatment time (Khan and Jiabi, 1998b).
o In case of prolong tablets a drug is released slowly and is available for a longer time for
absorption. However, there is an implication that onset is delayed because of an overall
slower release rate from the dosage form (Nigalaye et al., 1990).
o In case of repeat action matrix tablets the first dose of drug is released from the dosage
form just after the administration, while second and third doses are released after
sometime (Verma et al., 2000).
o Delayed release matrix tablets release the drug after sometime of administration (Matsuo
et al., 1996), e.g. enteric coated tablets (Fukui et al., 2000), pulsatile release tablets
(Sungthongjeen et al., 2004).
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 27
o Sustained release matrix tablet usually release an initial dose just after administrating and
then release the remaining amount rather slowly (Khullar et al., 1998, Reddy et al., 2003).
o Extended release matrix tablet usually release the drug slowly so as to maintain a constant
therapeutic concentration for a longer period of time (usually between 8-12 hours) (Park
et al., 2008, Timmins et al., 1997).
1.4.3.3. Lipid matrix systems
Lipid matrices are described as the systems which provide the sustained release profiles of
bioactive agents both in-vitro and in-vivo. These type of matrix are easy to manufacture using
standard direct compression (Abdelkader et al., 2008a), roller compaction (Ohmori and
Makino, 2000) or hot-melt granulation techniques (Crowley et al., 2007). The concept of
lipid matrix is worth considering, but these matrices are not now in common use. While
designing these type of systems, a typical formulation should consist of active drug, wax
matrix former, channeling agent, solubilizer and pH modifier, antiadherent/glidant and
lubricant (ÖzyazIcI et al., 2006). The matrix compacts are prepared from blends of powdered
components. Release of the drug from dosage form depends upon the solvent surrounding it,
which dissolved the channeling agent thereby producing pores through which a drug diffuses
out (Siepmann and Peppas, 2001, Sinha Roy and Rohera, 2002). Hydrophobic materials, that
are solid at room temperature and do not melt at body temperature, are used as matrix
formers. These include ethylcellulose (Shlieout and Zessin, 1996), microcrystalline wax
(Siepmann et al., 2006) and carnuba wax (Reza et al., 2003). Channeling agents are chosen to
be soluble in gastrointestinal tract and to leach from the formulation, so leaving tortuous
capillaries through which the dissolved drug may diffuse in order to be absorbed in the
gastrointestinal tract. The drug itself can be channeling agent, but a water soluble
pharmaceutically acceptable solid material is more likely to be used (González-Rodríguez et
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al., 2001). Typical example includes sodium chloride (Wei et al., 2006), sugar (Puranajoti,
2006) and polyols (Larsson et al., 2010).
1.4.3.4. Insoluble-polymer matrix systems
In this system a drug molecule is embedded in a polymer matrix which is insoluble in GI
fluids (Sánchez-Lafuente et al., 2002). Matrices usually remain intact during gastrointestinal
transit (Chourasia and K, 2003), and here have also been concerns that impaction may occur
in the large intestine and that patient may be concerned to see matrix, and polymers such as
ethylcellulose are finding favor (Streubel et al., 2000b). Drug release from inert matrices has
been compared to the leaching from a sponge. The release rate depends on the drug
molecules in aqueous solution diffusing through capillaries (Kuksal et al., 2006, Tiwari et al.,
2003b). It could also be observed that the release rate could be altered by changing the
porosity (Crowley et al., 2004) and tortuosity, i.e. its pore structure (Zhang et al., 2001). The
addition of pore forming hydrophilic salts or solutes will have a major influence, as can the
manipulation of processing variables. Compaction force controls drug release. Generally, a
more rigid and less porous matrix will release drug more slowly than a less consolidated
matrix (Streubel et al., 2003). The addition of excipients such as lubricants, fillers etc. is
necessary part of formulation process (Jivraj et al., 2000). However the presence of
excipients likely influences drug release. It may be anticipated that water soluble excipients
will add to the wetting of the matrix, or increase its tortuosity (Vueba et al., 2004, Rao et al.,
2001).
As discussed earlier that the polymer particle size may influence the release rate (Heng et al.,
2001b, Zuleger and Lippold, 2001), but the relationship between the two is not clearly
defined. One possible explanation may be a decrease in the tortuosity and release rate can be
related to drug solubility (Crowley et al., 2004).
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1.4.4. Reservoir systems
Reservoir system usually contains a rate-controlling polymer membrane surrounding a core
that contains the active drug moiety (Langer, 1993, Longer et al., 1985). When a reservoir
tablet is ingested the drug release is facilitated by gradual dissolution of the coat or of certain
components of the coat and is controlled by the thickness or solubility of the coating. A
thicker coating will be more resistant to penetration by the aqueous fluid and a coating that is
rich in lipophillic polymer will also delay drug release and dissolution. In this system water
enters the drug reservoir, dissolves or suspends the drug and pushes the drug out through a
predrilled orifice (Zhang et al., 2002, 2006b). Extended release potassium chloride (Micro-
K®) is an example of system containing individually containing microencapsulated
potassium chloride crystal that disperse within 1 minute on tablet disintegration. Potassium
chloride crystal are coated with an insoluble polymeric coating of ethylcellulose (Wu et al.,
2003). The coating allows fluids to pass and gradually dissolves the potassium chloride
within the microcapsules. The resulting solution of potassium chloride slowly diffuses
outward through the membrane. This permits the controlled release of potasium and chloride
over an sustained period of time. Because of the encapsulation of individual crystals, the
tablets can be broken in half for ease of administration (Venkatesh, 2009). The patient is also
informed that the tablet can be allowed to disintegrate in water before it is consumed. The
tablet should not be chewed or crushed, however this can break the extended coating, which
could result in dose dumping (2006d). In the reservoir type of system drug crystals
(Pargaonkar et al., 2005), pellets (Tunón et al., 2003) or granules (Frenning et al., 2003) may
be coated with polymer and then these pellets may either be encapsulated or compressed in to
tablets. Conversely, a tablet core may be coated with a polymer that controls the release of
the drug. Cellulose derivatives such as hydroxypropylmthylcellulose (Frohoff-Hülsmann et
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 30
al., 1999), cellulose acetate phathalate (Emanuel and Tuason, 1984), and ethylcellulose and
methacrylic acid are commonly used coating agents (Bauer et al., 1984).
1.4.5. Other technologies
1.4.5.1. Multi-particulate formualtion
It is a modified release tablet which is not uninform and contains subunits that may be either
the same or different. Multiple unit tablets provide much diversity in achieving profile
through the combinations of various types of subunits in a single tablet (Stanic Ljubin and
Kocevar, 2007). Adalat® CC tablet is composed of two portions, the core which contains the
active drug nifedipine as a fast-release formulation, and the coat, which contains nifedipine
mixed with a gel forming polymer as a slow release formulation, as the gastrointestinal fluid
permeates the hydrophillic polymer, a gel is formed. Thereafter, a constant rate drug release
occurs with ersosion of the matrix gel. In contrast to the coat matrix gel, which relesaes drug
at a slow rate, the core tablet releases drug at a comparatively fast rate (Plough, 2004).
A slightly modified version of multidose system is a multilayerd tablet, such formulations are
fixed-dose combination that contain one drug in an immediate-release outer layer and an
extended release portion of a second drug in core (Verma and Garg, 2001). Advicor® is an
example and it contains lovastatin as an immediate-release outer layer and niacin as an
extended-release inner core.
1.4.5.2. Phased drug delivery
Traditionally, extended or controlled release systems for once-daily administration provided
constant drug release to maintain a steady concentration of drug. For some drugs, however,
zero-order delivery or a constant rate of drug delivery may not be optimal (Portenoy et al.,
2002). The marketed product, Concerta®, (methylphenidate) contains three inner layers, two
drug layers and a push layer as well as an overcoat layer as a loading dose (2006a). The
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prsence of two drug layers provides increased flexibility and controll over the release of
medication from the system (Conley et al., 2006).
Another example that illustrates the concept of phase drug drug delivery is chronotherapeutic
delivery (Smolensky and Peppas, 2007). The incidence of myocardial infarction or ischemia,
strike, and sudden cardiac death increases during early morning hours. This is probably
because heart beat rate and blood pressure peak during that time. Chronotherapeutics
involves the alteration and adjustment of drug levels to match the circadian rythms. This can
be achieved by developing delivery systems with special release mechanisms that provide
peak plasma concentration during the early morning hours when it is most needed, such
delivery systems help to optimize the therapeutic outcomes and minimize side efects (Prisant
and J, 2003).
1.4.5.3. Ion-exchange systems
Ion-exchnage resins are water soluble materials that have been used as carriers of drugs to
sustain drug release. The resins are not absorbed from the body because they are insoluble
(Sriwongjanya and Bodmeier, 1998). They contain either basic or acidic groups and can form
complexes with oppositely charged drugs, having reversible interaction. The presence of
charged group on the drug is required to complex with the resin (Agarwal et al., 2000). The
resin can release the drug in GIT because of pH range or the presence of competing ions. The
rate of drug release is governed by properties of the resin (Jenquin et al., 1990).
Pennnkinetic® extended release suspension contains chlorpheniramine polistirex and
hydrocodone polistirex. Pennnkinetic® technology, developed by Pennwalt corporation,
involves the use of cation-exchange resins that complex with drug. The release of both drugs
in the formulation is prolonged, which allows doing every twelve hours. The resin-drug
complex can be coated with ethyl cellulose, which controls diffusion and helps to extend drug
release (Raghunathan et al., 1981).
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1.4.5.4. Bioadhesives
The use of mucoadhesive polymers to improve oral drug absorption or enhance the
performance of oral controlled drug delivery systems has received remarkable attention in the
past 10 to 15 years. Interest has been generated with several goals in mind, including
increasing local drug concentrations to improve absorption, retarding drug transit to take
advantage of upper gastrointestinal absorption windows, and targeting drug to specific region
of the GIT. The successful application of the bioadhesievtechnology requires the creativity
and expertise of the pharmaceutical scientist counter the physiologic mechanisms of the GIT
that function to dilute, mix and propel food substances in a proximal to distal directionin the
GIT.
1.4.5.5. Gastroretentive systems
Approximately 6 to 8 hours after oral ingestion, a tablet or capsule reaches the distal portion
of the GIT from which the drug is unlikely to get absorbed. For many drugs, the short
exposure time in the stomach and small intestine where maximal absorption usually takes
place may not be adequate to render the drug fully bioavailable. To increase this exposure
time, gastroretentive delivery systems have been developed. such products are retained in the
stomach for extended periods and therefore can release drug over a more prolonged time than
standard formulations. At present, no gastroretentive products are commercially available,
however, patents have been secured for gastroretentive formulations of acyclovir and the
bisphosphonate class of compounds that are used to treate osteoporosis (Bardonnet et al.,
2006, Klausner et al., 2003). Here we discuss the selected candidates for oral controlled
release matrix tablets.
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1.5. Model Drugs
1.5.1. Flurbiprofen
Flurbiprofen is a non-steroidal anti-inflammatory drug. It belongs to the group of propionic
acid derivatives. It is recommended in ankylosing spondilitis, in soft tissues disorders such as
sprains and strains, in mild to moderate pain including dysmenorrhoea, and for postoperative
pain, rheumatoid arthritis and osteoarthritis (Brooks and Day, 1991, Qiu and Bae, 2006).
Flurbiprofen usual dose is 150 to 200 mg daily by mouth in divided doses, increased to 300
mg daily in acute conditions, if necessary. Patients in dysmenorrhoea may be given an initial
dose of 100 mg followed by 50 to 100 mg every four to six hours to a maximum total daily
dose of 300 mg.
Figure 1.6. Molecular Structure of Flurbiprofen
Flurbiprofen is immediately absorbed from the GI tact thereby achieving a peak plasma
concentration within 1 to 2 hours. Protein biding is maximum (99%), with a shorter half-life
of 3.3-3.4 hours, with pKa value 4.2 (Greenblatt et al., 2006). Flurbiprofen may cause gastric
ulceration, abdominal cramps, nausea, kidney impairment and ringing in the ear. It is
metabolised mainly by hydroxylation and conjugation in the liver and excreted in urine.
Flurbiprofen is also excreted in very small amounts in breast milk (MARTINDALE, 1996).
Rarely, it causes the side effects, including abdominal burning, pain, cramping, gastritis, and
sometimes serious gastrointestinal bleeding and liver toxicity, stomach bleeding can occur.
Black tarry stools, weakness, and dizziness upon standing may be the only signs of internal
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 34
bleeding (Wechter et al., 1993). Various studies have been conducted to investigate the
effect of food upon oral administration flurbiprofen in human volunteers by (Pargal et al.,
1996) and it was concluded that the bioavailability of flurbiprofen was enhanced with meal.
1.5.2. Diclofenac Sodium
Diclofenac sodium, a phenylacetic acid derivative, is a non-steroidal anti-inflammatory drug
(NSAID). It is a prescription drug and is recommended in various conditions:
musculoskeletal and joint disorders such as particular disorders such as bursitis, and
tendinitis; rheumatoid arthritis, osteoarthritis and ankylosing spondilitis; soft tissue disorders
such as strains, sprains and renal-colic, acute gout, dysmenorrhoea. Oral dose of diclofenac
sodium is 75-150 mg daily in individual doses.
Figure 1.7. Molecular Structure of Diclofenac Sodium
Diclofenac sodium is rapidly absorbed when given as an oral solution, rectal suppository, or
by intramuscular injection. It is absorbed more slowly when given as enteric-coated tablets,
especially when this dosage form is given with food. Although, orally administered
diclofenac is almost completely absorbed, it is subjected to first pass metabolism so that
about 50% of the drug reaches the systemic circulation in the unchanged form. At the
therapeutic concentration, protein binding is 99%. Diclofenac sodium penetrates synovial
fluid where concentration may persist even when plasma concentrations fall, diclofenac
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 35
sodium has been detected in the breast milk. The terminal plasma half-life is about 1 to 2
hours, with pKa value of 4. Diclofenac sodium is metabolised to 4-hydroxydiclofenac, 5
hydroxydiclofenac, 3 hydroxydiclofenac and 4, 5-dihydroxydiclofenac. It is mainly excreted
in the urine in from of sulfate and glucuronoid conjugates (about 65%). it is also excreted in
the bile (about 35%) (MARTINDALE, 1996). Extensive clinical experiences have showed its
safety profile (Zacher et al., 2003, Todd and Sorkin, 1988). Occasionally, it causes gastric-
ulceration, edema and abdominal pain. (Cheng et al., 2004) investigated the role of
hydroxypropylmethylcellulose polymer to sustain the release of diclofenac sodium drug from
matrix tablets. Hydrophilic HPMC polymer was used as a matrix forming material. Polymer
particle size and its concentration were found to be the release controlling factors (Velasco et
al., 1999). Flurbiprofen and diclofenac sodium can be used as model drug for oral controlled
release matrix tablets using different polymers which are discussed below.
1.6. Controlled Release Polymers
Substances with short chain molecules containing relatively few monomers are called
oligomers, while the high molecular weight substance with large number of monomers are
called polymers (Flory, 1953). They owe their unique characteristics due to size, their three
dimensional shape and sometimes to their asymmetry. The chemical reactivity of the
polymers depends on the arrangement of monomers, which leads to the versatility of
synthetic polymers. Polymer cross-linking leads to a three dimensional and often insoluble
polymer network. The polymers, in which all the monomers are identical, are referred to as
homo-polymers while those formed with more than one monomer type are called co-
polymers (Florence and Attwood, 1998). During the last two decades the use of polymeric
materials as the delivery vehicles for bioactive agents has attracted huge attention. Polymer
and pharmaceutical scientists have been engaged in bringing out design predictable and
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controlled drug delivery of bioactive agents. Upsurge of biotechnology over the past decade
has benefited the controlled drug delivery research in terms of developing new materials.
Three basic approaches govern the design of drug delivery systems containing bio-degradable
polymers (Murthy, 1997).
o Surface and bulk erosion with connected release of embedded drug
o Cleavage of drug-polymer bond between the polymer and drug occurring in two
polymer bulk or at the surfaces.
o Diffusion-controlled release of the drug with bio-absorption of the polymer delayed
until after depletion.
1.6.1. Cellulose derivative polymers used for drug delivery
The need, for delivering a drug to the systemic circulation and making it available for its
desired therapeutic effect, has prompted the pharmaceutical industries to develop novel drug
delivery systems. Controlled release drug delivery technologies have made quantum
advances in the array of pharmaceutical science in the last three decades. Advances in
pharmaceutical technology have now brought new and more challenges in controlled
delivery. The pharmaceutical researchers working in this area have skillfully overcome many
of the problems that encumber the clinical applications of a therapeutic entity (Park and
Mrsny Randall, 2000). Drugs can now be made effectively bio-available at zero-order for
periods ranging from days to years. Technology advancements have designed many clinically
useful controlled release dosage forms, resulting in new lives to various existing drugs
molecules, which will require more than the sustained release approaches previously
provided by the highly successful lipid based systems. Controlled release technology has
found a suitable place in the area of pharmaceutical industry. It can better afford a consistent
bioavailability of a drug with lesser side effects (Shahrokh, 1997). Hydrophilic Hydrophobic
polymers provide several appositive outcomes in designing controlled release oral dosage
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forms, ranging from good stability at different pH values and moisture levels to well
established safe applications (Abdelkader et al., 2008b). A controlled release system designed
hydrophobic polymer improved the effectiveness of a drug therapy, reduced the side effect
and reduced the number of administrations. This system is simple and predictable (Tiwari et
al., 2003b). The most widely used polymers are derived from cellulose with the basic
structure containing β-anhyderoglucose unit. Cellulose itself is virtually insoluble in water,
but the aqueous solubility can be conferred by partial methylation and carboxymethylation.
Ethycellulose is 523125221262312 )( OHCOHCOHC n with a basic unit of β-anhyderoglucose
having three hydroxyl substituent groups which can be replaced by ethyl groups. “ n ” can
vary to provide a wide variety of molecular weights. Anhydroglucose unite are joined
together by acetate linkages. Ethylcellulose with less than 46.5% of ethoxyl groups is freely
soluble in various solvents namely chloroform, esters, ketones, alcohola, tetrahydrofuran and
aromatic compounds while that with not less than 46.5% of ethoxyl groups is freely soluble
in chloroform, ethanol, ethyl acetate, methanol and toluene (Raymond, 2002), (Ethocel,
1986). Viscosity grades of polymer determine its feasibility and suitability for controlled
release formulations. The apparent viscosity of ethylcellulose is the concentration of polymer
dissolved in as specified solvent at a specified temperature. Ethocel® is available in different
viscosity grades of 7, 10, 20, 45 and 100. The viscosity can be controlled by controlling the
degree of polymerization during production process (Moore and Brown, 1959).
Methylcellulose is methyl ether of cellulose containing about 29% of methoxy group. It is
slowly soluble in water. High viscosity grades are used as emulsifiers for liquids paraffin
while high viscosity grades are used as dispersing and thickening agents in suspensions.
Hydroxyproplymethylcellulose is mixed ether of cellulose containing 27-30% of 3OCH
groups and 4-7.5% of OHHOC 63 groups. It forms a viscous colloidal solution. There are
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various pharmaceutical grades available which are used as matrix forming material. Sodium
carcoxymethylcellulose (CMC) is soluble in water at all temperatures. And its mucilages are
more sensitive to change in pH than are those of methylcellulose. The viscosity of a sodium
carboxymethylcellulose (CMC) mucilage is decreased markedly below pH 5 or above pH 10
(Florence and Attwood, 1998). Ethylcellulose (Ethocel®) is an inert hydrophobic polymer
and has been used as a binder (Chowhan, 1980), as a film forming and matrix forming
material both for water soluble sparingly water soluble drugs (Shaikh et al., 1987). In
preparing microcapsule, microsphere and nanoparticles (Bodmeier and Chen, 1989, Atyabi et
al., 2007, Abdel-Mottaleb and Lamprecht, 2010), in controlled release matrices and hot-melt
extrusion for controlling dissolution rate of drugs (Dabbagh et al., 1996). Drug release from
the matrix containing ethylcellulose can be controlled by altering the its viscosity grades
(Shlieout and Zessin, 1996). It is non-toxic and stable when stored for a long time (Dubernet
et al., 1990). The role of ethylcellulose polymer can be evaluated by preparing FLB and
DCL-Na controlled release matrix tablet and investigating their release behavior in-vitro and
in-vivo. Various methods are used to study the release behavior of drugs from the matrix
tablets, as discussed below.
1.7. Tablet Preparation
1.7.1. Direct compression
Direct compression method consists of compressing tablets directly from powdered material
without modifying the physical nature of the materials itself. This method of tablet making is
of special interest for small group of crystalline chemicals having the entire physical
characteristic necessary for the formulation of a good tablet. Substances like chlorides,
chlorates, bromides, iodides, nitrates and permanganates, salts of potassium, ammonium
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chloride and methanamine etc are manufactured by direct compression as they have cohesive
properties.
1.7.2. Advantages of Direct Compression
Advantages of this method are simplicity of process, absence of granulating steps, avoidance
of moisture and drying step, minimum material handling, and rapidity of the total process.
1.7.3. Limitation of Direct Compression
The limitations of this method are that only a few crystalline drugs can be directly
compressed otherwise this process has no major limitation (Jivraj et al., 2000, Kanig and
Westbury, 1975, McCormick, 2005).
1.8. In-vitro Evaluation
The most common method for the evaluation of a drug or dosage form is the dissolution test
that was developed to estimate in-vivo bioavailability and drug release pattern from a drug
product. The concept of dissolution is now new. The earliest references can be found in the
articles of Noyes and Whiteny in 1897, Nernes and Brunner 1904, and Hixon and Crowell, in
1931. However, during 1950’s the pattern of investigation was changed and focused on the
examination of the effects of the dissolution behavior of the drug and biological activities of
the dosage form. In 1960 levy and Hayes correlated dissolution and absorption rates of
different commercial tablets. The later studies proved that in-vitro dissolution studies could
be used to explain the observed differences in in-vivo availability as it essentially completely
controlled the rate of absorption. Dissolution is a process by a a solid substance enters in a
solvent to yield a solution. Almost all pharmaceutical solids and solid-liquid dispersed dosage
forms undergo dissolution in the body followed by absorption into the systemic circulation.
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Several pharmaceutical factors must be taken into consideration, which can affect the rate of
dissolution. These include the physical characteristics of the dosage form, wettability of the
dosage unit, the penetration ability of the dissolution media, the swelling process, the
disintegration and degradation of the dosage form. Studies have shown that dissolution test
can provide valuable information to the formulator in the development of a more efficacious
and therapeutically optimal dosage form. The development and implementation of in-vitro
dissolution standards that reflects in-vivo drug performance will help to minimize to use of
human test subjects for bioavailability of testing of product. In general two types of
dissolution systems have evolved. The first one characterized by the stirred vessel which uses
a relatively large dissolution volume with minimal liquid exchange. Agitation of the liquid is
by the rotating blade or by motion of vessel itself. The other method involves flow thorough
column system which uses a relatively small dissolution cell through which a fresh solvent
flows at a constant rate with no additional agitation (Nelson, 1979).
The composition of dissolution medium should be aqueous in nature and buffered at different
pH to determine the pH sensitivity of the drug release from the dosage form which is
necessary to mimic the variable pH of the gastrointestinal tract. It is also important to
maintain the sink condition by keeping the concentration of the dissolved drug in the bulk
medium below 15% of saturation and to continue the test at 37±0.5 °C as both these factors
can affect the rate of drug release.
1.8.1. Bioavailability-Bioequivalence studies
The U.S Food and Drug administration defines bioavailability as the rate and extent to which
the active ingredient or active moiety is absorbed from a drug product and become available
at the site of action.
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1.8.2. Absolute bioavailability (F)
Absolute bioavailability is denoted by F, which is also the fraction of the dose that is
absorbed. After IV administration, the entire dose is placed into systemic circulation;
therefore, the fraction of the dose absorbed (F) or the absolute bioavailability is equal to
unity. For route other than IV administration F = ±1, absolute bioavailability is most
commonly expressed as a percentage, where an F of 1 is 100% bioavailability. Absolute
bioavailability can be calculated from the following equations:
From Plasma Data
DoseivAUC
DoseoralAUC
F)(
)(
1.8.3. Relative bioavailability (RA)
The relative bioavailability is the systemic availability of a drug from test drug product (A)
compared to reference drug product (B) relative bioavailability can be calculated from the
following equations
BAUCAAUCRA )(
)(
Where the doses are not equal, the dose adjusted AUC values should be used as follows.
doseBAUCdoseAAUCRA )(
)(
Pharmacokinetic parameters that give detail information on the amount of drug reaching the
systemic circulation (extent) and the time taken to reach the systemic circulation (rate) are
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used to assessing bioavailability. Bioavailability can be measured by direct and indirect
methods.
1.8.4. Direct method
Direct measures of bioavailability can be based on plasma drug concentrations. Drug
concentration in the blood and plasma are the frequently used methods for the determination
of the systemic availability of drug. The pharmacokinetic parameters that describe the rate
and extent of absorption and systemic exposure based on plasma drug concentration data are
given below.
AUC is the measure of the extent of the bioavailability. The area under the plasma drug
concentration (AUC0- t or AUC0- ∞) gives measure of the total systemic exposure.
1.8.5. Indirect method
Indirect method of bioavailability can be assessing by the following ways:
From urinary excretion data:
This can be used if urinary excretion of unchanged drug is the major mechanism of
elimination of the drug and the urine samples have been collected in intervals as short as
possible to measure the rate and amount of excretion as possible. Bioavailability can be
accessed from equation using the urinary excretion data as given below.
fDoseDuF //
Where Du∞ = cumulative amount of drug excreted in the urine
F = Fraction of dose absorbed
ƒ = Fraction of unchanged drug excreted in the urine
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The pharmacokinetic parameters that give detail information about the rate and extent of
absorption and systemic exposure based on the urine excretion data are as Cumulative
amount of drug excreted in the urine (Du∞). It is directly related with the total amount of
drug absorbed. When the plasma concentration reaches to zero, then the maximum amount of
drug excreted in the urine is obtained. Thus, it measures the extent of drug absorption
(Ronald, 2002).
o Study to evaluate the absolute bioavailability of an oral, topical, intramuscular, or any
other dosage form. Ideally, the test dosage form should be compared with an
intravenous reference dose. In reality, however, a suitable intravenous form may not
be readily available, and the test dosage form is usually compared, instead, with an
oral solution or suspension to determine if the former would be adequate for
subsequent clinical studies. Normally, the study is conducted in 6-12 subjects using a
single-dose crossover design.
o Dose proportionality study to determine if bioavailability parameters (i.e., peak
concentration (Cmax) and area under concentration-time curve (AUC)] are linear over
the proposed dose range to be used in medical practice. Oral range for a single dose
and tested using a three-way crossover design (low, mid, and high dose) in 12-18
subjects.
o Intra/inter-subject variability study to determine what the variability of bioavailability
parameters are at any one dose level. Oral doses at one dose level are usually given as
a solution or suspension in a mock three-way crossover design.
o Dosage form(s) study to determine if that used during clinical trials is bioequivalent to
that proposed for marketing. This is normally a single-dose crossover study evaluating
the highest strength of the proposed marketed dosage form. The numbers of subjects
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to be used is dependent on available information on dose proportionality and
inter/inter-subject variability.
o Dosage form proportionality study to determine if equipotent drug treatments
administered as different dose strengths of the market form produce equivalent drug
bioavailability. Normally, multiple strengths are evaluated by bracketing (i.e.,
studying the lowest and highest strengths at the same dose level in a single-dose
crossover design).the number of subjects again is based on dose proportionality and
inters-and inter-subject variability of the drug.
o Effect of various types of intervention studies to examine the effects of, for example,
food and concomitant medication on bioavailability parameters. These are normally
single or multiple-dose studies conducted using the dosage form proposed for
marketing.
o Bioequivalence study needed as a result of changes in the formulation or
manufacturing process (i.e., to show that the old and new products are equivalent).
o Bioequivalence studies conducted for the purpose of filling an abbreviated a new drug
application (ANDA), the goal is to show that a generic drug is bioequivalent to the
innovator’s product in order to make claims of therapeutic equivalence (Peter et al.,
1991).
1.9. High Performance Liquid Chromatographic Analysis
1.9.1. Method Validation
The test methods used in the research laboratories for the quality control analysis of drug
products need to meet the desired standards of accuracy (USP, 2005). It is a fact that the
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accuracy and reliability of a method plays a vital role to assure the product quality, its safety
and efficacy. It has been suggested that before a method is used, it must be validated
according to the standard guidelines. In order to validate a method standard guidelines have
been provided by different organizations including International Conference on
Harmonization, Food and Drug Administration and United States Pharmacopoeial
Convention (USP) (Swartz and Kurll, 1997, Davidson, 1996). Therefore, a new method
should be developed according to the CGMP guidelines given below.
1.9.2. Linearity
The linearity tells us about the relationship of the concentration of an analyte to the response
within the specified range (USP, 2005, Swartz and Kurll, 1997). Interval between upper and
lower levels of analyte is known as the range of the method that could be investigated with
appropriate level of linearity, precisian and accuracy (USP, 2005, Swartz and Kurll, 1997,
Rosinga et al., 2000).
According to the ICH guidelines, minimum 5 (five) concentration levels should be used to
analyze linearity. The peak height of the drug and that of internal standard were calculated
and a calibration curve was drawn to determine the correlation between the response and
concentration (Rosinga et al., 2000).
1.9.3. Precision
Precisian could be defined as the capability to generate accurate analytical results from a
number of measurements according to the particular assay conditions (Rosinga et al., 2000).
It can be categorized further into intra-day precisian, inter-day precisian and the
reproducibility (ICH, 2005) In order to judge the precisian of a chain of measurement
standard deviation and % relative standard deviation are used (Thompson and Ellison, 2002).
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1.9.4. Repeatability or intra-day precision
Repeatability could be considered as the precisian of a method with a fine range of deviation
chances in the experimental condition. It is achieved in the laboratory by one analyst using
the same equipment on the same day. It has been suggested by (Rosinga et al., 2000) that
repeatability can be determined using three different concentrations, low, medium and high
range of calibration curve with minimum of five replicates analyzed per concentration level.
1.9.5. Intermediate precision or inter-day precision
Within the lab difference could be expressed as inter-day precisian. It could be tested by
different analysts on different days within the same lab, using different equipment. Usually
three different concentrations are used as low, medium and high range of the already
developed calibration curve (USP, 2005).
1.9.6. Reproducibility
Reproducibility of an analytical methods means to bring about the same result of an
analytical method developed at different labs (USP, 2005, Swartz and Kurll, 1997). If the
method is repeatable then the reproducibility studies are not conducted, as these results are
sufficient to confirm the precisian of the method. Reproducibility is usually known as the
method standardization procedure (USP, 2005).
1.9.7. Accuracy
It could be known the correctness of an analytical method and usually describes the limit of
result deviation from that of an expected one (Swartz and Kurll, 1997). It is considered as an
important criterion for the determination of the error associated with an analytical method
(Rosinga et al., 2000). It could also be known as the amount of analyte recovered (USP,
2005). A statistical t-test can also be used to investigate the difference between the true data
and the mean value at 95% level of confidence (Rosinga et al., 2000).
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1.9.8. Limit of quantitation (LOQ)/ limit of detection (LOD)
LOD is an easy approach used to describe the minimum quantity that can readily be
measured by the developed analytical method. While LOQ is the smallest concentration at
which analyte cannot be determined but at which some goals for imprecision meet (ICH,
2005).
1.10. Aims of the work
In order to minimize or to annihilate of the patient compliance problems once-daily oral
controlled release matrix tablets of flurbiprofen and diclofenac sodium are desired. To
achieve these aims, the research project will explore and investigate the following objectives:
o To develop and validate an analytical method for flurbiprofen and diclofenac sodium
for accurate and selective drug determination in the prepared formulations.
o To Study the basic physicochemical properties of flurbiprofen, diclofenac sodium
powders and their physical mixtures such as angle of repose, compressibility index,
content uniformity, bulk density, taped density, hausner’s ratio, FTIR-spectroscopy,
X-Ray diffraction and scanning electron microscopy.
o To prepare controlled release matrix tablets and to evaluate the characteristics of
tablets including weight variation test, friability, hardness, content uniformity,
thickness and diameter tests.
o To conduct in-vitro in-vivo release studies, using 7.4pH phosphate buffer and New
Zealand albino rabbits.
o To applying different kinetic and pharmacokinetic parameters to the drug release data.
o To study the stability of various selected formulation.
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 48
2. REVIEWOFLITREATURE
Polymer Based Modified Release Formulations
(Faith et al., 2010) investigated that polymer based controlled release formulations were
more innovative technologies widely used to prolong therapeutic action. Usually it was found
that rate of polymer matrix hydration and erosion was mainly dependent on the polymer
ratios used, which in turn affected the rate and mechanism of drug release from these
formulations. It could also be found that the changes in the microstructure of matrix tablets
could be dependant of the rates of drug release from these formulations.
(Kazunori et al., 2010) evaluated the controlled release formulation of Organogel given
orally. Ibuprofen was used as a model drug. It has been investigated that absorption of drug
was decreased and hence the action was prolonged.
(Yassin and Mona, 2010) studied the preparation of compression-coated tablets (CCTs) of
lornoxicam. The research study provided an opportunity to prolong lornoxicam release to
meet the requirements of currently available control the release matrix tablets of lornoxicam
in the market and to prolong action drug.
(Hindustan et al., 2010) used Hibiscus rosa-sinensis leaves mucilage to prepare matrix
tablets of Diclofenac sodium. Different physicochemical properties were evaluated for
Hibiscus rosa-sinensis leaves. The prepared controlled release tablets were found to have
good weight uniformity, hardness, friability and drug content. In-vitro dissolution studies
proved the ability of Hibiscus leaves to prolong the release rate effectively.
(Ekarat et al., 2009) predicted the in-vivo performance of a modified release dosage form
using In-vitro bio-relevant dissolution tests. The overall experimental project shown good in-
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 49
vitro drug release and in-vivo correlations between absorption of drug in both pre and post
prandial states using the current bio-relevant dissolution methods.
(Syed et al., 2009) the study was used to design oral sustained release matrix tablets of
flurbiprofen, using matrix polymers. The drug release characteristics from the matrix tablets
were evaluated by using response surface methodology. The test tablets shown the zero order
kinetics which could be considered as the drug release from the matrix tablets avoiding
gastric effects.
(Grzegorz et al., 2008) studied the in-vitro dissolution behavior of diclofenac sodium from
the extended release tablets using two dissolution apparatus. In-vitro dissolution data showed
multiple peaks in the release profiles of diclofenac sodium drug, which might be due to
physical stress.
(Shah et al., 2007) used metoprolol tartrate as a model drug to prepare matrix tablets and
investigated the release studies using a developed prediction-model. For this purpose Shah et
al. studied various physicochemical properties and dissolution behavior of the tablets,
prepared by direct compression and wet-granulation techniques.
(Lin et al., 2007) developed sustained release matrix tablets of aspirin model drug using
direct compression technique using polymer based formulation containing polymethyl
methacrylate-silica composites as matrix forming agent. Various physicochemical studies
were conducted and was concluded that the dissolution profile followed Fickian-diffusion
model.
(Marcos et al., 2007) evaluated the role poly-(N Isopropyl-acrylamid) as a matrix forming
agent in sustained release cellulosic-pellets. It was observed that pellet-coating did not affect
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 50
the physicochemical properties of the pellets but caused a decrease in the porosity of the
matrix, hence sustained the release rate up to many hours.
(Adnan et al., 2006) conducted a study to formulate the sustained release matrix tablets of
tripelennamine-hydrochloride using wax as a matrix forming agent. Physical properties of the
tablets were kept constant. Different studies were conducted to investigate the possible
interaction between the drug and polymer. In-vitro dissolution study was conducted and
found that the addition of povidone as a channeling agent effectively controlled the drug
release rate more than 10 hours.
(Alan and Patrick, 2006) formulated amoxicillin-trihydrate controlled release matrix tablets
using hyrdoxypropylmethylcellulose-acetate-succinate as matrix forming agent. Pre-
formulation and physicochemical tests of the prepared tablets showed that these process
variables kept content to form a uniform tablet. Later, an ethanolic technique was used to
design the final tablet. Effect of co-excipient like HPMC was also evaluated and was found
that the test tablets designed showed a good sustained release effect.
(Cherng-Ju, 2005) prepared and evaluated sustained-release triple-layer matrix tablet using
cellulose derivate polymers, hydroxypropylmethylcellulose-acetate-succinate and
ethylcellulose. Labetalol-HCl was used as a model drug. Core of the tablets or the middle
layer was made up of hydroxypropylmethylcellulose-acetate-succinate while the top and
bottom layers were made up of hydrophobic cellulose polymer. In-vitro dissolution study
proved that the release mechanism followed zero-order kinetics.
(Philip and Pathak, 2006) developed a non-disintegrating flurbiprofen capsules containing
asymmetric membrane. The role of potential excipients was investigated using dissolution
studies. The release mechanism showed Fickian behavior. An unpredictable poor correlation
was observed between the drug release profile in-vitro and drug absorbance in-vivo.
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 51
(Kiortsis et al., 2005) used ibuprofen, diclofenac sodium, naproxen and indomethacin model
drugs to formulate sustained release tablets using HPMC polymer. Preformulation studies
were conducted for the drug powder material. Solubility was also investigated by equilibrium
solubility method. A wet granulation technique was used to prepare the tablets. It has been
evaluated from the release data that wet-granulation technique effectively controlled the
release rate.
(Kashappa and Pramod, 2004) used propranolol-HLC as a model drug to design and
evaluate buccal-adhesive system. Preliminary studies were conducted prior to dissolution.
Hydrophilic HPMC K4M was used as a matrix forming agent. The release mechanism from
the test tablets was found to be non-Fickian and followed first order kinetics.
(Sanju et al., 2004) prepared chitosan-microspheres and studied the drug interaction with
mucin. It has been suggested that the drug interact with mucin which mainly depend upon the
process variables and the quantities used. It has also been investigated that the attachment of
mucin with the drug depends upon zeta-potential of the microspheres.
(Crowley et al., 2004) used Guaifencsin as a model drug to investigate the release behavior
of ethylcellulose ether derivative hydrophobic polymer using direct-compression and hot melt
extrusion techniques. It has been found that Guifencsin is a water soluble drug while
Ethocel® is hydrophobic polymer. It has been observed that the viscosity grades of
ethylcellulose played a vital role in the release controlling mechanism.
(Fukui et al., 2004) examined the release properties of phyenypropanolamine HCl granules
prepared by hot-melt-extrusion granulation technique. Validity of the treatments was
confirmed by the fitness of a simulation curve with the measured curve. In the first stage,
PPA was released from the gel layer of swollen EC in the matrix granules. In the second
stage, the drug existing below the gel layer dissolved and was released through the gel layer.
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 52
The effect of the binder solution on the release from EC matrix granules was also examined.
The binder solutions were prepared from various EC and ethanol concentration. The media
changes from good solvent to poor solvent with decreasing ethyl alcohol concentration. The
matrix structure changed from loose to compact with increasing EC concentration.
(Tiwari et al., 2003a) used tramadol as a model drug to design sustained release tablets using
hot-melt extrusion and wet-granulation techniques. The study involved the use of hydrophilic
hydrophobic polymers as matrix forming agents. Dissolution studies, >20 Hours, revealed
that cellulose polymer might have assisted the controlled release rate due to its hydrophobic
nature. The release mechanism showed zero-order kinetics as a result of a stable diffusional-
path-length.
(Selim et al., 2003) investigated the effect of various release controlling polymers like
Kollidon, Carnauba and HPMC on the release kinetics of three model drugs. A comparative
evaluation was made for different release profiles. HPMC was thought to make a gelatin
layer when came in contact with water drug its sink condition thereby controlling the release
rate for 12 hours.
(Carla et al., 2002) incorporated didanosine, a nucleoside analog used in treatment of
acquired immunodeficiency syndrome (AIDS) into directly compressed monolithic matrices.
Technological characterization such as drug particle morphology, mean weight, diameter,
thickness and hardness of tablets was carried out and in-vitro drug release behavior was
measured using the USP basket apparatus. The effect of varying the Eudragit-Ethocel® ratio
as well as the drug to polymeric matrix ratio was evaluated. The results showed that Eudragit-
Ethocel® combination of the moderate swelling properties of eudragit with the plastic
properties of the more hydrophobic Ethocel allowed suitable modulation of the didanosine
release.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 53
(Angeles et al., 2002) salbutamol and ketoprofen as model drugs to investigate the release
mechanism of directly compressed matrix tablets formulated with
hydroxypropylmethylcellulose hydrophilic polymer. Diffusion test was carried which
confirmed the chiral interaction between drug and polymer.
(Amaral et al., 2001) conducted a study to evaluate 160 mg naproxen matrix tablets with a
two fold increase in the tablet weight and then compared their release profiles. Different
confirmatory studies were conducted to check the drug interaction with the hydrophilic
HPMC polymer. The release data obtained from the dissolution from a perfect sink condition
revealed that the release profiles were same.
(Sajeev and Saha, 2001) used ethylcellulose ether derivative polymer to formulate controlled
release tablets using matrix embedding technique. All of the test tablets fall within the
acceptable limits. In-vitro dissolution studies showed the extended release of the drug
following zero-order kinetics. It has also been observed that the reduction in the embedded
granule size controlled the drug release more efficiently. Stability study showed the all the
test tablets were reproducible.
(Perumal, 2001) prepared modified release microspheres of ibuprofen. The effect of various
types of polymers has been investigated upon the release studies. All micromeritics
characteristics fall in the acceptable range.
(Qiu et al., 1998) prepared new layered matrix systems of pesudoephedrine hydrochloride for
zero-order sustained release. The in-vitro release was evaluated.
(Chidambaram et al., 1998) prepared layered diffusional matrices of pseudoephedrine
hydrochloride for zero-order sustained release. The effect of certain matrix formulations
variables on the in-vitro release was statistically analyzed.
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 54
(Hoffman, 1998) investigated the paharmacodynamic aspects of sustained release
preparations.
Hydrophilic Matrix System
(Wenchang et al., 2009) investigated the behavior of hydrophilic matrix tablets using a
hydrophilic polymer to deliver water-soluble drug. Wet granulation technique was used to
prepare guar-based hydrophilic matrix tablets containing water-soluble total alkaloids of
sophora alopecuroides.
(Farhad et al., 2009) used an innovative NMR micro imaging technique to investigate the
effect of various additives of modified release tablets in-vitro. Tablet dissolution and erosion
fronts were evaluated during the experiment. The solubility of additives and the mass transfer
were investigated from the gel layers formed during the dissolution.
(Lütfi and Esmaeil, 2008) used direct compression method to prepared ketorolac
tromethamine controlled release tablets using hydroxypropylmethylcellulose,
hydroxyethylcellulose, and carboxymethylcellulose polymers. It has been found that the as
the polymer concentration was increased, a slow release rate of ketorolac was obtained.
(Royce et al., 2004) formulated controlled release 6-N Cyclohexyul-2’-O-methyladenosine
tablets and investigated the release profiles in-vitro. Various formulations principals were
used in the current study.
(Scheen, 2003) reported that Gliclazide modified release is recommended once-a-day it has
been observed that gliclazide biodisperibility was increased, which release the drug for
prolonged period of time.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 55
(Schernthaner, 2003) reported that Gliclazide controlled release tablets offered a great
potential for controlled release system. The drug was thought to be bio-available for a longer
period of time. The release profiles followed the Fick’s Law.
(Giunchedi et al., 2000) prepared the hydrophilic matrix tablets of ketoperofen using direct
compression technique. HPMC, calcium gluconate and sodium alginate were used as a matrix
forming agents. Different confirmatory studies and release evaluation showed that only
HPMC controlled the drug release from the matrix system.
(Eddington et al., 1998) developed hydrophilic matrix extended release metoprolol tablet.
The dissolution data was analyzed.
Matrix Forming Agents
(Farhan et al., 2010) investigated the role of twelve selected amino-acids as matrix forming
agents. After the incorporation of amino-acids different parameters were evaluated including
mechanical properties, disintegration and dissolution and suitability for free drying were
studied.
(Anna et al., 2009a) investigated the role of hydroxypropylmethylcellulose as matrix
forming agent. It has been found that the polymer swelling and erosion played a significant
role in the drug release.
(Tiwari and Rajabi, 2008) presented the hydrophilic monolithic tablets and evaluated
various parameters to investigate the drug release studies of the selected test tablets. It was
observed that a satisfactory release rate could be obtained by using controlled in process
parameters.
(Parojcic et al., 2004) developed 50 and 100 mg DCL-Na matrix tablets using direct
compression technique, using galactomanan, xanthane and exopolysaccharide as matrix
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 56
forming agents. Dissolution studies were performed which and zero order drug release was
observed with the erosion mechanism.
(Hasan et al., 2003) designed Metaclopromide-HCl tablets using Sod. alginate and Chtosan
as matrix forming agents. It was apparent from dissolution studies that the drug release
followed the first order mechanism using Higuchi model.
(Miyazaki et al., 2004) prepared theophylline tablets with 5 diethyl amino ethyl dextran and
carboxymethyldextran mixture, carboxymethyldextran, and a mixture of ethyldextran and
dextran sulfate. The matrix tablets were prepared by direct compression technique and were
physicochemical parameters were evaluated. Dissolution studies proved that swelling and
erosion were the main mechanisms to control the drug release rate from hydrophilic tablets.
(Qiu et al., 2003) reported that in the design of dosage forms with modified drug release,
matrix tablets with a dispersed active ingredient are the simplest concept. The release form
these systems, after initial liberation of portion of the active ingredient form the surface, takes
place by diffusion and erosion, mechanisms in the independence on the solubility of the
contained active ingredient, if they contain a swelling polymer as auxiliary substances.
(Grazia et al., 2002) used freeze drying technique to prepare Dexamethasone matrix tablets
using PVA hydrogel. It was observed that the amount of drug released was decreased by
increasing hydrogels concentration.
Cellulose Derivative Polymer in Modified Release Formulations
(Harikrishna et al., 2010) studied Theophyllin buccal tablets prepared by direct compression
technique. For this purpose muco-adhesive polymers were used to as matrix forming agents.
Different parameters including water-uptake, tensile strength, in-vitro and ex-vivo studies
were evaluated.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 57
(Anna et al., 2009b) studied the efficiency of HPMC to design prolonged release hydrophilic
matrix tablets. It was observed that the drug was substituted with HPMC polymer chain
resulting in the sustained release pattern. A good correlation was found between drug release
and substituent pattern.
(Gohel et al., 2008) studied indomethacin matrix tablet using polyethlene glycol by mold
technique using cellulose derivative polymer. It has been investigated that HPMC could
prolong the drug release. Drug release mechanism from tablets followed Fickian diffusion,
coupled with erosion.
(Gohel et al., 2008) prepared venlafaxine hydrocholoride modified-release press-coated
tablets of using two different grades of HPMC K4m and K100m as release modifier.
Dimension analysis, crushing strength, friability and in-vitro drug release were determined.
The release kinetic study followed anomalous release behavior.
(Ribeiro et al., 2005) formulated vinpocetine (VP) - Cyclodextrin tartaric acid tablets and
different in-process parameters were evaluated. Polymer concentration played a dominant
role in controlling the release rate over a period of 12 hours.
(Varshosaz et al., 2006) prepared tramadol-HCl-100 mg tablets using a direct compression
technique using natural gums. Formulation contained different ratios of natural gum.
Dissolution behavior was evaluated indicating the release pattern depends upon the
concentration of natural gums and followed anomalous release (diffusion coupled with
polymer erosion).
(Crowley et al., 2004) studied the release controlling behavior of ether derivative polymer
from directly compressed matrix tablets using hot melt extrusion techniques. Various
physicochemical parameters were evaluated and release study was conducted.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 58
(Katikaneni et al., 1995) investigated release behavior of water-soluble drug from
ethylcellulose polymer matrix tablets prepared by direct compression technique. In this study
various viscosity grades were used to evaluate the release mechanism.
Polymer Type
(Chambin et al., 2004) investigated the effects of the cellulose derivatives currently used as
carrier matrices (Microcrystalline Cellulose (MCC), hydroxpropylmethylcellulose (HPMC)
and ethylcellulose (EC) on drug release mechanism. In-vitro dissolution studies were
performed. Different release behavior of these three matrices (Immediate release for MCC,
steady release for HPMC and sustained release for EC) were observed.
(Vueba et al., 2004) prepared the hydrophilic matrix tablets ketoprofen using substituted
cellulose, methylcellulose, hydroxpropylcellulose and hyroxypropylmethylcellulose. After
preformulation studies tablets were compressed and subjected to physical evaluation.
Methycellulose-25 and hydroxypropyl methylcellulose were found not be suitable candidates
for sustained release tablets. Hydroxypropylmethylcellulose was found to be the best
candidate in controlling the drug release rate thereby following zero order kinetics.
(Emami et al., 2004) formulated Lithium Carbonate 450mg SR tablets with Carbopol
polymer using direct-compression and wet-granulation techniques. In-vitro in-vivo studies
were conducted and a best correlation was found.
(Reddy et al., 2003) used Eudragit 100-RS, ethylcellulose and polyvinyl pyrrolidone as
polymeric materials to formulated Nicorndil matrix tablets. Preformulation studies were
conducted to evaluate the physical properties of the starting materials and dissolution
behavior was evaluated using perfect sink condition. It was found that diffusion controlled
mechanism followed the zero-order release.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 59
(Reza et al., 2003) developed theophylline, diltiazin HCl and DCL-Na tablets. Drug release
rate was decreased by the higher polymeric content (75%) in the matrix because of increased
tortuosity and descreased porposity. The rate and extent of drug release was increased at
lower polymeric level (25%) physico-chemical nature of drug molecule also influenced the
release rate. From all the matrix system, theophylline and ditiazem HCL released faster,
beings soluble in nature than diclofenac sodium. Biexponential equation was used to study
the release mechanism. HMPC matrix systems followed Zero-order kinetics whereas
kollidion SR matrix system followed Fickian (Case I) Transport Mechanism.
Polymer Ratio
(Basak et al., 2006) Developed sustained release monolithic matrix tablets of ambroxol
hydrochoride (75mg) using hydroxpropylmethycellulose polymer by direct compression.
Physicochemical tests were performed and the dissolution behavior showed diffusion
dominant character. Some formulation also showed anomalous release mechanism as well.
(Savaser et al., 2005) prepared DCL-Na matrix tablets by wet-granulation and direct
compression techniques. Different polymeric approaches were used to investigate the drug
release mechanism. Reference market brand of DCL-Na was also tested and correlation was
developed. Market brand showed sustained while test formulation showed controlled release
behavior in-vitro.
Polymer Concentration
(Nerurkar et al., 2005) prepared ibuprofen controlled release matrix tablet from polymer
blends containing carrageenans or cellulose ethers by direct compression. Ethylecllulose
polymer and carrageenans were used as matrix forming agents. Polymer particle size and
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 60
concentration were found to be the main release determining factors. Test formulations
showed zero order release with linearity ranging from 0.960 to 0.990.
(Koester et al., 2003) designed and evaluated Beta Cyclodextrin and Carbamazepine tablets
using 15-30% hydrophilic cellulose derivative HPMC polymer. Gelling and matrix formation
was impaired in formulation containing 15% hydroxypropylmethycellulose.
(Juarez et al., 2001) formulated the matrix tablet of 4-Aminopuridine. Hydrophilic polymers
such as HPMC and CMC were used in different proportions. It has been evaluated that
decreasing release constant values showed a logarithmic relationship with increasing with
increasing values of the exponent indicated zero-order release.
(Khan and Jiabi, 1998a) investigated the release behavior of ibuprofen (IBU) from freshly
prepared tablets. Carbopol polymer was used to control the drug release rate. Effect of
process variables and different exciepients were evaluated in the study. Linearity was
observed in the release mechanism there by indication a concentration independent controlled
release behavior of IBU.
Polymer Grades
Several studies have demonstrated that increasing the viscosity grade of HPMC decreases the
drug release rate. For example (Rao et al., 2009) prepared an effervescent floating tablet
formulation of salbutamol sulfate by wet granulation using two viscosity grades of HPMC,
HPMC K4M and HPMC K100M CR, as matrix material, containing stearic acid, talc,
dicalcium phsphate, polyvinyl pyrrolidone, and magensium stearate. Formulation was
optimized. The in-vitro drug release mechanism showed anomalous transport. Release rate
decreased as the concentration and viscosity grade of the polymer increased. The drug release
was no significantly affected by the viscosity, at a higher concentration of HPMC.
Controlled Release Tablets of Selected NSAIDs Chapter 2…. Review of Literature
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 61
(Chandira et al., 2009) formulated a single tablet in which combination of Atorvastatin
(antihyperlipidemic) and Gliclazide (antidiabetic) were used by wet granulation method using
two grades of HPMC i.e., HPMC 4000cps and HPMC 100cps as retardant material. Granules
property and tablets characteristics were evaluated in-vitro dissolution studies were
performed up to 08 hours. Release rate was nearly similar to marketed products.
(Zema et al., 2007) used three different hyroxpropylmethylcellulose grades to formulate a
pulsatile-delivery system. A diffusion layer was formed when hydrophilic HPMC came in
contact with the dissolution medium. Drug diffusion along with water-uptake and swelling
impaired controlled drug release. It was also observed that increase in the viscosity grade of
the HPMC polymer decreased the drug release rate.
(Khan and Meidan, 2007) studied the preparation of ibuprofen CR tablets, using various
viscosity grades of ethylcellulose ether derivative polymer Ethocel®. Different studies were
conducted on starting materials to investigate the role of various parameters on drug release
kinetics. Along with Ethocel® polymer co-excipients, such as HPMC was also added to
evaluate the release mechanism of ibuprofen drug. It was found that polymer particle size,
concentration and viscosity grades were the main release controlling factors.
(Siepmann et al., 2002) prepared chlorpheniramine maleate, propranolol HCL,
acetaminophen, Theophylline and diclofenac sodium tablets using hydrophilic HPMC
polymer. Physicochemical phenomena which were involved in the swelling and drug release
from hydrophilic matrix tablets using the “Sequential Layer” model were studied. The in-
vitro release was evaluated.
(William et al., 2001) developed a reverse-phase HPLC method for recovery of the lipophilic
Drug, alprazolam, from matrix tablets containing the hydrophilic polymer
hydroxpropylmethycellulose. With this validated method, the dissolution results of
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 62
alprazolam were not influenced by different molecular weight distribution of the HMPC
polymer, such as huydroxypropylmethylcellulose K4M and K100LV.
Polymer Particle Size
The particle size and size distribution of the HPMC affect the hydration rate of HPMC and
thus the rate of Gel formation and drug release form tablet matrices. For Example (Miranda
et al., 2007b) developed the hydrophilic matrix tablets of Labenzarit disodium using
hydroxypropylmethylcellulose ether derivative polymer. It has been found that polymer
viscosity grade and particle size might influence the release rate.
Drug Release Mechanism
(Escudero et al., 2008) investigated the role of hydroxypropylcellulose-methyl-methacrylate
(HCMMA) as a release controlling polymer and prepared directly compressed matrix tablets.
Various technological variables were studies and it has been found that the swelling, the
porosity, tortuosity and water uptake capacity from inert matrices were the min release
controlling mechanisms.
(Fu et al., 2004) derived working-equation and predicted a drug release from polymer matrix.
Different concentrations of hydroxypropylmethylcellulose (16.5 to 5.5%) were used to
formulate matrices embedded with drug.
(Siepmann et al., 2002) investigated the spectrum of mathematical models including
“Higuchi model”, “simple empirical model” and “complex mechanistic theories”. The model
tells about the dissolution process, diffusion and swelling behavior of the polymer.
(Khan and Jiabi, 1998b) prepared ibuprofen tablets by direct compression technique, using
carbopol® 934P and resin 971P as matrix forming agents. Effect of polymer matrix and
various co-exciepients was evaluated in-vitro.
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(Khan and Zhu, 1998) formulated the ibuprofen (IBF) tablets using surelease as a granulating
agent by the wet granulation method. Release mechanism was investigated. The effect of the
certain parameter such as the levels of the surelease solid content (SSC), pH of dissolution
media, selected dissolution method and agitation speed on the release profiles of IBF was
studied.
(Velasco et al., 1999) evaluated the role of different excipients and various process variables
upon the release of diclofenac sodium model drug. Hydroxypropylmethylcellulose K15M
was used as matrix forming material. It was found that the drug release rate was enhanced
with increase of polymer concentration.
(Bashar and Bassam, 2003) designed diclofenac sodium matrix tablets, using HPMC and
eudragit polymers. Dissolution behavior of DCL-Na buffer tablets was studied in buffer
solutions (pH 5.9 and 7.4). The rate was found to be linear as a function of time. It has been
observed that the matrix swelling increased with increase of the pH of dissolution medium.
Controlled Release Tablets of Selected NSAIDs Chapter 3….Materials and Methods
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 64
3. MATREIALS & METHODS
3.1. Materials
Flurbiprofen (FLB) was received as a gift from Abbott Laboratory, Pakistan and Diclofenac
Sodium (DCL-Na) from Danas Pharmaceuticals, Pakistan. Froben SR® Flurbiprofen 200 mg
capsules by Abbott Laboratory, Pakistan, Voltral® Diclofenac Sodium 100 mg tablets by
Novartis Pharma (Pakistan) limited (purchased from the local market). Monobasic Potassium
Phosphate (KH2PO4) (Merck, Germany), Disodium Hydrogen Phosphate (Na2HPO4) (Merck,
Germany) , Sodium Hydroxide (NaOH) (Merck, Germany), Magnesium Stearate (Solomon
Enterprise, Karachi) Lactose (BDH Chemical limited, Pool, England), Ethylcellulose (EC)
Ethocel® Grade 7, 10 and 100, FP and Simple Course Polymers,
Hydroxypropylmethylcellulose (HPMC K100M) (Dow Chemical Company, Midland, USA),
Carboxymethylcellulose (CMC) (Merck, Germany) and Starch (Merck, Germany).
Acetonirile, Phosphoric Acid, HPLC Grade Water (Fisher, England) and Sample tubes
Eppendrof (Eppendrof Netheler Hinz GmbH, Hamburg, Germany) were purchased from the
local market. All other chemicals used during the experiment were of analytical grade.
Albino rabbits were obtained from animal house, Faculty of Pharmacy, Gomal University,
D.I.Khan, KPK, Pakistan.
3.2. Equipments
UV-Visible Spectrophotometer (Shimadzu 1601, Japan), Dissolution Apparatus (Pahrma
Test, PTWS-11/P, Hunburg, Germany), HPLC system (Agilent 1200, Agilent Corporation,
Germany). Electronic Balance (AX-200, Japan), pH meter (Inolab, Germany), Magnetic
Stirrer (VelpScientica, Germany), Oven (Mammert, Germany), Vernier Caliper (Germany),
Whatman Filter Papers (Whatman, Germany), Friabilator (Erweka, Germany), Hardness
Tester (Erweka, Germany), Conical Flasks, Beakers, Test Tubes (Pyrex, Japan), Vortex
Controlled Release Tablets of Selected NSAIDs Chapter 3….Materials and Methods
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 65
Mixer (Gyromixer, Pakland scientific, Pakistan), Centrifuge (Helttich, Germany), Water
distillation apparatus (IRMECO, GmbH, IM-100, Germany), Shaking water bath (Shel Lab,
1217-2E, USA) Particle size distribution analyzer (Horiba, LA-300, Japan), DSC (Mettler
Teledo DSC 822e, Switzerland), FTIR Spectrophotometer (Perkin Elmer, UK), Scanning
Electron Microscope (SEM), X-Ray Difractometer (XRD).
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 66
3.3. Methods
3.3.1. Particle Size Analysis
Sieve analysis was performed for the bulk powder of FLB and DCL-Na. From each 100 g of
each drug powder samples the particles were separated in particle-size-fractions using
mechanical shaker with standard sieves placed one oveR the other in descending order of
pore diameters. Six sieved fractions viz. 0-40, 40-60, 60-80, 80-100 and 100-120 µm of the
powder particles were obtained.
3.3.2. Particle size distribution
Particle size distribution (Horiba Laser Scattering Particle Size Distribution Analyzer LA,
300, USA) was used to measure the broader range of particle size distribution of FLB, DCL-
Na and different viscosity grades (7, 10 & 100 FP and Simple Satndard) of Ethocel® polymer.
The features of the experiment were found to be rapid measurement capability, good,
repeatable accuracy and ease of use. Particle size distribution was measured, by laser
scattering measuring principle, from the scattered light intensity distribution (scattering
pattern) which was created after laser irradiation of the particles.
3.3.3. UV Spectrophotometric analysis
3.3.3.1. Selection of suitable wavelength
In order to determine the λmax for FLB and DCL-Na, Stock solutions of FLB and DCL-Na
were prepared in 0.1 N HCL, pH 7.4 phospahte buffer solutions and 0.1 N HaOH, by
dissolving 20 mg of the respective drugs in one litre of each solvent, separately. After a
suitable dilution of (10 µg/ml), the solutions were scanned between 200-400 nm, using UV-
visible spectrophotometer (UV-1601, Shimadzu, Japan).
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3.3.3.2. Standard Curve of FLB and DCL-Na
Different concentrations of 2, 4, 8, 12, 16 and 20 µg/ml of FLB and DCL-Na were prepared
in pH 7.4 phosphate buffer, from their respective stock solutions and were analyzed
spectrophotometrically at 247 and 276 nm, respectively. The absorbance values versus drugs
conventions of the respective solutions were used to construct the standard curves.
3.3.4. Pre-formulation studies
3.3.4.1. Equilibrium solubility
Solubility studies of FLB and DCL-Na were performed using equilibrium solubility method
in seven different solvents, pH ranging from 1.5 to 10 at 37° C±0.5° C, as reported by
Higuchi and Connors (Higuchi and Connors, 1965). Excess amount of drugs were taken in
100 ml stoppered conical flasks and were shaken mechanically for 24 hours in the
thermostatically controlled shaking water bath. After another two days, aliquots were
withdrawn, filtered using 0.22 μm filters and diluted with their respective solvents. The
samples were analyzed spectrophotometrically at 247 and 276 nm, both for flurbiprofen and
diclofenac sodium, respectively, using UV-visible spectrophotometer (UV-1601, Shimadzu,
Japan).
3.3.4.2. Preparation of solid dispersions
Solid dispersions of each FLB and DCL-Na drug were prepared with Ethocel® polymer by
the solvent evaporation technique as reported by (Najib et al., 1986, Shivakumar et al., 2008).
The required amount of drug was dissolved in chloroform followed by the addition of
ethylcellulose Ethocel® FP 7 standard premium polymer (drug: polymer 10:3) and stirred on
a magnetic stirrer (100rpm) at room temperature for about 4 hours. The solvent was then
evaporated over a warm water bath. Later, a rotary evaporator (100 rpm) was used, till
complete evaporation of the organic solvent. The solid residue was collected and dried at
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40°C in a vacuum oven for 24 hours. The samples were passed through 100# mesh to get
incorrigible uniform solid dispersions and were stored in air tight amber colored glass
containers till further use.
3.3.4.3. Bulk density
Bulk density was determined, according to the method reported by (Reddy et al., 2003). A
quantity of 2 g FLB and DCL-Na powders, physical mixtures and solid dispersions,
previously lightly shaken to break any agglomerate formed, were taken in 10 ml measuring
cylinder. After the initial volume was observed, the cylinder was allowed to fall under its
own weight onto a hard surface from the height of 2.5 cm at 2 seconds intervals. The tapping
was continued until no further change in volume was observed. Bulk density was calculated
using the equation 1.
Bulks
sV
WBDDensity )( (1)
Where “ sW ” is sample weight and “ sV ” is the sample volume.
3.3.4.4. Tapped density
Tape density is the indirect measurement of flow, mixing and tableting properties of powder
and is used to investigate the packing properties of the powder molecules. It was calculated
for FLB, DCL-Na, physical mixture and solid dispersions by a conventional method using 10
ml measuring cylinder with 100 tappings. After the initial powder volume was noted in the
cylinder, the cylinder was allowed to fall freely under its own weight onto a hard surface
from the height of 2.5 cm at 2 seconds time intervals. The tapping was continued until plateau
condition was perceived with no further change in the volume (Lachman et al., 1987).
Tapped density was calculated by the equation 2.
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TappedW
WTDDensity i)( (2)
Where “ 1W ” is the initial weight the mixture and “ W ” is final weight of the mixture after
tapping.
3.3.4.5. Hausner’s ratio
It is called as index of flowability and is the indirect measurement of inter-particle friction. It
is calculated by the formula (Abdelkader et al., 2008b).
sHausner ' BDTDRatio (3)
Hausner’s Ratio less than 1.2 is preferable for free flow of powder material, while the value
close to 1 indicates good flow properties (Shariff et al., 2007).
3.3.4.6. Angle of repose
Angle of repose was determined by funnel and cone method. A petri dish was taken and its
diameter was determined. A funnel was fixed above the petri dish and accurately weighed
amount of FLB and DCL-Na, physical mixtures and solid dispersions (4 g) were poured from
funnel with its tip at 2 cm height H, until the apex of the heap formed reached the lower end
of the funnel as shown in the figure 3.1. The mean diameter , 2R, of the powder cone base
was measured and the angle of repose was calculated by the following equation (Lee and
Herman, 1993).
R
HTan
(4)
Where “ H ” is the height of the cone and “ R ” is the radius of the cone base.
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Figure 3.1. Schematic presentation of angle of repose
3.3.4.7. Compressibility index
Compressibility index of FLB and DCL-Na, physical mixtures and solid dispersions was
determined by carr’s compressibility percentage using the following equation 5 (Lachman et
al., 1987).
100%
f
f
D
DDilityCompressib
(5)
Where “ fD ” is the tape bulk density “ D ” is the fluff bulk density.
3.3.5. Differential Scanning Calorimetery (DSC)
The physicochemical compatibility of the drug and the used polymer and excipients were
tested by differential scanning calorimetric (DSC) analysis, using DSC instrument with a
thermal analysis data station system, computer and a plotter interface. The instrument was
calibrated with an indium standard. The sample (5-10 mg) was weighed in aluminium pan
and sealed with a lid using a punch. The sample were heated (50-300° C) at a constant
scanning speed of 10° C/min in sealed aluminium pan using nitrogen as purging gas.
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3.3.6. Infra-Red Absorption Spectroscopy
A computerized FTIR (Perkin Elmer, England) was used to study the possible interaction of
drugs with polymer and other excipients. Sample of approximately 10 mg was placed on the
plate, enough pressure was applied and sharp peaks were obtained at suitable intensity. FTIR
spectroscopy of FLB, DCL-Na, EC, their physical mixtures and solid dispersions was carried
out in the range of 500-4000 1cm to investigate possible interaction of drug with EC
polymer and other excipients such as HPMC, CMC and starch (Ranjha et al., 2010).
3.3.7. Scanning electron microscopy
SEM (SEM; Joel JSM-5910, Japan) images of FLB, DCL-Na, FLB-EC, physical mixtures
and solid dispersions were taken to scrutinize the surface morphology of the drug, physical
mixtures and solid dispersions. A suitable amount of sample was mounted on a metal stub
using double sided adhesive tape and was coated with cold for conductivity. The micrographs
were obtained at different magnifications 1000 and 2500.
3.3.8. X-ray diffractometery
FLB, DCL-Na, FLB-EC and DCL-Na-EC physical mixtures and solid dispersions were
analyzed, using X-ray diffractometer, Phillips PW1830 powder diffractormeter (Phillips,
Eindhoven, Netherland), using nickel-filtered CuKα, 30 kV and 20 mA voltage and current
respectively. The spectra were taken in the range of 0-20°. The time for each run was 2
seconds and the step size was kept at 0.05°.
3.3.9. Preparation of matrix tablets
3.3.9.1. Preparation of 100 mg each of FLB and DCL-Na tables
Each of FLB and DCL-Na 100 mg powder was mixed with Ethocel® (ethylcellulose) polymer
and other exciepients including, lactose, HPMC, CMC and Starch except magnesium stearate
(0.5%). The physical mixtures were thoroughly mixed in poly bags for about 20 minutes. The
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physical mixtures were passed through number 30-mesh size, and then the required amount
of magnesium striate was added as lubricant. The mixtures were further mixed and passed
through the same mesh size. The physical mixtures of each formulation were compressed
using a single punch tablet machine (Erweka, AR 400 GMBH, Germany), using biconcave 2
mm punches and applying 450 kg force for about 2 sec. Composition details are shown in
tables 3.1-3.9.
Table 3.1: Composition of each of FLB and DCL-Na 100 mg tablets without polymer
Batch D:P Drug Ethocel®
Lactose Co-
excipient
Mg. St. FP Simple
F-0 10:3 100 --- --- 99 --- 1
Table 3.2: Composition of each FLB and DCL-Na 100 mg matrix tablets containing Ethocel®
FP standard premium polymer
Batch D:P Drug Ethocel®
Lactose Co-
excpients Mg.St.
FP Simple
Ethocel® 7 Standard Premium
F-1 10:1 100 10 --- 89 --- 1
F-2 10:2 100 20 --- 79 --- 1
F-3 10:3 100 30 --- 69 --- 1
Ethocel® 10 Standard Premium
F-4 10:1 100 10 --- 89 --- 1
F-5 10:2 100 20 --- 79 --- 1
F-6 10:3 100 30 --- 69 --- 1
Ethocel® 100 Standard Premium
F-7 10:1 100 10 --- 89 --- 1
F-8 10:2 100 20 --- 79 --- 1
F-9 10:3 100 30 --- 69 --- 1
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Table 3.3: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel® simple
standard premium polymer
Batch D:P Drug Ethocel®
Lactose Co-
excipients Mg.St.
FP Simple
Ethocel® 7 Standard Premium
F-10 10:1 100 --- 10 89 --- 1
F-11 10:2 100 --- 20 79 --- 1
F-12 10:3 100 --- 30 69 --- 1
Ethocel® 10 Standard Premium
F-13 10:1 100 --- 10 89 --- 1
F-14 10:2 100 --- 20 79 --- 1
F-15 10:3 100 --- 30 69 --- 1
Ethocel® 100 Standard Premium
F-16 10:1 100 --- 10 89 --- 1
F-17 10:2 100 --- 20 79 --- 1
F-18 10:3 100 --- 30 69 --- 1
Table 3.4: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel® FP
standard premium polymer and HPMC
Batch D:P Drug Ethocel®
Lactose Co-
excipient HPMC
Mg. St. FP Simple
Ethocel® 7 Standard Premium
F-19 10:1 100 10 --- 62.3 26.7 1
F-20 10:2 100 20 --- 52.3 23.7 1
F-21 10:3 100 30 --- 48.3 20.7 1
Ethocel® 10 Standard Premium
F-22 10:1 100 10 --- 89 26.7 1
F-23 10:2 100 20 --- 79 23.7 1
F-24 10:3 100 30 --- 69 20.7 1
Ethocel® 100 Standard Premium
F-25 10:1 100 10 --- 89 26.7 1
F-26 10:2 100 20 --- 79 23.7 1
F-27 10:3 100 30 --- 69 20.7 1
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Table 3.5: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel® simple
standard premium polymer and HPMC
Batch D:P Drug Ethocel®
Lactose Co-
excipient HPMC
Mg. St. FP Simple
Ethocel® 7 Standard Premium
F-28 10:1 100 --- 10 62.3 26.7 1
F-29 10:2 100 --- 20 52.3 23.7 1
F-30 10:3 100 --- 30 48.3 20.7 1
Ethocel® 10 Standard Premium
F-31 10:1 100 --- 10 89 26.7 1
F-32 10:2 100 --- 20 79 23.7 1
F-33 10:3 100 --- 30 69 20.7 1
Ethocel® 100 Standard Premium
F-34 10:1 100 --- 10 89 26.7 1
F-35 10:2 100 --- 20 79 23.7 1
F-36 10:3 100 --- 30 69 20.7 1
Table 3.6: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel® FP
standard premium polymer and CMC
Batch D:P Drug Ethocel®
Lactose Co-
excipient CMC
Mg. St. FP Simple
Ethocel® 7 Standard Premium
F-37 10:1 100 10 --- 62.3 26.7 1
F-38 10:2 100 20 --- 52.3 23.7 1
F-39 10:3 100 30 --- 48.3 20.7 1
Ethocel 10 Standard Premium
F-40 10:1 100 10 --- 89 26.7 1
F-41 10:2 100 20 --- 79 23.7 1
F-42 10:3 100 30 --- 69 20.7 1
Ethocel® 100 Standard Premium
F-43 10:1 100 10 --- 89 26.7 1
F-44 10:2 100 20 --- 79 23.7 1
F-45 10:3 100 30 --- 69 20.7 1
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Table 3.7: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel® simple
standard premium polymer and CMC
Batch D:P Drug Ethocel®
Lactose Co-
excipient CMC
Mg. St. FP Simple
Ethocel® 7 Standard Premium
F-46 10:1 100 --- 10 62.3 26.7 1
F-47 10:2 100 --- 20 52.3 23.7 1
F-48 10:3 100 --- 30 48.3 20.7 1
Ethocel® 10 Standard Premium
F-49 10:1 100 --- 10 89 26.7 1
F-50 10:2 100 --- 20 79 23.7 1
F-51 10:3 100 --- 30 69 20.7 1
Ethocel® 100 Standard Premium
F-52 10:1 100 --- 10 89 26.7 1
F-53 10:2 100 --- 20 79 23.7 1
F-54 10:3 100 --- 30 69 20.7 1
Table 3.8: Composition of each of FLB/DCL-Na 100 mg matrix tablets containing Ethocel®
FP standard premium polymer and Starch
Batch D:P Drug Ethocel®
Lactose Co-
excipient Starch
Mg. St. FP Simple
Ethocel® 7 Standard Premium
F-55 10:1 100 10 --- 62.3 26.7 1
F-56 10:2 100 20 --- 52.3 23.7 1
F-57 10:3 100 30 --- 48.3 20.7 1
Ethocel® 10 Standard Premium
F-58 10:1 100 10 --- 89 26.7 1
F-59 10:2 100 20 --- 79 23.7 1
F-60 10:3 100 30 --- 69 20.7 1
Ethocel® 100 Standard Premium
F-61 10:1 100 10 --- 89 26.7 1
F-62 10:2 100 20 --- 79 23.7 1
F-63 10:3 100 30 --- 69 20.7 1
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Table 3.9: Composition of each of FLB and DCL-Na 100 mg matrix tablets containing
Ethocel® simple standard premium polymer and Starch
Batch D:P Drug Ethocel®
Lactose Co-
excipient Starch
Mg. St. FP Simple
Ethocel® 7 Standard Premium
F-64 10:1 100 --- 10 62.3 26.7 1
F-65 10:2 100 --- 20 52.3 23.7 1
F-66 10:3 100 --- 30 48.3 20.7 1
Ethocel® 10 Standard Premium
F-67 10:1 100 --- 10 89 26.7 1
F-68 10:2 100 --- 20 79 23.7 1
F-69 10:3 100 --- 30 69 20.7 1
Ethocel® 100 Standard Premium
F-70 10:1 100 --- 10 89 26.7 1
F-71 10:2 100 --- 20 79 23.7 1
F-72 10:3 100 --- 30 69 20.7 1
3.3.9.2. Preparation of 100 mg FLB and DCL-Na solid dispersions tablets
An amount equivalent to each of 100 mg FLB and DCL-Na solid dispersions were taken as
separately and mixed with the excipients thoroughly. After a sufficient mixing the mixtures
were compressed by the method discussed in the section 3.4.9.1. Composition details are
given in the table 3.10.
Table 3.10: Composition of each of FLB and DCL-Na 100 mg solid dispersions tablets
containing Ethocel® FP standard premium polymer
Batch D:P Drug Ethocel® Lactose Mg. St. Co-
excipient FP Simple
F-73 10:3 100 30 --- 69 1 ---
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3.3.9.3. Preparation of 200 mg FLB tablets
FLB 200 mg matrix tablets were prepared according to the method discussed in section
3.4.9.1, using the composition given in table 3.11.
Table 3.11: Composition of FLB 200 mg matrix tablets containing Ethocel® FP standard
premium polymer
Batch D:P Drug Ethocel® Lactose Mg. St. Co-
excipient FP Simple
F-74 10:3 200 60 --- 38.5 1.5 ---
3.3.10. Physical characteristics of matrix tablets
3.3.10.1. Thickness and diameter
A compressed tablet’s shaped and dimensions are determined by tooling during compression
process. The thickness of the tablet is the only dimensional variable related to the process. At
a constant, compressive load, tablet thickness varies with variation in compressive load. The
thickness of 40 tablets from each batch were determined by using vernier caliper (E-base
measuring tools co., Taiwan), reported in millimeters with their mean and standard deviation
(SD±).
The Pharmacopoeia does not insist on a standard weight for official tablets, it nevertheless
specifies their diameter. The thickness is directly controlled, but in practice most
manufacturers make uncoated tablets of thickness equal to half the diameter since this result
is an elegant and pleasing shape. If the diameter and thickness both are defined, the volume
and weight of tablet are obviously fixed, and there is no or very little variation in dimension
of official tablets produced by different manufacturers (USP, 2005).
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Similarly, the diameter of the 40 tablets from each formulation were determined using vernier
caliper (E-base measuring tools co., Taiwan), reported in millimeters with their means and
standard deviation (SD±).
The pharmacopoeia permits slight deviations, usually ±5% from the nominal diameter
(Carter, 1972).
3.3.10.2. Hardness
Hardness of the tablet is defined as the force required to break a tablet in a diametrical
compression test. Adequate tablet hardness, resistance to powder and friability are necessary
requisites for consumer acceptance. The resistance of the tablets to chip, abrasion or break
under conditions of storage, transportation and handling before usage also depends on
hardness (Rudnic and Schwartz, 1995). The hardness of 20 tablets from each batch was
determined by using hardness tester (Erweka, Germany) and was reported in Kg.
3.3.10.3. Weight variation
Tablet is designed to contain a specific amount of drug in a specific amount of tablet formula.
To check whether a tablet contain a proportionate amount of drug, weight of tablet is
routinely measured.
Weight variation tolerance is presented below in the table (Table 3.12). Statistically the
process is said to be under control when all weight of individual tablets lie between upper
control limit (UCL), which is three standard deviations above the mean and lower control
limit (LCL), which is three standard deviations below the mean (LACHMAN et al., 1986).
The weight variation test was run by weighing 20 tablets individually, from each formulation,
using electronic balance model number, AX-200 (Shimadzu, Japan) and the values were
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reported in milligrams with their means and standard deviations (SD±), using computer based
excel program.
Table 3.12: Weight variation tolerance for controlled release matrix tablets (USP, 2005)
Average Weight of Tablet (mg)
Maximum Percentage Difference Allowed
130 or less 10
130-324 7.5
More than 324 5
3.3.10.4. Friability test
Tablets that tender to powder, chip and fragment when handled, lack elegance and consumer
acceptance, and can create excessively dirty processes in such areas of manufacturing such as
coating and packaging. They can also add to a tablet’s weight variation or content uniformity
problems. Therefore, as a measure of a tablet’s strength, its friability is often measured.
A friabilator subjects a specified number of tablets to the combined effects of abrasion and
shock by utilizing a drum, with an internal diameter between 283 and 291 mm and a depth
between 36 and 40 mm, of transparent synthetic polymer with polished internal surfaces, and
not subject to static build-up. One side of the drum is removable. The tablets re tumbled at
each turn of the drum by a curved projection with an inside radius between 75.5 and 85.5 mm
that extends from middle of the drum to the outer wall. The drum is attached to the horizontal
axis of a device that rotates at 25 ± 1rpm, thus, at each turn the tablets roll or slide and fail
onto the drum wall or onto each other.
The tablets were de dusted carefully prior to testing. For each formulation 10 tablets were
weighed, placed in the rotating disc of friabilator (Erweka, Germany) and were subjected to
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100 rotations in 4 minutes. After 4 minutes tablets were collected, de-dusted, reweighed and
friability was calculated as the percentage weight loss, using following equation.
1001
21
W
WWFriability (Eq. 7)
Where “ 1W ” is the initial weight, and 2"W ” is the final weight of the tablets.
Generally, the test is run once, if obviously cracked, cleaved or broken tablets are present in
the tablet sample after tumbling, the sample fails the test. If the results are doubtful or if the
weight loss is greater than the targeted value, the test should be repeated twice and the mean
of the three tests determined. A maximum weight loss of not more than 1% of the weight of
the tablets being tested is considered acceptable for most products. In case of new
formulations, an initial weight loss of 0.8% would be permitted until sufficient packaging
data are obtained to extent the limit to a targeted value of 1% (USP, 2005).
3.3.10.5. Content uniformity test
From each formulation, 5 tablets were weighed individually, placed in a mortar and
powdered with a pestle. Then an amount equivalent to 25 mg of FLB or DCL-Na was taken,
dissolved in 100 ml of pH 7.4 phosphate buffer solutions and was sonicated for 15 minutes.
The solution was filtered through 0.22 μm pore size filter, diluted with the respective solvent
and the drug contents were measured by analyzing spectrophotometrically at 247 and 276
nm, respectively. Same process was adopted for 25 mg FLB and DCL tablet prepared from
the solid dispersions powders and were analyzed sepectrophotometrically.
3.3.11. In-vitro drug release study
Drug release studies of market brand and the prepared tablets formulations were performed
according to USP apparatus 1, using 8 station dissolution apparatus (Pharma Test Dissolution
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Apparatus PTWS-11/P, TPT, Hamburg, Germany) (Figure 3.2). Each flask was filled up to
900ml dissolution medium (0.2 M phosphate buffer solution pH 7. 4) maintained at 37 ±
0.1°C and stirred at 100 rpm (Perfect sink conditions). Tablets were placed in different
baskets and at predetermined time intervals of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24
hours, sample was taken using 0.45 μm filter and was replaced with the same fresh medium.
The samples were then diluted with the same solvent and were analyzed at 247 and 276 nm
with the help of UV-visible spectrophotometer. Calibration curves of both FLB and DCL-Na
drugs were used to calculate percent drug release from the tablets. The mean of three tablets
was used to evaluate the drug release for each of the formulation.
Figure 3.2. Pharma Test Dissolution Apparatus PTWS-11/P, TPT (Hamburg, Germany)
3.3.12. Drug release kinetics
To investigate the drug release mechanism from matrix tablets, the data obtained from drug
release studies was plotted in various kinetics models, viz. Zero order, First order, Hixson’s
Crowell equation, Higuchi’s model and Korsmeyer-Pappas equation.
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3.3.12.1. Zero-Order Kinetic Model
The zero-order kinetic describes the systems in which the drug-release rate is independent of
its concentration (Singh et al., 1967).
tkW 1 (Eq. 8)
Where, 1k is the zero-order rate constant expressed in the units of concentration/time and “ t ”
is the time in hours.
In this way, a graph of the amount of drug released versus time will be linear with slope equal
to 1k .
3.3.12.2. First-Order Kinetic Model
The first-order kinetic describes the release from the systems in which the release rate is
concentration dependant.
tkW 2100ln)100ln( (Eq. 9)
Where, 2k is the first order constant and 100ln is the initial drug concentration.
In this way, a graph of the decimal logarithm of the amount of drug remaining versus time
will be linear.
3.3.12.3. Hixson Crowell’s Equation or Erosion Model
The Hixson Crowell equation describes the drug release from systems in which there is a
change in the surface area and the diameter of the particles present in the tablet (Hixson and
Crowell, 1931).
tkW 33/13/1 100)100( (Eq. 10)
Where, 3k is the rate constant for Hixson Crowell’s equation, 3/1)100( W is the initial
concentration while 3/1100 is the amount of drug released in time “ t ”.
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A graphic of the cube root of the present drug remaining in matrix versus time will be linear.
3.3.12.4. Higuchi’s Kinetic Model
Higuchi described the release of drugs from an insoluble matrix as a square root of the time-
dependant process on the basis of Fickian diffusion (Higuchi, 1963).
2/14tkW
(Eq. 11)
Where, 4k reflects the design variable of the system and is the constant. “ t ” is the time in
hours.
3.3.12.5. Korsmeyer-Peppas equation
The mechanism of drug release from DCL-Na controlled release matrix tablets was evaluated
by plotting the first 60% drug release data of each formulation and commercial products in
Korsmeyer-Peppas equation (Eq. 12) as log cumulative percentage of drug released vs. log
time and exponent “ n ” was calculated through slope of the straight line (Korsmeyer et al.,
1983).
nt tkMM
5
(Eq. 12)
Where, M
Mt is the fractional solute release, 5k is power law constant of drug-polymer
system and “ n ” is an exponent that indicates drug release mechanism from matrix tablets.
For cylindrical shaped matrix tablets, if exponent, n = 0.45, then drug release mechanism is
called Fickian diffusion” and if 0.45 ≤ n ≤ 0.89, then it is called Non-Fickian or anomalous
diffusion (Table 3.13). Exponent value of 0.89 is an indicative of “Case-II Transport” or
typical Zero-Order release. Fickian diffusional release and a case-II relaxational release are
the limits of this phenomenon. Fickian diffusional release occurs by the usual molecular
diffusion of the drug due to a chemical potential gradient. Case-II relaxational release is the
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drug transport mechanism associated with stresses and state-transition in hydrophilic glassy
polymers which swell in water or biological fluids. This term also indicates polymer
disentanglement and matrix erosion. non-Fickian release is described by two mechanisms, the
coupling of drug diffusion and polymer relaxation (Ritger and Peppas, 1987).
Table 3.13: Release exponent and mechanism of diffusional release from various controlled
release matrix tablets (Ritger and Peppas, 1987)
Release Exponent Drug Release Mechanism
Thin Film Cylindrical Sample Spherical Sample From Matrix Tablets
0.5 0.45 0.43 Fickian Diffusion
0.5 ≤ n ≥1.0 0.45 ≤ n ≤ 0.89 0.43 ≤ n ≤ 0.85 Anomalous Release (non-
Fickian)
1.0 0.89 0.85 Case-II Transport (Zero-Order)
3.3.13. Polymer hydration or water uptake
Polymer swelling studies were conducted by equilibrium weighed gain method as reported by
(Efentakis and Vlachou, 2000, Sai Cheong Wan et al., 1995), using USP apparatus 1. The
initial weight of selected formulations, F-1-9 and F-74, of both FLB and DCL-Na matrix
tablets, was determined and the tablets were placed in baskets containing 900 ml phosphate
buffer solution (pH 7.4), maintained at 37 ± 0.5° C. At predetermined regular intervals of 0.5,
1, 1.5, 2, 3, 4, 5 and 6 hours, the pre-weighed baskets were withdrawn from the dissolution
apparatus, slightly blotted with tissue paper to remove the excess water from the baskets, and
were re-weighed. The degree of swelling matrix, at each time point, was calculated using the
following equation.
Water% 1001
W
WWUptake (Eq. 13)
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Where “ 1W ” is the weight of the swollen matrix at time‘t’ and “ W ” is the initial weight of
the tablet. Mean of three tablets were used to evaluate the swelling behavior of matrices.
3.3.14. Matrix Erosion
Erosion studies were performed using the method reported by (Sriamornsak et al., 2007,
Mehta et al., 2001). The selected wet-tablets were taken out of the dissolution medium at
specified time intervals of 0.5, 1, 1.5, 2, 3, 4, 5, & 6 hrs, dried carefully in oven at 60° C to a
constant weight. The matrix erosion was calculated by the following equation.
Matrix% 100
i
ti
W
WWErosion (Eq. 14)
Where iW is the initial weight of the matrix and tW is the weight of the matrix subjected to
erosion for specified time ‘t’. Mean of three tablets were used to evaluate the erosion of
matrices.
3.3.15. Testing Dissolution Equivalency
A simple model-independent approach that uses a similarity factor, as reported by (Shah et
al., 1998), was applied to compare the release profiles of selected FLB and DCL-Na
formulations (F-3) after six months storage. The similarity dissimilarity factors are used to
compare two formulations, f1 is called difference factor while f2 is known as similarity
factor, also known as f1 and f2 fit factors. The model has also been recommended by USA
FDA to compare two formulations (FDA, 1997) and was originally reported by (Moore and
Flanner, 1996). Difference factor f1 is used to calculate the %age difference between the two
dissolution profiles at each time point. Following equation is used to calculate the difference
factor.
(Eq. 15) 100][
1
t
tt
R
TRf
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Where n is the number of pull-points. Rt is the dissolution profile of the reference tablet while
Tt is the dissolution profile of test tablet at time t.
Similarity in % dissolution curves are calculated by a similarity model/factor f2. Following
equation is used to calculate similarity factor.
(Eq. 16)
Where “n” is the number of data points collected, Rt and Tt are the percent drug dissolved at
each time point for reference and test tablets, respectively. It has been suggested that if the
similarity factor is close to 100 and difference factor close to zero, then the formulation
release data could be consider as similar to each other (Shah et al., 1998).
3.3.16. Effect of aging on the release of FLB and DCL-Na from controlled release matrix tablets.
In order to investigate the effect of aging on release from selected optimized FLB and DCL-
Na controlled release matrix tablets (F-3) by storing the tablets in amber bottles at ambient
conditions (temperature 25°C and relative humidity 65%) and accelerated condition
temperature 40°C and relative humidity (RH) of 75±5%), in a stability chamber in
accordance with International Commission for Harmonization (ICH) guidelines for a period
of 0 (pre-storage), 1, 2, 3, 6, 9, and 12 months. The aged samples were tested for appearance,
thickness, diameter, friability, harness, weight variation, contents uniformity and dissolution
profiles at time intervals of 0 (pre-storage), 1, 2, 3, 6, 9, and 12. The in-vitro drug dissolution
studies were performed on the aged tablets as described in the in-vitro release studies section
3.4.11.
100
)(1
1
1.502
2tt TR
n
Logf
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3.3.17. High performance liquid chromatography (HPLC) method development
An HPLC system (Agilent 1200, Agilent Corporation, Germany) comprising a quaternary
pump, an automatic sampler and a photodiode array (PDA) detector was used with data
acquisition by ChemStation® software (Agilent Corporation, Germany). The chromatographic
separation was achieved using a phenomenex C18 column (5 µm; 4.6 mm×250 mm, Luna,
USA) maintained at 25◦C. The mobile phase was prepared and premixed. Fifty parts (by
volume) of disodium hydrogen phosphate solution (30 mM) pH 7.0 were mixed with fifty
parts (by volume) of acetonitrile (1:1); and the isocratic flow rate was 1.0 ml/min. An
acetonitrile:water (50:50 v/v) mixture was used as a rinse solution for the injector, and the
injection volume was fixed at 5 µl. Detection was carried out using a wavelength of 247 and
276 nm for FLB and DCL-Na respectively.
3.3.17.1. Preparation of the HPLC analytical method
The developed method was validated according to International Conference on
Harmonisation (ICH) guidelines (Shah et al., 1992).
Approximately 10 mg of each FLB and DCL-Na powder was accurately weighed, transferred
into a 10 ml volumetric flask and dissolved in triple-distilled water (obtained in-house by
reverse osmosis and commercially known as Milli-Q water (MilliQ, Millipore, USA)) to
yield a stock solution of 1.0 mg/ml. From the stock solution, a serial dilutions were
performed using acetonitrile:water (50:50 v/v) mixture to yield a standard calibration curve
with a concentration range from 5 to 50 µg/ml.
3.3.17.2. Precision and accuracy
Intra-day and inter-day variabilities were determined by repeated injections of quality control
(QC) samples. The QC samples were prepared at 8, 18 and 40 µg/ml representing low,
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middle and high controls respectively. Accuracy was assessed by comparing the predicted
concentrations of the QC samples with the nominal 8, 18 and 40 µg/ml concentrations.
3.3.17.3. Limit of detection (LOD) and limit of quantitation (LOQ)
LOD is the lowest amount of analyte in a sample which can be detected but not necessarily
quantitated as an exact value, calculated using equation 17.
SLOD
3 (Eq. 17)
Where σ is standard deviation of the intercept and S is slope of the calibration curve
LOQ is the lowest amount of analyte in a sample, which can be quantitatively determined in
suitable precision and accuracy calculated using equation 18.
SLOQ
10 (Eq. 18)
3.3.17.4. Specificity (peak purity determination)
The HPLC-PDA detector with the Agilent ChemStation software allowed online data
acquisition of UV spectra between 190-400 nm during peak elution. The PDA detector
provides more information on sample composition than single-wavelength detection (Krull
and Szulc, 1997, Sinha et al., 2007). UV spectra were obtained at five different points across
the FLB and DCL-Na peaks; two points before the peak apex (leading front), one point at the
apex and two points after the apex (tailing front). The peak purity was assessed by examining
the similarity of the UV spectra obtained at the five points. If an impurity or degradation
product co-elutes with the FLB and DCL-Na peaks, the five UV spectra obtained across the
peak are different. The peak purity analysis was carried out for all FLB and DCL-Na samples
throughout the study.
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3.3.18. In-Vivo Studies
3.3.18.1. Study Protocol and Design
The in-vivo research proposal was approved by research and Ethical committee. The whole
in-vivo experiments were conducted in accordance with the animal scientific procedure Act,
1986. In order to compare the pharmacokinetic Parameters, of the optimized controlled
release test-tablet and the respective sustained release reference tablets (Market Brand), were
studied in two animal groups 12 rabbits in each group) in a parallel study design. The
relative-bioavailability and in-vitro in-vivo correlation were determined using suitable
pharmacokinetic parameters.
3.3.18.2. Selection of animals
Healthy male albino rabbits were selected for the in-vivo studies, weighing about 2.5±0.3 kg.
The method was already used by (Nagarwal et al., 2010) (Malkawi et al., 2008) and (Charde
et al., 2008). In order to evaluate the pharmacokinetic parameters of the test formulation F-3
and market brand, with acceptable physicochemical characteristics, rabbits were divided into
two groups, each comprising of twelve experimental units. Rabbits were kept fasting for 24
hours before administration of tablets and until 24 hrs post dosing. Nevertheless, during the
whole experimental period water was allowed ad libitum.
3.3.18.3. Animal Housing and Maintenance
The recipe was composed of 40% bran, 20% grass meal, 18% middling’s 12% ground oats
and 10% white fish meat. The standard food was given to the rabbits for at least three days
prior to drug administration. The rabbits were weighed and the food was withdrawn for 24
hour. Water was allowed ad labium during the fasting period (Kelley et al., 1992).
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3.3.18.4. Dose Administration
At the time of dose administration, the rabbits were shifted to placement restraints (wooden
holder) and the tablets were given orally, using a 3 ml syringe with its barrel smoothly cut at
the needle end (care was taken to smoothen the edges of the cut end of the syringe to avoid
damage to the oral mucosa of rabbit and to prevent any internal injury). Once tablet
swallowing was confirmed, 10 ml tape water was given to the rabbit, with the help of a 10 ml
syringe with oral tube in order of mime human dosing.
Forty eight rabbits were divided into four groups each group containing 12 rabbits and were
fasted for 24 hours. First batch was fed with 200 mg FLB test tablets; the second batch was
given 200 mg FLB market SR tablets. Third batch was given 100 mg DCL-Na test tablets
while the fourth batch was given 100 mg DCL-Na market SR tablets. Water was given ad
libitum during fasting and throughout the sampling time.
3.3.18.5. Collection of blood samples
Blood samples (0.7 ml each time) were collected from the marginal ear vein into heparinized
centrifuge tubes just before dosing and at intervals of 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 30, 36
& 42 hours, both for FLB and DCL-Na test and market brands, during the study after dosing
(Figure 3.3).
3.3.18.6. Extraction of Drug from Serum
The collected blood was allowed to clot for about 30 minutes. The resulting clot was
remimed with a sterile wooden stick and placed still in the original collection tube in the
refrigerator for about one hour. Blood samples were centrifuged at 1500 rev/min and the
plasma was separated. One undosed plasma sample was kept as blank. To 1 ml each of the
plasma samples, 5 ml of diethyl ether was added and the tubes were then centrifuged at 2500
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rev/min for 15 minutes. About 4 ml of the supernatant was pipetted out which was evaporated
at room temperature. The residue was reconstituted with 5 ml of acetonitrile and drugs
concentrations were determined by HPLC, using the method as discussed in the section
2.2.12, at 247 and 276 nm for FLB and DCL-Na respectively (Joseph et al., 2002).
Figure 3.3: Blood sampling from rabbit marginal ear vein after dosing
3.3.18.7. Preparation of standard curve
The calibration curves for FLB and DCL-Na were constructed as follows. Drug solutions in
acetonitrile were prepared at concentrations of 5, 10, 20, 40 and 50 μg/ml. One milliliter of
these solutions was made up to 5 ml using diethyl ether. To each of these solutions, 1 ml of
plasma from undosed rabbit blood was added and the contents centrifuged at 2500 rev/min
for 15 minutes. Supernatant 4 ml was then pipetted out and evaporated. The residue was then
reconstituted with 5 ml of acetonitrile and the absorbance was measured at 247 and 276 nm
for FLB and DCL-Na, respectively. The blank was prepared using plasma from the undosed
animal and acetonitrile in exactly the same way. The calibration curves for FLB and DCL-
Na, plotted at absorbance of 247 and 276 nm versus concentration, using HPLC method
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discussed in section of method validation, were linear over the range of 5–50 μg/ml with
correlation coefficients of 0.9994 and 0.9997, respectively.
3.3.18.8. Analysis of FLB and DCL-Na
The chromatographic separation of FLB and DCL-Na were carried out using the same high
performance liquid chromatographic technique as discussed in section of method validation.
3.3.18.9. Pharmacokinetic analysis
Pharmacokinetic parameters, such as area under the curve (AUC), peak concentration
(Cmax), time to attain peak concentration (Tmax) and Elimination half-lives (t1/2) were derived
from the plasma concentration versus time data using Kinetica ver 5.0. For the computation
of the above pharmacokinetic parameters, a non-compartmental approach implemented in
Kinetica was used. The values of the rate constant for elimination (kel) were used to calculate
the absorbed and unabsorbed fractions of drugs using Wegnar-Nelson method given in Pk-Fit
ver 2.01.
3.3.19. In-Vitro In-Vivo Correlation
In-vitro In-vivo correlation of the optimized formulation (F-3) was investigated by plotting
the percent drug absorbed (pa) against percent drug released (pr). Percent drug dissolved
values were taken from the in-vitro release data and the percent drug absorbed values were
calculated by Wagner-Nelson method (Wagner and Nelson, 1964).
3.3.20. Statistical Analysis
Unpaired t-test, using Prism Graph Pad, were carried out to compare the pharmacokinetic
parameters of FLB and DCL-Na controlled release test tablets. P values of ≤0.05 were
considered as significant.
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4. RESULTS & DISCUSSION
The study aims to design, evaluate and formulate once-daily controlled release matrix tablets
of each of flurbiprofen (FLB) and diclofenac sodium (DCL-Na) non-steroidal anti-
inflammatory drugs both in-vitro and in-vivo, using 7, 10 and 100 viscosity grades of
ethylcellulose ether derivative polymer (Ethocel®). Role of various co-excipients like HPMC,
CMC and starch and various process parameters including polymer swelling, erosion and
drug release mechanism have also been investigated.
4.1. Particle Size Analysis
Particle size fractions of FLB and DCL-Na powders were classified into five different
particle size sieved fractions of 0-40, 40-60, 60-80, 80-100 and 100-120 µm, using standard
sieves. The histograms of particle size distribution of two drugs are shown in Figure 4.1. It
can be seen that the differential percent of the finer particle was more than 70 percent. The
best mode of particle size distribution of both drugs belongs to 80-100 µm range and was best
dissolved in the pH 7.4 phosphate buffer solution. The results indicated the best range of the
drug particles suitable for controlled release tablets.
Figure 4.1: Particle size distribution of FLB and DCL-Na powders: Differential Percent through Sieving
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4.2. Particle size distribution
Apart from the size of the particle, the particle size distribution too, plays an important role in
the release of drug from matrix systems. Particle size of drug plays a vital role in the drug
release mechanism from a controlled release dosage form (Khan and Jiabi, 1998a). The mean
particle size of FLB, DCL-Na, Ethocel® 7, 10, 100 FP and simple grades were found to be
22.52, 1.97, 5.26, 9.14, 35.37, 58.32, 136.13 and 294.59 µm. It has been observed that drug
and polymer particle size might contribute to powder compressibility and may produce more
uniform matrices with uniform channels for water to diffuse and to dissolve the drug in a
controlled manner. The histograms of FLB, DCL-Na and Ethocel® 7, 10, and 100 FP and
simple coarser grades are given in figures 4.2-4.9.
Figure 4.2: Flurbiprofen particle size distribution though laser scattering
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Figure 4.3: Diclofenac Sodium particle size distribution though laser scattering
Figure 4.4: Ethocel® 7 FP particle size distribution though laser scattering
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Figure 4.5: Ethocel® 7 Simple particle size distribution though laser scattering
Figure 4.6: Ethocel® 10 FP particle size distribution though laser scattering
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Figure 4.7: Ethocel® 10 Simple particle size distribution though laser scattering
Figure 4.8: Ethocel® 100 FP particle size distribution though laser scattering
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Figure 4.9: Ethocel® 100 Simple particle size distribution though laser scattering
4.3. UV-Spectrophotometric Analysis
4.3.1. Selection of suitable wavelength
The U.V spectra of FLB and DCL-Na in three different solvents 0.1 N HCL, pH 7.4
phosphate buffer and 0.1 N NaOH, are shown in figures 4.10-4.15, indicating maximas of the
two drugs at 247 and 276 nm, respectively. The results are in good agreement with the USP
standards (Figures 4.10-4.15).
Figure 4.10: UV spectrum of FLB in 0.1 N HCl
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Figure 4.11: UV spectrum of FLB in pH 7.4 phosphate buffer solution
Figure 4.12: UV spectrum of FLB in 0.1 N NaOH
Figure 4.13: UV spectrum of DCL-Na in 0.1 N HCl
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Figure 4.14: UV spectrum of FLB in pH 7.4 phosphate buffer solution
Figure 4.15: UV spectrum of DCL-Na in 0.1 N NaOH
3.3.2. Standard Curve of FLB and DCL-Na
Figures 4.16 and 4.17 show the standard curves of FLB and DCL-Na, constructed by using
the concentration versus absorbance values, in pH 7.4 phosphate buffer solution and. The
regression lines for FLB and DCL-Na, along with their linearity of 0.9998 and 0.9999,
respectively.
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Figure 4.16: Standard curve for FLB in pH 7.4 phosphate buffer solution at 247 nm
Figure 4.17: Standard curve for FLB in pH 7.4 phosphate buffer solution at 247 nm
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4.4. Pre-formulation study
4.4.1. Equilibrium Solubility
Solubility of FLB at various pH values have been investigated by equilibrium solubility
method (Higuchi and Connors, 1965). Measurement of solubility reported in literature can
differ dramatically. Various conditions used to measure the solubility must be reported
accurately, as minor changes in pH, temperature, dissolved salt can affect the solubility
(Antonio et al., 2007). Flurbiprofen is a monoprotic drug with pKa value 4.22 ± 0.03 and its
solubility ranges from 1.474 to 6.961 (Anderson and Conradi, 1985). Solubility values at pH
1.2, 6.8, 7, 7.2, 7.4 and 10 were found to be 1.474, 4.308, 4.800, 5.868, 6.661 and 6.961
mg/ml at 25, 37 & 40° C. The drug solubility was increased at pH 6.8 and above, having
maximum value at pH 10, because of drug ionization; while at pH 1.2 it was low due to un-
ionized form of FLB present in the solution. As shown in figure 4.18 (Li and Zhao, 2003).
Figure 4.18: Solubility FLB in different pH media
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DCL-Na is a salt of week acidic with pKa value 3.99±0.01 (Llinàs et al., 2007). Its solubility
at different pH values of 1.2, 4.5, 6.8, 7, 7.2, 7.4 and 10, ranged from 0.005 to 12.20 mg/ml at
three different temperatures of 25, 37 & 40° C. Solubility was found to increase beyond the
pH 7, achieving its maximum value of 12.20 at pH 10 and temperature at 40° C, as shown by
graphical presentation below. Both the calculated solubility and pKa value of DCL-Na were
found in good agreement. Because of acidic nature of DCL-Na, the active part of the drug
might be very slightly soluble at acidic pH 1.2, as the pH increased; solubility also increased
achieving its maximum value beyond pH 7 because of drug ionization at basic pH. Figure
4.19 presents the solubility of DCL-Na.
Figure 4.19: Solubility DCL-Na in different pH media
4.4.2. Preparation of solid dispersions
The solid dispersions of FLB and DCL-Na were prepared by solvent evaporation method.
Solid dispersions were mixed with excipients and subjected to further preformulation studies.
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4.4.3. Bulk density
Bulk density and tapped density are usually measured for the pharmaceutical processability
and are considered the most important parameters to design a solid oral dosage form. It could
be observed that bulk and tapped densities affect the preparation of different dosage forms
such as tablets, capsules, suspensions etc. Usually the in-process flowability of a drug
powders is inferred from the ratio of these two densities. Bulk densities for FLB and DCL
powders were found to be 0.228 and 0.932, while those for FLB and DCL-Na physical
mixtures and solid dispersions ranged from 0.285±0.00 to 0.3880.02 and 0.250±0.09 to
0.376±0.00, respectively (Tables 4.1-4.8). It has also been investigated that the powder
particle size and shape might affect the bulk density, tapped density and finally the powder
flowability and compressibility.
4.4.4. Tapped density
The tapped densities were found to be 0.582 and 0.930 for FLB and DCL-Na active drug
powders. While that for their physical mixtures and solid dispersions of FLB and DCL-Na
ranged from 0.250±0.09 to 0.394±0.01 and 0.338±0.03 to 0.398±0.07 (Tables 4.1-4.8). These
results could be the obvious indication that there was no conclusive effect of physical mixing
of drug and various excipients and co-excipients upon the powder particle size. Tapped
density could also be referred as the maximum packing density of powder drug and physical
mixtures, achieved under the influence of compression force while processing. Various
factors could be involved in the minimum packed density of a powder and could also affect
the powder flowability and compressibility, such as true density, particle size distribution,
particle shape etc. Pure drug powders were found to be more fluffy and bulky, as the highest
tapped density of the pure drug indicates the high inter-particular spaces.
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4.4.5. Hausner’s ratio
HF values ranged from 1.01±0.01 to 1.32±0.00 and 1.01±0.02 to 1.34±0.08 both for FLB and
DCL-Na physical mixtures and solid dispersions, respectively (Tables 4.1-4.8). These results
could be the indication of good flow properties and compressibility of all physical mixtures
and solid dispersions (Khan et al., 2007). The density measurements mentioned above and
the detailed discussion made on the powder flowability and its packing mechanism suggested
taking advantage of the procedure developed to consistently obtain dense packing of the
physical mixture without compaction, to improve the flowability criteria of the formulations
based on density. Tap to bulk density ratio, given in the tables below, have already shown
that materials were free flowing and effectively compressible to design a tablet. Although the
excipient like lactose is a cohesive powder that could limit the particle movements and hence
the overall powder flowability, but, the ratio known with the name of hausner’s ratio (HR)
already introduced above is a good choice. It properly compared the packed and dilated
condition for the same powder (Reynolds, 1885), and suggested that the powder material
must dilate to start flowing. However, the HR which uses as numerator the tap density
defined above is known to be severely dependent on the operator and hence critical in its use
in the industrial practice. However, the final result may overlook specific features of the
powder that were apparent in the packing process, if the different number of strokes to
achieve the final goal is not relevant, nor recorded. It is not unusual that the same powder
with a different degree of moisture can be forced, by changing the total number of strokes, to
achieve the same final tap density, while it is dramatically evident the different flowing
behavior. Perhaps the most critical objection to the tap density procedures is the uncontrolled
packing obtainable. Not only its uniformity in space is not guaranteed by the procedures, but
such packing can also easily become a compaction, i.e. forcing the particle to modify their
shapes to reach a higher filling and accurate weight of a unit dosage form.
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4.4.6. Angle of repose
Angle of repose was found to be 29.64˚ and 32.64° for FLB and DCL-Na powders and that
for their physical mixtures and solid dispersions ranged from 11.53˚±0.09 to 27.72˚±0.00 and
17.01±0.02 to 29.88±0.01 (Table 4.1-4.8). Due to irregular shape and high fineness of the
powder, it was very difficult for the powder drugs to pass through the funnel during the
experiment. It could be observed that the reduced angle of repose, in case of all physical
mixtures, attributed to fair flow properties which in turn improved the speed of production
process, reduced the risk of stoppage, and finally improved the blend quality. It could also be
realized that the frictional force in the loose powder was in acceptable range, but the addition
of polymer and other excipients more improved the powder flow and reduced the inter-
particulate cohesiveness up to a negligible extent during the compression process, which
could be attributed to the addition of magnesium stearate (Sharma, 2008).
4.4.7. Compressibility index
Compressibility index developed by Carr (USP, 2005), from the bulk densities of FLB
indicating indirect measurement of flow property of powdered drug, its bulk density, size and
shape, moisture content surface area, was calculated and evaluated. Percent compressibility
of FLB and DCL-Na powders were found to be 55.25 and 39.45% which were in good
agreement with angle repose, while those for the physical mixtures and solid dispersions
ranged from 11.21±0.02 to 23.45±0.10% and 11.27±0.02 to 28.55±0.01%, indicating the
improved compressibility and flowability of physical mixtures and solid dispersions. It was
observed that all the formulations exhibited low hausner’s ratio and low angle of repose
values which could be the sign of excellent flow properties and compressibility (Lachman L,
1987, Raghuram RK, 2003) (Table 4.1-4.8).
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Table 4.1: Physical evaluation of starting material
Formulation
Bulk Density (g/cm3)
Tapped Density (g/cm3)
Hausner’s Ratio
Angle of Repose (θ)
Compressibility Index (%)
FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-0 0.3770.11 0.3870.34 0.3690.03 0.3890.12 1.050.06 1.160.05 18.580.13 22.740.10 19.780.10 17.150.04
F-1 0.3300.02 0.2860.04 0.3670.03 0.3210.04 1.110.03 1.120.00 22.130.02 24.320.03 11.210.02 13.980.01
F-2 0.3500.00 0.3010.09 0.3891.00 0.3350.04 1.230.02 1.110.09 21.320.02 22.110.12 13.320.00 12.260.09
F-3 0.2990.00 0.2960.02 0.3680.10 0.3650.01 1.100.08 1.230.05 22.420.10 23.320.10 12.280.00 28.550.01
F-4 0.3820.02 0.3940.01 0.3860.01 0.3980.04 1.210.04 1.010.02 25.510.01 22.100.09 14.150.12 29.150.02
F-5 0.3280.01 0.3160.00 0.3650.00 0.3450.01 1.110.10 1.090.01 15.630.00 18.220.09 17.730.01 17.290.10
F-6 0.3410.02 0.3420.00 0.3550.01 0.3870.06 1.040.01 1.130.04 27.720.00 20.220.09 23.450.10 15.980.01
F-7 0.2850.00 0.3160.02 0.3450.02 0.3550.09 1.210.09/ 1.120.02 20.160.00 21.920.01 18.920.10 13.990.12
F-8 0.3750.00 0.3370.01 0.3870.10 0.3880.02 1.030.00 1.150.10 24.550.00 20.120.01 12.830.02 20.310.09
F-9 0.3560.00 0.3420.02 0.3770.00 0.3690.04 1.100.09 1.130.02 22.340.10 21.180.02 19.020.02 15.660.10
Table 4.2: Physical evaluation of starting material
Formulation
Bulk Density (g/cm3)
Tapped Density (g/cm3) Hausner’s Ratio
Angle of Repose (θ)
Compressibility Index (%)
FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-10 0.3130.01 0.2740.02 0.3480.09 0.3210.00 1.110.00 1.170.07 23.530.00 18.120.01 17.210.00 19.560.06
F11 0.3660.00 0.2760.01 0.3740.00 0.3350.01 1.020.01 1.210.03 22.520.02 21.110.09 19.320.02 19.370.03
F-12 0.3060.10 0.3040.01 0.3770.10 0.3650.00 1.230.10 1.200.06 21.170.09 21.270.03 15.280.10 20.360.08
F-13 0.2900.00 0.3500.03 0.3840.01 0.3980.02 1.320.00 1.120.04 23.650.02 20.120.02 18.150.09 25.570.01
F-14 0.3120.09 0.2970.10 0.3470.09 0.3450.04 1.110.01 1.160.05 16.530.03 14.320.04 19.730.01 16.920.05
F-15 0.3620.10 0.3300.09 0.3990.00 0.3870.09 1.100.01 1.170.06 22.220.01 20.520.04 20.450.00 17.880.03
F-16 0.3840.12 0.3250.09 0.3960.09 0.3550.09 1.030.10 1.090.02 22.210.00 20.120.03 18.920.01 12.260.04
F-17 0.3180.01 0.3490.09 0.3380.03 0.3880.00 1.060.03 1.110.00 23.550.00 22.020.02 18.830.00 18.670.02
F-18 0.3260.00 0.3640.10 0.3390.02 0.3600.01 1.090.02 1.120.02 20.220.01 18.720.00 18.920.00 22.280.02
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Table 4.3: Physical evaluation of starting material
Formulation
Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index
(%)
FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-19 0.3330.02 0.2970.00 0.3970.00 0.3210.09 1.190.01 1.080.00 20.220.00 24.530.01 13.230.00 13.230.00
F-20 0.3410.00 0.3190.02 0.3650.01 0.3350.04 1.070.01 1.050.01 21.610.09 22.320.04 12.320.01 12.320.01
F-21 0.3510.09 0.3250.01 0.3760.02 0.3650.01 1.040.09 1.120.01 23.270.01 21.220.03 11.270.02 11.270.02
F-22 0.3220.10 0.3260.03 0.3580.01 0.3980.02 1.110.01 1.220.10 19.100.01 22.510.03 18.160.01 18.160.01
F-23 0.3860.08 0.3080.06 0.3980.03 0.3450.04 1.030.00 1.120.02 15.720.00 11.330.06 15.730.01 15.730.01
F-24 0.3580.10 0.3450.03 0.3760.04 0.3870.07 1.050.10 1.120.09 22.520.10 23.220.01 25.450.09 25.450.09
F-25 0.3250.07 0.3080.01 0.3580.00 0.3550.00 1.100.00 1.150.01 22.120.01 20.010.00 14.980.01 14.980.01
F-26 0.2960.10 0.3760.00 0.3560.04 0.3880.01 1.200.10 1.030.04 22.180.01 20.500.01 18.840.00 18.840.00
F-27 0.3200.01 0.3520.01 0.3630.02 0.3870.02 1.090.01 1.110.02 20.910.0- 18.710.09 22.910.09 22.910.09
Table 4.4: Physical evaluation of starting material
Formulation
Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index (%)
FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-28 0.3270.00 0.2890.01 0.3990.00 0.3210.00 1.220.01 1.110.00 23.020.01 22.120.00 14.200.02 28.540.01
F-29 0.3790.03 0.2860.09 0.3870.09 0.3350.02 1.020.08 1.170.02 25.320.00 21.010.01 13.320.07 16.350.03
F-30 0.3140.03 0.2800.08 0.3580.01 0.3650.03 1.140.04 1.300.00 26.110.09 23.170.03 15.180.04 20.350.02
F-31 0.3550.02 0.3230.05 0.3980.08 0.3980.00 1.120.04 1.230.04 22.640.04 22.100.03 17.130.02 25.170.03
F-32 0.3400.00 0.2850.03 0.3780.03 0.3450.09 1.110.05 1.210.00 13.250.01 19.120.04 15.730.03 12.370.04
F-33 0.3400.01 0.3550.06 0.3780.09 0.3870.02 1.110.03 1.090.01 22.620.02 19.220.05 22.420.04 18.830.07
F-34 0.3220.00 0.3250.10 0.3970.03 0.3550.00 1.230.02 1.090.03 24.010.03 24.120.01 11.930.05 10.990.03
F-35 0.3240.02 0.3100.01 0.3990.04 0.3880.02 1.230.07 1.250.02 25.140.00 22.020.08 17.820.03 19.190.01
F-36 0.3320.00 0.3420.09 0.3980.01 0.3770.04 1.100.04 1.250.00 23.440.02 20.910.05 20.710.02 20.710.02
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Table 4.5: Physical evaluation of starting material
Formulation
Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index
(%)
FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-37 0.3560.01 0.2630.03 0.3670.01 0.3210.01 1.030.01 1.220.03 20.230.01 18.920.01 11.220.01 12.570.02
F-38 0.3450.09 0.3130.04 0.3560.07 0.3350.04 1.030.01 1.070.03 21.120.04 17.010.02 12.120.02 17.930.02
F-39 0.3640.01 0.3140.04 0.3750.02 0.3650.03 1.030.01 1.160.01 23.620.01 21.250.00 14.340.02 23.290.03
F-40 0.3180.04 0.3370.00 0.3470.02 0.3980.00 1.090.01 1.180.07 22.710.02 17.160.03 15.140.01 20.470.01
F-41 0.3720.01 0.2920.01 0.3840.01 0.3450.00 1.030.00 1.180.02 11.830.01 18.320.01 15.560.04 19.460.01
F-42 0.3490.03 0.2880.03 0.3880.01 0.3870.01 1.110.02 1.340.01 24.520.02 20.520.04 24.540.01 17.470.01
F-43 0.3720.01 0.2880.04 0.3840.03 0.3550.02 1.030.04 1.230.05 17.410.01 22.320.02 15.300.01 15.870.02
F-44 0.3440.01 0.3200.03 0.3790.06 0.3880.04 1.100.01 1.210.03 18.440.00 21.180.01 13.340.03 19.830.02
F-45 0.3550.01 0.3100.08 0.3650.01 0.3760.06 1.090.04 1.200.07 19.010.01 29.880.01 15.520.01 22.180.01
Table 4.6: Physical evaluation of starting material
Formulation
Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index (%)
FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-46 0.3880.01 0.2890.01 0.3960.04 0.3210.02 1.020.02 1.110.05 22.010.02 21.040.05 11.410.03 11.410.08
F-47 0.3570.03 0.2720.09 0.3680.03 0.3350.01 1.030.01 1.230.04 18.180.03 21.330.01 12.230.02 12.230.01
F-48 0.3290.05 0.3250.06 0.3560.02 0.3650.01 1.080.04 1.120.03 23.270.02 21.120.01 13.380.01 13.380.07
F-49 0.3370.06 0.3200.04 0.3480.01 0.3980.04 1.030.02 1.240.04 24.110.02 21.620.02 15.350.01 15.350.01
F-50 0.3630.06 0.2850.01 0.3740.00 0.3450.02 1.030.02 1.210.02 18.120.01 12.120.05 16.230.00 16.230.04
F-51 0.3520.03 0.2680.01 0.3950.05 0.3870.03 1.120.02 1.440.02 27.320.01 22.320.02 23.250.02 23.250.09
F-52 0.3730.01 0.2900.02 0.3850.06 0.3550.01 1.030.04 1.220.00 21.190.05 19.020.03 12.420.01 12.420.01
F-53 0.3470.01 0.3340.03 0.3580.09 0.3880.04 1.030.01 1.160.04 26.250.00 17.570.02 19.330.03 19.330.06
F-54 0.3660.01 0.3000.01 0.3780.01 0.3630.05 1.090.02 1.110.01 25.110.02 18.920.05 17.810.01 17.810.03
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Table 4.7: Physical evaluation of starting material
Formulation
Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index (%)
FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-55 0.3650.09 0.2940.02 0.3960.04 0.3210.02 1.020.02 1.110.05 22.010.02 21.040.05 11.410.03 11.410.08
F-56 0.3400.04 0.2500.12 0.3680.03 0.3350.01 1.030.01 1.230.04 18.180.03 21.330.01 12.230.02 12.230.01
F-57 0.3740.05 0.2920.04 0.3560.02 0.3650.01 1.080.04 1.120.03 23.270.02 21.120.01 13.380.01 13.380.07
F-58 0.3870.04 0.3430.09 0.3480.01 0.3980.04 1.030.02 1.240.04 24.110.02 21.620.02 15.350.01 15.350.01
F-59 0.3490.03 0.2820.09 0.3740.00 0.3450.02 1.030.02 1.210.02 18.120.01 12.120.05 16.230.00 16.230.04
F-60 0.3200.02 0.3390.03 0.3950.05 0.3870.03 1.120.02 1.440.02 27.320.01 22.320.02 23.250.02 23.250.09
F-61 0.3570.08 0.3060.01 0.3850.06 0.3550.01 1.030.04 1.220.00 21.190.05 19.020.03 12.420.01 12.420.01
F-62 0.3540.07 0.3310.04 0.3580.09 0.3880.04 1.030.01 1.160.04 26.250.00 17.570.02 19.330.03 19.330.06
F-63 0.3500.01 0.3240.11 0.3780.01 0.3630.05 1.090.02 1.110.01 25.110.02 18.920.05 17.810.01 17.810.03
Table 4.8: Physical evaluation of starting material
Formulation
Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index (%)
FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-64 0.3650.09 0.2940.11 0.3690.01 0.3210.01 1.010.01 1.090.02 25.130.08 21.170.10 14.220.02 12.760.01
F-65 0.3400.09 0.2500.09 0.3680.02 0.3350.09 1.080.04 1.340.08 24.220.11 21.190.02 12.340.01 17.490.04
F-66 0.3740.04 0.3650.02 0.3860.03 0.3650.08 1.030.12 1.250.12 23.420.12 20.160.01 13.260.03 23.1430.03
F-67 0.3870.03 0.3430.01 0.3990.09 0.3980.07 1.030.03 1.160.11 22.210.02 23.150.02 19.170.06 22.650.07
F-68 0.3490.00 0.2820.09 0.3670.07 0.3450.09 1.050.01 1.220.09 11.530.09 25.220.11 20.730.08 16.670.05
F-69 0.3200.14 0.3390.08 0.3560.04 0.3870.02 1.110.13 1.140.11 20.320.07 25.120.03 23.420.01 11.930.01
F-70 0.3570.04 0.3060.04 0.3680.11 0.3350.04 1.030.18 1.160.02 19.510.07 25.120.07 21.100.00 17.200.02
F-71 0.3540.11 0.3310.01 0.3860.02 0.3880.03 1.090.09 1.170.03 17.140.02 24.190.09 18.100.01 17.570.12
F-72 0.3500.10 0.3240.02 0.3720.12 0.3680.01 1.080.01 1.130.04 18.920.01 22.340.11 19.920.11 17.010.09
F-73 0.3880.09 0.3540.08 0.3560.10 0.3760.10 1.020.09 1.150.10 18.670.11 22.020.15 19.870.12 17.110.09
F-74 0.3790.15 0.3370.09 0.3980.03 0.3600.02 1.050.11 1.100.09 18.780.11 22.660.08 19.810.05 17.400.05
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4.7. Differential Scanning Calorimeter (DSC)
Figure 4.20 shows the thermograms of FLB drug, physical mixture and solid dispersions
(10:3 wt/wt). DSC study was conducted to investigate the interaction of drug with polymer or
other excipients. The DSC analysis of FLB alone showed sharp endothermic peaks at 114°C
corresponding to its melting point (Jan-Olav and Maria, 1999). It was found that the
endothermic peaks of physical mixtures and solid dispersions of FLB reflected the
characteristic features of the drug alone when compared with the respective peak of the drug.
Thus it was thought that there was no conclusive evidence of interaction between the drug,
polymer and other excipients.
Figure 4.20: Differential Scanning Calorimetric Thermograms of FLB (A), FLB physical mixture (B), FLB solid dispersions (C)
Differential scanning calorimetric studies were also conducted for DCL-Na drug powder,
physical mixture and solid dispersions to determine any interaction of drug with polymer or
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other excipinets. DSC thermogram of DCL-Na drug, physical mixture and solid dispersions.
Thermogram showed a single endothermic peak at 280°C, corresponding to it melting point
(Petar et al., 2001) (Figure 4.21). DSC analysis showed that DCL-Na, physical mixtures, and
solid dispersions gave the endothermic peaks at the same temperature as that of the pure drug.
These results might indicate that there is no conclusive interaction of DCL-Na with polymer,
solid dispersions or other excipients.
Figure 4.21: Differential Scanning Calorimetric Thermograms of DCL-Na (A), DCL-Na physical mixture (B) and DCL-Na solid dispersions (C)
4.8. Fourier Transform Infra-Red Absorption Spectroscopy (FTIR)
FTIR spectroscopy of FLB (A), EC (B), FLB-EC (C), FLB-EC-Starch (D), FLB-EC-CMC
(E) and FLB-EC-HPMC (F) and FLB solid dispersions (G) was conducted to investigate any
interaction of FLB drug with polymer or other excipient. FTIR spectra of FLB, physical
mixtures with polymer and other excipients such as hydroxypropylmethylcellulose,
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carboxymethylcellulose, starch, lactose and magnesium strearate are shown in figure 4.22.
FLB Spectra showed principal peaks at 1695 cm‾¹ which corresponds to carboxyl group
(C=O). Smaller peaks in the region of 1000-1700 cm‾¹ could be due to the presence of
benzene ring in the drug molecule (Shrivastava et al., 2009, Ranjha et al., 2010). It could be
concluded that as there was so change in the characteristic peaks of FLB drug, so there was
no conclusive interaction of the drug with polymer or other excipients.
Figure 4.22: FTIR Spectroscopy of FLB (A), EC (B), FLB-EC (C), FLB-EC-HPMC (D),
FLB-EC-Starch (E), FLB-EC-CMC (F) and FLB solid dispersions (G)
FTIR studies of DCL-Na (A), EC (B), DCL-Na-EC (C), DCL-Na-EC-starch (D), DCL-Na-
EC-CMC (E) and DCL-Na-EC-HPMC (F) and DCL-Na solid dispersions (G), are presented
in figure 4.23. The spectroscopy was conducted to investigate drug-polymer interaction. In
case of pure DCL-Na drug spectra showed principal peaks at 1572, 756 due to chlorine
bonding (C-Cl). Smaller peaks at 1504 (C=C), 775 and 1586 (C=C, aromatic) could be due to
aromatic as shown in figure 4.23 (Adeyeye and Li, 1990). The FTIR spectra of pure drug,
physical mixtures and solid dispersions showed principal peaks at the same region, which
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could be ascribed as simple addition of Ethocel® (EC) and other excipients to DCL-Na drug.
Other minor changes in case of all physical mixtures and solid dispersions could be due to
variations in the resonance structure, stretching and bending, rotation of a part of molecule or
certain bonds or minor distortion of bond angles. The similar study was conducted by the
other researchers (Kulkarni et al., 2007, Brigtwell and Davey, 2005, Diclofenac, 2005,
Gokulakumar and Narayanaswamy 2008).
Figure 4.23: FTIR Spectroscopy of DCL-Na (A), EC (B), DCL-Na-EC (C), DCL-Na-EC-
HPMC (D), DCL-Na-EC-Starch (E), DCL-Na-EC-CMC (F) and DCL-Na solid dispersions
(G)
4.9. Scanning Electron Microscopy (SEM)
Figure 4.24 shows SEM images of FLB (A), FLB physical mixture (B) FLB solid dispersions
(C), DCL-Na (D), DCL-Na-polymer physical mixture (E), and DCL-Na solid dispersions (F),
at different resolutions of 1000 and 2500. The SEM photomicrographs of FLB and DCL-Na,
their physical mixtures and solid dispersions systems showed that that the elongated crystals
of FLB and DCL-Na were clearly visible. In case of physical mixtures of both FLB and
DCL-Na drug irregular, spherical and cylindrical shaped small crystal were visible, while in
case of solid dispersions the crystalline forms of FLB and DCL-Na were changed to large
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irregular amorphous form, as shown below (Dong-Han et al., 2005, Shobhan Sabnis, 1997).
And the same findings were confirmed by XRD studies as shown in the figures 4.25 and
4.26.
A A
A
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A B
B
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B
C
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C
C
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D
D
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E
E
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E
F
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Figure 4.24: Scanning Electron Micrographs of FLB (A), FLB physical mixture (B), FLB
solid dispersions (C), DCL-Na (D), DCL-Na physical mixture (E) and DCL-Na solid
dispersions (F)
F
F
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4.10. X-Ray Diffraction (XRD)
X-ray diffraction results of DCL-Na, physical mixture and solid dispersions were measured
in θ angle from 0 to 20°. Due to crystalline nature of DCL-Na and FLB, x-ray diffraction
pattern showed sharp peaks both for DCL-Na and FLB powders and their physical mixtures,
around 20°, while the drugs peaks were found shorter in the x-ray diffraction pattern of solid
dispersions. This alteration could be due to the reduction in particle size of drug as a result of
solvent evaporation as shown in figures 4.25 and 4.26. SEM micrographs (Figure 4.24) are
also in good agreement with XRD results that incase of physical mixture of both FLB and
DCL-Na regular, spherical and cylindrical crystals could be found, while in case of solid
dispersions crystalline form might be changed to large amorphous irregular shaped
molecules. Similar findings were observed by other investigators (Saravanan et al., 2004,
Aceves et al., 2000).
Figure 4.25: X-Ray diffraction pattern of FLB (A), FLB-EC physical mixture (B) & FLB
solid dispersions (C)
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Figure 4.26: X-Ray diffraction pattern of DCL-Na (A), DCL-Na-EC physical mixture (C) & DCL-Na solid dispersions (C)
4.11. Preparation of matrix tablets
It has been observed that sometime high drug concentration can lead to cohesive particle
bonding during compression process (Shangraw, 1991). High friction during tabletig can
cause a serious problems, including inadequate tablet quality (capping or even fragmentation
of tablets during ejection and vertical scratches on tablet edges), which may even stop
production (Alderborn, 2002). Proper quantities of the ingredients and suitable process
techniques, lead to model controlled release matrix tablets. Sufficient quantities of drugs and
other excipients led to easy and clean ejection of tablets from die cavity, after compression.
In this work the direct compression technique was adopted so as to avoid the unwanted
swelling of the polymer and to reduce production time and hence costs as it before minimizes
the number of operations involved in the pre-treatment of the powder mixture before
tableting. As heat and water are not involved, product stability can also be improved.
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Numerous studies have shown that oral controlled release products were prepared by direct
compression technique (Heng et al., 2001a, Miranda et al., 2007a).
(Keijiro and Keisuke, 2002) evaluated that direct compression was able to products tablets at
a lower cost than wet granulation and tableting method, due to a fewer items of process
validation. In that study it was confirmed that tablets produced by direct compression were
similar in physical properties in tablets produced by wet granulation and tab letting method.
Further, it was suggested that use of a dry-type binder would make it possible to provide a
tablet having higher content of the medicine with excellent physical Properties.
Prior to in-vitro in-vivo evaluation, compressed tablets were subjected to the physical
evaluation processes, including, thickness & diameter, hardness, friability, weight variation
and content uniformity.
4.12. Physical characteristics of matrix tablets
The specifications for pharmaceutical tablets usually include appearance, thickness &
diameter, hardness, friability, weight variation and content uniformity test. These
specifications are established to ensure that the tablets will have sufficient mechanical
strength to withstand packaging, shipping, and handling and are physically and chemically
stable to deliver the accurate amount of drug at the desired dissolution rate when consumed
by a patient. Any changes in these characteristics may significantly affect the safety and
efficacy of the tablets. All of the above mentioned tests were carried out in strict compliance
of Good Laboratory Practices (GLP).
All tablet formulations prepared by direct compression showed acceptable pharmacotechnical
and mechanical properties and complied with in-house specifications for thickness &
diameter, hardness, friability, weight variation and content uniformity. Variation in physical
characteristics may change the release the drug release profile.
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4.12.1. Thickness and Diameter
Thickness and diameter affect the internal stress of the tablet and are counted during drug
handling. Thickness and diameter of both FLB and DCL-Na tablets ranged from 2.10 ± 0.00
to 2.3 ± 0.3 mm and 4.0 ± 0.1 to 4.8 ± 0.6 mm, which were found to be in acceptable range.
The overall results are presented in tables 4.9-4.16. A tablet thickness cannot be
independently controlled, because it is related to the tablet weight, which must also be closely
adjusted and controlled. The weight variation test below have shown that the tablet weight
was controlled and was found to be in the range of 200 ± 0.01 to 204 ± 0.04 mg, hence, the
thickness and diameter was also found to be in a good agreement with tablets weight. Results
showed that thickness and diameter were not affected by the addition of polymer and/or other
excipients. Similar findings were observed by other researchers (Banker and Anderson,
1986).
4.12.2. Hardness
Hardness of the test tablets, for all batches, ranged from 6.0±0.12 to 8.2 ± 0.02 3cmkg ,
which could be suitable to reduce the tendency to cap, as thickness affects the internal stress
of the tablet. Hardness of the tablets was found to be in good acceptable limit. It could be
observed that the Ethocel® FP polymer with fine particles improved compressibility which
does not negatively impact the compressibility of the formulations, and helped to control the
release rate of the drug from matrix tablets.
4.12.3. Friability
For all batches the tablets were found to be within the acceptable range of friability i.e. less
than 1% (Tables 4.9-4.16) and are an indicative that tablet surfaces were strong enough to
stand with the mechanical shock during storage and transportation till consumed. Friability
calculated was in the acceptable range of 0.10 ± 0.01 to 0.75 ± 0.07 ww , and it increased
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 127
with the increase of polymer grade. The best friability results were found with Ethocel® FP
polymer with 10:3 drug to polymer ratio. The results confirm the findings of other
researchers (Khan and Meidan, 2007, Akhlaq et al., 2011).
4.12.4. Weight variation
Weight variation test showed that all of the tablets were in the acceptable range of 200 ± 0.01
to 204 ± 0.04 mg. All batches of the test tablets were found to be uniform in weight (RSD <
1%). The results showed that there was no variation in tablet weights, because weight of the
tablets was kept constant for all formulations. The fulfillment of Pharmacopeial limits
indicates not only the satisfactory flow properties but also the proper blending of ingredients
for the proposed formulations. Improper mixing of glidant can cause weight variation by not
allowing the uniform flow of the powder (Delonca et al., 1969).
4.12.5. Content uniformity
Content uniformity test fell in the best suitable range of 98.02 ± 0.09 to 99.9 ± 0.10%, both
for FLB and DCL-Na tablets, whereas the drug content for FLB and DCL-Na pure drugs
showed 99.0±0.01 and 99.98±0.08% of drug purity.
Table 4.9: Thickness & Diameter, Hardness, Friability, Weight variation and Content Uniformity of test tablets (as mentioned in section 3.3.10) expressed as Mean ± SD
Formulation
Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation (mg) Content Uniformity (%)
FLB DCL-
Na FLB
DCL-Na
FLB DCL-
Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-0 2.3±0.1 2.1±0.5 2.2±0.3 4.7±0.5 4.2±0.5 6.2±0.07 6.5±0.16 0.49±0.08 0.30±0.19 201±0.6 200±0.09 99.07±0.15
F-1 2.1±0.4 2.2±0.1 4.3±0.1 4.4±0.1 7.3±0.10 7.5±0.12 0.17±0.04 0.32±0.04 200±0.02 200±0.02 99.18±0.02 98.92±0.03
F-2 2.2±0.5 2.0±0.4 4.4±0.1 4.6±0.2 7.6±0.42 6.7±0.23 0.23±0.03 0.23±0.24 202±0.02 202±0.02 99.19±0.01 98.93±0.04
F-3 2.1±0.6 2.1±0.3 4.5±0.2 4.7±0.1 7.9±0.24 8.1±0.01 0.36±0.02 0.29±0.01 201±0.03 201±0.03 99.01±0.10 99.04±0.04
F-4 2.3±0.3 2.1±0.1 4.6±0.3 4.5±0.2 7.0±0.52 7.4±0.32 0.46±0.06 0.61±0.09 201±0.02 201±0.02 99.17±0.02 99.02±0.03
F-5 2.0±0.2 2.1±0.2 4.5±0.2 4.3±0.2 7.4±0.87 7.6±0.03 0.53±0.08 0.54±0.02 200±0.01 200±0.01 99.22±0.52 98.94±0.03
F-6 2.0±0.7 2.2±0.4 4.4±0.1 4.3±0.3 7.5±0.45 7.8±0.02 0.59±0.09 0.74±0.00 200±0.04 200±0.04 99.21±0.11 98.93±0.03
F-7 2.0±0.6 2.2±0.1 4.3±0.3 4.2±0.1 7.3±0.34 6.4±0.18 0.62±0.09 0.54±0.03 200±0.05 200±0.05 98.81±0.21 98.84±0.02
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 128
F-8 2.2±0.5 2.1±0.4 4.8±0.4 4.6±0.1 6.5±0.23 6.9±0.22 0.69±0.08 0.74±0.34 201±0.06 201±0.06 98.21±0.23 98.75±0.09
F-9 2.1±0.5 2.0±0.0 4.5±0.2 4.2±0.2 7.7±0.38 7.5±0.08 0.75±0.07 0.72±0.12 200±0.09 200±0.09 99.23±0.20 99.16±0.04
Table 4.10: Thickness & Diameter, Hardness, Friability, Weight variation and Content Uniformity of test tablets (as mentioned in section 3.3.10) expressed as Mean ± SD
Formulation
Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation
(mg) Content Uniformity (%)
FLB DCL-
Na FLB
DCL-Na
FLB DCL-
Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-10 2.2±0.1 2.2±0.1 4.1±0.2 4.4±0.1 6.4±0.29 6.3±0.02 0.16±0.02 0.31±0.06 201±0.1 200±0.02 99.18±0.02 98.92±0.03
F-11 2.1±0.2 2.0±0.2 4.2±0.2 4.5±0.3 6.9±0.12 6.7±0.02 0.45±0.03 0.22±0.23 201±0.2 202±0.02 99.19±0.01 98.93±0.04
F-12 2.1±0.3 2.1±0.2 4.3±0.2 4.6±0.1 6.2±0.02 6.9±0.24 0.33±0.02 0.23±0.02 202±0.3 201±0.03 99.01±0.10 99.04±0.04
F-13 2.0±0.0 2.1±0.2 4.2±0.1 4.6±0.2 6.9±0.23 6.8±0.22 0.20±0.05 0.14±0.04 202±1.4 201±0.02 99.17±0.02 99.02±0.03
F-14 2.0±12 2.0±0.5 4.1±0.2 4.4±0.3 7.1±0.01 6.4±0.12 0.20±0.01 0.56±0.03 201±0.3 200±0.01 99.22±0.52 98.94±0.03
F-15 2.0±0.3 2.2±0.4 4.2±0.2 4.2±0.3 7.2±0.03 7.5±0.09 0.22±0.03 0.32±0.04 202±1.5 200±0.04 99.21±0.11 98.93±0.03
F-16 2.0±0.4 2.2±0.3 4.1±0.5 4.5±0.1 7.4±0.10 6.5±0.20 0.74±0.02 0.33±0.06 201±0.3 200±0.05 98.81±0.21 98.84±0.02
F-17 2.2±0.3 2.1±0.0 4.5±0.3 4.5±0.1 6.5±0.19 6.3±0.20 0.32±0.02 0.49±0.33 202±1.0 201±0.06 98.20±0.20 98.75±0.09
F-18 2.0±0.7 2.0±0.2 4.8±0.5 4.1±0.3 7.4±0.20 6.2±0.18 0.45±0.04 0.36±0.17 201±0.3 200±0.09 99.23±0.20 99.16±0.04
Table 4.11: Thickness & Diameter, Hardness, Friability, Weight variation and Content Uniformity of test tablets (as mentioned in section 3.3.10) expressed as Mean ± SD
Formulation
Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation
(mg) Content Uniformity (%)
FLB DCL-
Na FLB
DCL-Na
FLB DCL-
Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-19 2.1±0.1 2.2±0.2 4.2±0.2 4.2±0.2 7.5±0.12 7.3±0.12 0.12±0.04 0.31±0.03 200±0.01 201±0.01 99.24±0.02 98.92±0.02
F-20 2.1±0.2 2.02±0.3 4.1±0.2 4.3±0.2 7.6±0.43 7.9±0.22 0.41±0.03 0.21±0.22 202±0.20 202±0.02 99.33±0.03 98.92±0.13
F-21 2.2±0.2 2.1±0.4 4.2±0.1 4.4±0.3 7.7±0.23 8.2±0.02 0.32±0.02 0.21±0.09 201±0.10 201±0.05 99.12±0.12 99.01±0.02
F-22 2.0±0.3 2.0±0.2 4.3±0.2 4.2±0.4 6.7±0.54 7.3±0.11 0.23±0.06 0.10±0.02 201±1.02 200±0.02 99.55±0.14 99.02±0.09
F-23 2.0±0.2 2.0±0.2 4.4±0.3 4.1±0.3 7.0±0.83 7.3±0.02 0.23±0.08 0.50±0.03 202±0.07 202±0.03 99.26±0.53 98.92±0.02
F-24 2.0±0.5 2.0±0.1 4.6±0.2 4.1±0.2 7.3±0.04 7.4±0.01 0.29±0.02 0.32±0.04 201±1.30 200±0.08 99.27±0.11 98.92±0.09
F-25 2.0±0.3 2.1±0.3 4.3±0.3 4.2±0.1 7.7±0.34 7.4±0.11 0.72±0.03/0 0.30±0.08 201±0.04 202±0.01 98.84±0.21 98.87±0.20
F-26 2.0±0.4 2.0±0.2 4.0±0.2 4.1±0.1 6.9±0.21 7.5±0.21 0.39±0.03 0.41±0.20 200±1.40 201±0.02 98.23±0.27 98.72±0.03
F-27 2.2±0.2 2.2±0.3 4.2±0.1 4.0±0.3 7.5±0.31 7.3±0.02 0.45±0.04 0.30±0.15 201±0.02 201±0.07 99.02±0.21 99.12±0.02
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 129
Table 4.12: Thickness & Diameter, Hardness, Friability, Weight variation and Content Uniformity of test tablets (as mentioned in section 3.3.10) expressed as Mean ± SD
Formulation
Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation
(mg) Content Uniformity (%)
FLB DCL-
Na FLB
DCL-Na
FLB DCL-
Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-28 2.0±0.4 2.0±0.4 4.3±0.1 4.3±0.1 6.4±0.11 6.3±0.01 0.12±0.05 0.10±0.01 201±0.1 202±0.02 99.22±0.10 98.93±0.02
F-29 2.0±0.5 2.0±0.5 4.4±0.1 4.1±0.2 6.4±0.42 6.3±0.02 0.43±0.05 0.22±0.22 200±0.2 203±0.06 99.32±0.09 98.94±0.11
F-30 2.0±0.6 2.0±0.6 4.5±0.2 4.2±0.3 6.5±0.21 6.2±0.01 0.32±0.06 0.22±0.01 200±0.3 204±0.04 99.11±0.19 99.05±0.01
F-31 2.1±0.3 2.1±0.3 4.6±0.3 4.1±0.3 6.6±0.52 6.1±0.09 0.22±0.04 0.11±0.02 200±1.3 202±0.04 99.02±0.10 99.06±0.01
F-32 2.2±0.2 2.2±0.2 4.5±0.2 4.1±0.1 7.2±0.81 6.1±0.02 0.23±0.03 0.52±0.02 201±0.2 201±0.03 99.20±0.51 98.97±0.02
F-33 2.0±0.3 2.0±0.3 4.4±0.1 4.2±0.0 7.1±0.42 7.7±0.03 0.22±0.02 0.32±0.04 200±1.3 200±0.03 99.18±0.11 98.98±001
F-34 2.0±0.3 2.0±0.3 4.3±0.3 4.1±0.1 7.2±0.31 6.5±0.13 0.73±0.02 0.33±0.04 200±0.0 201±0.02 98.02±0.21 98.80±0.02
F-35 2.2±0.4 2.2±0.4 4.8±0.4 4.1±0.2 6.3±0.21 6.5±0.20 0.32±0.01 0.43±0.36 202±1.1 201±0.02 98.20±0.02 98.72±0.04
F-36 2.1±0.1 2.1±0.1 4.5±0.2 4.1±0.1 7.4±0.30 6.2±0.02 0.47±0.01 0.35±0.14 201±0.5 201±0.01 99.19±0.03 99.12±0.03
Table 4.13 Thickness & Diameter, Hardness, Friability, Weight variation and Content Uniformity of test tablets (as mentioned in section 3.3.10) expressed as Mean ± SD
Formulation
Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation
(mg) Content Uniformity (%)
FLB DCL-
Na FLB
DCL-Na
FLB DCL-
Na FLB DCL-Na FLB
DCL-Na
FLB DCL-Na
F-37 2.0±0.4 2.0±0.4 4.3±0.1 4.3±0.1 7.4±0.11 7.3±0.10 0.11±0.01 0.11±0.01 200±0.2 200±0.2 99.22±0.02 98.90±0.02
F-38 2.0±0.5 2.0±0.5 4.4±0.1 4.1±0.2 7.3±0.42 7.7±0.20 0.42±0.02 0.42±0.02 200±0.9 200±0.9 99.32±0.01 98.92±0.08
F-39 2.0±0.6 2.0±0.6 4.5±0.2 4.2±0.3 7.9±0.21 8.0±0.09 0.33±0.01 0.33±0.01 200±0.4 200±0.4 99.11±0.12 99.03±0.03
F-40 2.1±0.3 2.1±0.3 4.6±0.3 4.1±0.3 7.3±0.52 7.2±0.03 0.23±0.01 0.23±0.01 200±1.0 200±1.0 99.51±0.09 99.02±0.04
F-41 2.2±0.2 2.2±0.2 4.5±0.2 4.1±0.1 7.4±0.81 7.3±0.06 0.21±0.03 0.21±0.03 201±0.7 201±0.7 99.22±0.00 98.91±0.09
F-42 2.0±0.3 2.0±0.3 4.4±0.1 4.2±0.0 7.4±0.40 7.3±0.09 0.23±0.04 0.23±0.04 200±1.6 200±1.6 99.21±0.02 98.91±0.10
F-43 2.0±0.3 2.0±0.3 4.3±0.3 4.1±0.1 .3±0.31 7.2±0.18 0.72±0.02 0.72±0.02 202±0.2 202±0.2 98.81±0.03 98.82±0.205
F-44 2.2±0.4 2.2±0.4 4.8±0.4 4.1±0.2 6.9±0.22 6.9±0.20 0.32±0.02 0.32±0.02 200±1.2 200±1.2 98.22±0.09 98.73±0.05
F-45 2.1±0.1 2.1±0.1 4.5±0.2 4.1±0.1 6.5±0.31 7.5±0.10 0.42±0.09 0.42±0..09 202±0.8 202±0.8 99.01±0.03 99.13±0.09
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 130
Table 4.14: Thickness & Diameter, Hardness, Friability, Weight variation and Content Uniformity of test tablets (as mentioned in section 3.3.10) expressed as Mean ± SD
Formulation
Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation
(mg) Content Uniformity (%)
FLB DCL-
Na FLB
DCL-Na
FLB DCL-
Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-46 2.0±0.2 2.1±0.2 4.4±0.3 4.1±0.2 6.2±0.12 6.2±0.11 0.11±0.01 0.02±0.01 200±0.2 201±0.01 99.12±0.00 98.90±0.04
F-47 2.1±0.4 2.2±0.4 4.3±0.4 4.3±0.1 6.3±0.43 6.2±0.22 0.42±0.02 0.22±0.22 202±0.9 200±0.02 99.33±0.011 98.9±0.1
F-48 2.1±0.3 2.2±0.3 4.4±0.5 4.4±0.3 6.6±0.24 6.6±0.24 0.33±0.03 0.21±0.03 202±0.4 202±0.03 99.13±0.11 99.01±0.09
F-49 2.1±0.2 2.3±0.2 4.4±0.3 4.4±0.4 6.6±0.55 6.6±0.55 0.20±0.04 0.12±0.02 200±1.0 202±0.03 99.54±0.02 99.04±0.12
F-50 2.1±0.3 2.1±0.3 4.3±0.4 4.8±0.2 7.3±0.85 7.3±0.85 0.23±0.04 0.52±0.01 200±0.7 201±0.03 99.25±0.50 98.95±0.03
F-51 2.2±0.7 2.2±0.3 4.1±0.4 4.4±0.3 7.3±0.43 7.3±0.43 0.22±0.05 0.31±0.02 200±1.6 202±0.08 99.23±0.12 98.96±0.13
F-52 2.2±0.5 2.1±0.1 4.2±0.2 4.6±0.1 7.3±0.32 7.3±0.32 0.71±0.02 0.20±0.02 200±0.2 202±0.02 98.85±0.23 98.86±0.24
F-53 2.1±0.5 2.0±0.4 4.3±0.5 4.4±0.1 6.5±0.21 6.5±0.21 0.32±0.01 0.40±0.32 200±1.2 201±0.04 98.24±0.21 98.77±0.05
F-54 2.1±0.1 2.0±0.3 4.5±0.2 4.0±0.6 7.6±0.32 7.6±0.32 0.41±0.01 0.31±0.12 201±0.8 201±0.03 99.03±0.21 99.14±0.02
Table 4.15: Thickness & Diameter, Hardness, Friability, Weight variation and Content Uniformity of test tablets (as mentioned in section 3.3.10) expressed as Mean ± SD
Formulation
Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation
(mg) Content Uniformity (%)
FLB DCL-
Na FLB
DCL-Na
FLB DCL-
Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-55 2.0±0.7 2.2±0.2 4.4±0.4 4.3±0.5 7.3±0.11 7.6±0.12 0.13±0.03 0.30±0.02 200±0.0 200±0.01 99.22±0.00 98.97±0.01
F-56 2.1±0.3 2.1±0.6 4.0±0.2 4.2±0.4 7.8±0.42 7.8±0.22 0.42±0.05 0.12±0.25 201±0.4 201±0.04 99.32±0.06 98.95±0.10
F-57 2.0±0.2 2.2±0.3 4.2±0.2 4.6±0.2 7.7±0.23 7.3±0.03 0.33±0.06 0.20±0.08 201±0.2 202±0.05 99.11±0.10 99.03±0.10
F-58 2.2±0.9 2.1±0.0 4.2±0.7 4.5±0.3 6.9±0.52 6.8±0.34 0.21±0.05 0.10±0.03 200±1.1 201±0.06 99.16±0.19 99.09±0.10
F-59 2.0±0.1 2.0±0.4 4.8±0.4 4.2±0.1 7.4±0.80 6.9±0.02 0.24±0.04 0.02±0.07 201±0.3 200±0.02 99.20±0.15 98.90±0.05
F-60 2.2±0.5 2.0±0.3 4.0±0.3 4.8±0.6 7.6±0.41 7.3±0.03 0.24±0.05 0.32±0.06 200±1.0 201±0.06 99.22±0.19 98.90±0.11
F-61 2.2±0.6 2.0±0.7 4.5±0.5 4.0±0.9 7.2±0.32 7.3±0.10 0.75±0.03 0.30±0.11 202±0.2 201±0.07 98.08±0.03 98.18±0.20
F-62 2.2±0.9 2.2±0.3 4.2±0.6 4.3±0.1 6.8±0.22 7.4±0.20 0.36±0.04 0.04±0.30 201±1.0 200±0.03 98.02±0.09 98.70±0.01
F-63 2.1±0.3 2.2±0.8 4.0±0.3 4.0±0.0 7.5±0.32 7.2±0.04 0.40±0.04 0.30±0.01 200±0.2 200±0.09 99.09±0.12 99.01±0.01
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 131
Table 4.16 Thickness & Diameter, Hardness, Friability, Weight variation and Content Uniformity of test tablets (as mentioned in section 3.3.10 expressed as Mean ± SD
Formulation
Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation
(mg) Content Uniformity (%)
FLB DCL-
Na FLB
DCL-Na
FLB DCL-
Na FLB DCL-Na FLB DCL-Na FLB DCL-Na
F-64 2.0±0.2 2.0±0.2 4.3±0.1 4.4±0.1 6.4±0.11 6.0±0.10 0.19±0.19 0.30±0.02 201±0.9 201±0.01 99.22±0.01 98.97±0.06
F-65 2.1±0.3 2.2±0.3 4.0±0.1 4.6±0.3 6.2±0.02 6.4±0.20 0.40±0.12 0.20±0.21 202±0.3 200±0.02 99.36±0.09 98.95±0.07
F-66 2.0±0.2 2.1±0.4 4.2±0.2 4.7±0.3 6.8±0.25 6.2±0.06 0.32±0.08 0.20±0.01 203±0.5 202±0.03 99.11±0.12 99.07±0.04
F-67 2.0±0.5 2.2±0.0 4.1±0.3 4.5±0.1 6.4±0.12 6.1±0.30 0.17±0.02 0.19±0.04 201±1.6 202±0.05 99.55±0.03 99.08±0.10
F-68 2.2±0.1 2.2±0.0 4.4±0.2 4.3±0.5 7.2±0.11 6.0±0.12 0.20±0.09 0.24±0.09 200±0.3 201±0.03 99.20±0.01 98.99±0.05
F-69 2.1±0.3 2.0±0.2 4.8±0.1 4.3±0.1 7.6±0.04 7.0±0.09 0.31±0.12 0.32±0.02 200±1.7 202±0.05 99.38±0.10 98.93±0.02
F-70 2.1±0.7 2.1±0.2 4.2±0.3 4.2±0.4 7.2±0.19 6.3±0.10 0.70±0.10 0.09±0.06 200±0.4 201±0.03 98.02±0.20 98.82±0.01
F-71 2.2±0.2 2.1±0.1 4.2±0.4 4.6±0.4 6.3±0.02 6.1±0.20 0.31±0.02 0.41±0.13 200±0.7 202±0.07 98.10±0.21 98.71±0.09
F-72 2.1±0.9 2.2±0.4 4.2±0.5 4.2±0.2 7.1±0.03 6.0±0.12 0.46±0.09 0.30±0.17 200±0.9 200±0.04 99.07±0.20 99.11±0.00
F-73 2.5±0.5 2.1±0.7 4.4±0.6 4.7±0.8 6.9±0.15 6.9±0.10 0.57±0.11 0.39±0.21 201±0.8 200±0.06 99.02±0.22 98.77±0.03
F-74 2.1±0.4 2.2±0.9 4.4±0.7 4.3±0.8 7.0±0.13 6.5±0.16 0.65±0.07 0.55±0.19 202±0.8 200±0.09 99.10±0.15 99.13±0.08
4.13. In-vitro drug release study
In order to achieve nearly a zero order release profiles both in-vitro and in-vivo, different
formulation factors were evaluated including polymer viscosity grades, polymer
concentration, addition ox excipients like HPMC, CMC and Starch etc. For the above said
purpose the test tablets of FLB and DCL-Na model drugs were prepared using Ethocel®
polymer (Viscosity grades 7, 10 & 100 Simple and FP Standard Premium), with drug to
polymer ratios of 10:1, 10:2 & 10:3. Later, the effect of partial addition of excipients like
HPMC, CMC and Starch on release profiles of FLB and DCL-Na drugs was also studied.
4.13.1. Release of Drug from tablets prepared without polymer
The release profiles of FLB and DCL-Na tablets, prepared without polymer, are shown in the
Figure 4.27 and 4.28, respectively. It could be observed that both of the tablets released
maximum amount of drug within an hour. As there was no polymer matrix available to
control the release rate, and at the same time hydrophilic nature of starch release absorbed
water and released maximum amount of drug (Khan and Jiabi, 1998b).
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Figure 4.27: FLB release profiles from matrix tablets prepared without polymer
Figure 4.28: DCL-Na release profiles from matrix tablets prepared without polymer
4.13.2. Effect of Ethocel® Viscosity Grade (Molecular Weight)
As shown in figures 4.29 & 4.30, the granular Ethocel® standard 7 premium released 98.73,
97.45, 94.60 and 99.44, 91.06 & 70.01% FLB and DCL-Na after 24 hrs from the tablets at
D:P ratios of 10:1, 10:2 and 10:3, respectively. On the other hand, Ethocel® standard 7 FP
premium released 98.13, 77.42 & 47.84 FLB and 98.20, 92.26, 48.03% DCL-Na after 8 hrs,
with similar D:P, respectively. The cumulative percentage of the drugs released from
Ethocel® standard 10 premium and 10 FP premium polymers at 10:1, 10:2 and 10:3, were
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found to be 97.51, 86.60, 75.76% and 57.09, 54.03 & 29.73% of FLB, while, 98.28, 91.86,
77.19 and 59.80, 54.01 & 32.51 of DCL-Na after 4 hrs, respectively. Similarly, Ethocel®
standard 100 premium and Ethocel® 100 FP premium polymers released 98.09, 97.47, 79.16
and 66.05, 56.17 & 33.21% FLB, and 98.12, 99.40, 97.44 and 68.63, 58,69 & 35.99 of DCL-
Na, after 4 hrs, respectively, at above mentioned D:P ratios. In case of F-2, DCL-Na drug
release profile showed minor fluctuation after 5th hour which might be due to moisture
absorbance or process variation.
Figure 4.29: FLB release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below)
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Figure 4.30: DCL-Na release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below)
4.13.3. The effect of drug to polymer Ratios (D: P)
Figures 4.29 and 4.30 show the effect of D: P ratio on the cumulative percentage of FLB and
DCL-Na from controlled release matrix tablets in 24 hrs. It could be observed that an increase
in the amount of Ethocel® decreased the drug release rates. This might be attributed to the
strength of the matrix tablets, because the matrix at higher concentration of Ethocel® should
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 135
be expectedly stronger. The kind of matrix would cause a reduction of water penetration
through the micropores and drug diffusion, resulting in slower release rate.
4.13.4. Ethocel® Standard Premium vs. Ethocel® Standard FP Premium
Figures 4.29 and 4.30 also show the comparative release profiles obtained from the tablets
containing Ethocel® standard 7 premium and 7 FP premium, standard 10 premium and 10 FP
premium, and 100 premium and 100 FP premium polymers at three different D:P ratios. It
could be observed that the polymer particle size and polymer concentration had a pronounced
effect on FLB and DCL-Na release rates from all formulations studied.
It was found that the viscosity grade (molecular weight) of Ethocel® ethylcellulose ether
derivative polymer played a vital role in drug release from matrix tablets during dissolution.
The viscosity grades used in the current study included Ethocel® 7, 10 & 100 FP and simple
standard premium. The lower viscosity grades of Ethocel® produced harder tablets than those
of higher viscosity grades, during compression. As hardness also plays a significant role in
drug release kinetics, so in order to separate the hardness effect from the constituent effect,
the tablets were compressed, separately, to hardness level in the range of 6 to 8 kg. With an
increase in viscosity grade and corresponding particle size, a decrease in compressibility was
observed. Tablets with required hardness were achieved with each of the lower viscosity
grade and fine particle size polymer using reduced pressure. The reason quoted is that the
smaller particle size and fragmentation rate of Ethocel® with lower molecular weight
(viscosity grade) are more effective than those with higher molecular weights, regarding the
compressibility of tablets.
The release profiles of FLB and DCL-Na from Ethocel® polymer matrices with different
viscosity grades at various D: P ratios are shown in figures 4.29 & 4.30. It could be observed
that Ethocel® 7 FP showed the slowest release rate and Ethocel® 100 FP and simple standard
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 136
premium the fastest release rate among the formulations evaluated. That might be due to the
fact that tablets containing Ethocel® with higher viscosity grades (granular or coarser form,
with larger particle size and thus higher porosity), might not have produced a matrix with
pores or openings small enough to trap the drug and controlled its release during dissolution.
Moreover, the release profiles show that the influence of viscosity grade on drug release rates
from the formulations containing Ethocel® with intermediate viscosity grades in not
noticeable. It could be due the fact that Ethocel® is water-insoluble and no hydration of
ethycellulose (Ethocel®) occurred during dissolution test, consequently the polymer viscosity
grade had little effect on drug release rates. These results confirmed the findings of (Khan
and Meidan, 2007). However, our results contradict the statement of (Shaikh et al., 1987) that
higher the viscosity grade of ethycellulose polymer the slower the release of drugs from the
tablets. Hence it could be concluded that Ethocel® is the most suitable agent widely used to
design controlled release matrices. This effect might be ascribed to an increase in the extent
of gel formation in the diffusion layer formed by the polymer (Alderman, 1984), with more
toutosity, compressibility, swellability and slow diffusion and erosion. Matrices formulated
with Ethocel® polymer might have formed uniform channels for water to diffuse into the
matrix, to dissolve and to release the drug in controlled manner (Katikaneni et al., 1995). The
overall results are shown in the figures 4.29 and 4.30.
4.13.5. Effect of Partial replacement of HPMC
It could be observed that partial substitution of lactose with 30% HPMC resulted in
somewhat higher release rates both from FLB and DCL-Na controlled release matrix tablets.
The release profiles obtained from directly compressed matrices are shown in the figures 4.31
and 4.32.
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As discussed earlier that Ethocel® Standard 7 Premium and Ethocel® Standard 7 FP released
98.73, 97.45, 94.60 and 99.44, 91.06 & 70.01% FLB and DCL-Na after 24 hrs and 98.73,
97.45, 94.60 and 99.44, 91.06 & 70.01% FLB and DCL after 8 hrs, at D:P ratios of 10:1, 10:2
and 10:3, respectively. After the addition of hydroxypropylmethylcellulose (HPMC) as a co-
excipient, Ethocel® Standard 7 Premium and Ethocel® Standard 7 FP released 98.80, 79.65,
78.23 and 45.40, 25.61 & 16.18% of FLB after 2 hrs, and 99.00, 77.06, 75.72 and 22.34,
19.18 & 14.01% DCL-Na in 1.5 hrs, respectively. A probable reason for this is that the water
soluble HPMC dissolves following water absorption, creating osmotic forces within the
matrices. This confirms, partially, the findings of (Alderman, 1984), (Ford et al., 1987) and
Khan & Zhu (Khan and Zhu, 1998, Khan and Jiabi, 1998b), that small amounts of HPMC can
act as channeling agent, causing higher release rates. Swellability and polymer chain
relaxation of HPMC plays a vital role to sustain the drug release rate (Siepmann and Peppas,
2001). It could be observed that HPMC formed gel layer when it came in contact with water
having a longer diffusional path. It was also suggested that in small quantities HPMC could
act as channeling agent, and enhance the drug release rates from a matrix system (Maggi et
al., 2000, Velasco et al., 1999). Minor fluctuations in case of F-20 and F-23 of FLB and
DCL-Na release profiles might be due to moisture absorbance or process variation.
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Figure 4.31: FLB release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below) with partial replacement of HPMC
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
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Figure 4.32: DCL-Na release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below) with partial replacement of HPMC
4.13.6. Effect of Partial replacement of CMC
The release studies of FLB and DCL-Na from controlled release matrix tablets showed that
the partial replacement of lactose with 30% CMC resulted in somewhat higher release rates.
The drug release profiles obtained from directly compressed matrices are shown in the
figures 4.31 and 4.34. After the addition of carboxymethylcellulose (CMC) as a co-excipient
to Ethocel® standard 7 Premium and Ethocel® standard 7 FP tablets released 99.48, 99.02,
99.90 and 99.17, 99.02 & 99.81% FLB in 2 hrs, and 99.67, 99.80, 98.64 and 99.04, 99.40 &
99.13% DCL-Na in 1.5 hrs, at D:P of 10:1, 10:2 and 10:3, respectively.
Carboxymethylcellulose is water soluble in nature, and when used as co-excipient might
enhance the drug release rate from matrix tablets. This result confirms the findings of Khan &
Zhu (Khan and Jiabi, 1998b) that water-soluble co-excipients can create osmotic forces that
may break up the membranous barrier, resulting in higher release rate. It has been observed
when the concentration of CMC increased, the hydrophillicity of the network also increased,
thereby resulting in enhanced water sorption by the matrix (Bajpai and Mishra, 2005). The
results are presented in figure 4.33 and 4.34.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 140
Figure 4.33: FLB release profiles from matrix tablets containing Eethocel® 7 FP (upper) and
simple standard premium (below) with partial replacement of CMC
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Figure 4.34: DCL-Na release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below) with partial replacement of CMC
4.13.7. Effect of Partial replacement of Starch
Drug release rate from FLB and DCL-Na controlled release matrix tablets was found
somewhat higher when lactose was partially replaced with 30% Starch. Drug release profiles
obtained from directly compressed matrices are shown in the figure 4.35 and 4.36.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 142
Ethocel® standard 7 Premium and Ethocel® standard 7 FP tablets released 35.44% and
15.60% of FLB, while, 37.60% and 16.37% DCL-Na in 2 hours respectively. After the
addition of coexcipient (Starch), Ethocel® standard 7 Premium and Ethocel® standard 7 FP
tablets released 98.89% and 98.99% FLB, while, 98.11% and 98.86% DCL-Na in 2 hours
respectively. Starch is insoluble in water. Insoluble solids may produce non-uniformity of
polymeric membrane around the drug, causing the imperfection of membranes, leading to
quick release of drug from the matrix tablets. Starch is water-swellable and cause rupture of
polymeric membrane causing increase in the release rates of drugs. This result confirms the
findings of (Khan and Jiabi, 1998b, Akhlaq et al., 2011) that the reason for enhancement of
drug release rates could be the water-swellable nature of starch. This property of starch might
rupture the polymeric membrane causing a tremendous increase in the release rates of drug.
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 143
Figure 4.35: FLB release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below) with partial replacement of Starch
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 144
Figure 4.36: DCL-Na release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below) with partial replacement of Starch
4.13.8. Release of Drug from Solid Dispersions Tablets
Solid dispersions of each of FLB and DCL-Na drugs were prepared by solvent evaporation
technique. The main precedence of this technique is thermal decomposition of drugs or
carriers can be prevented because of the relatively low temperatures required for the
evaporation of organic solvents. Solid dispersions is one of the most promising approaches
for solubility enhancement. The development of solid dispersions is considered as a best
technique to enhance the bioavailability of poorly water soluble drugs and to overcome the
limitations of previous approaches such as salt formation, solubalization by cosolvents, and
particle size reduction. It could also be used to prolong the release rate of a hydrophilic drug
from an inert hydrophobic polymer. Ethylcellulose (Ethocel®) has been effectively used to
prepared solid dispersions of various drugs (Huang et al., 2006). Ethylcellulose has also been
used in combination with hydrophilic polymer like hydroxypropylmethylcellulose to prepare
extended release solid dispersions (Ohara et al., 2005). Figure 4.37 and 4.38 show the release
profiles of FLB and DCL-Na solid dispersion in comparison with Ethocel® and without
polymer tablets. The solid dispersions tablets of both FLB and DCL-Na drugs showed a
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prolonged release from the polymer matrix, which extended the drug release rate and released
90% drug up to 24 hrs.
Figure 4.37: FLB release profiles from matrix tablets prepared with Ethocel® polymer and
solid dispersions tablet
Figure 4.38: DCL-Na release profiles of tablets prepared with polymer, without polymer and
solid dispersions tablet
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4.14. Drug release kinetics
Model dependant approaches for data analysis require that model specifications,
characterized by suitable mathematical functions, in order to describe the dissolution data, are
established. Once a mathematical function is selected, the dissolution profiles are evaluated in
terms of the resultant model parameters. Dissolution profiles are generated using a number of
time points, until either 80% of the drug has been released or the dissolution profile reaches
an asymptote. The use of model dependant approaches has been recommended for the
evaluation of dissolution rate profiles, consisting of at least four or more dissolution rate
profiles, consisting of at least four or more dissolution data points and excluding zero. The
model dependant approaches could therefore not be used effectively to evaluate dissolution
data from those formulations which release 80% of the drug in less than 30 minutes resulting
in too few data points being available to perform data modeling.
Mathematical models have been extensively used for the parametric representation of drug
release kinetics from sustained and controlled release matrix tablets. FLB release data was
evaluated by zero-order, first-order and Higuchi models. As the dissolution of controlled
release matrices followed the anomalous (combination of diffusion and erosion) release of
drug so the Higuchi model failed to explain the release behavior, therefore, Korsmeyer
equation was applied to the dissolution of drug from the matrices, which is always used to
describe anomalous the release behavior from the matrices (Abdelkader et al., 2007).
Korsmeyer model describes the release of the drug from matrices while ‘n’ is the release
exponent that actually characterizes the release mechanism of the drug. If n = 0.45, then the
drug release from the polymer matrix is Fickian, and if 0.45 ≤ n ≤ 0.89 then it is non-Fickian.
While 0.98 value of ‘n’ exponent indicates typical zero-order release (Hamid A. Merchant,
2006).
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Tables 4.17-4.34 show the data of the parameters of the above described kinetics models (Eq.
8-12), for FLB and DCL-Na release profiles from the controlled release matrix tablets using
Ethocel® standard premium and Ethocel® standard FP premium polymers of different
viscosity grades., at different D:P ratios. Based on the aforementioned kinetic models, it
could be observed that for Ethocel® standard 7 premium the best linear relation was the
maximum ‘r’ value found when the drug release data was fitted to equation 12. However,
better linear relation at lower Ethocel® level, and the best linear relation at higher levels also
fitted equations 9-11. Moreover, reasonably linear relations were also found to fit equation 8.
In case of Ethocel® standard FP premium polymers the best linear relations fitted, equally to
equations 9-12, with the highest reproducibility (± SD ≤ 0.001 for Eq. 11 and 12). Equation 8
gave acceptably linear relation too. Ethocel® standard 10 premium polymers demonstrated
maximum ‘r’ values when the release data was fitted to equation 11 and 12. On the other
hand, in case of Ethocel® standard 10 FP premium polymers the best linear relation was
found to fit equations 8-12, however, the ‘r’ values were inversely related to the Ethocel®
levels when data was fitted to equation 9 and 10, while direct relation existed between ‘r’
value and Ethocel® levels when equations 11 and 12 were used; fluctuations were found in ‘r’
values in case of equation 1.
Summarizing the kinetic analysis of FLB and DLC-Na release data based on the above
mentioned kinetic models it could be concluded that for all the formulations containing
Ethocel® polymer and also HPMC as co-excipient studied the best linear relation was shown
when the release data as fitted to equations 11 and 12. The release data obtained from the
formulations containing CMC and Starch as co-excipients were not best fitted to any of the
equations, as maximum drug was released with first 2 hrs. However, formulations containing
Ethocel® standard 7 simple and FP premium and all Ethocel® standard FP grades could
demonstrate acceptably linear relation fitting the release data to any of the 5 models. At
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Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 148
higher Ethocel® levels most of the formulations provided with the release data linearly
fittable equations 9-12, while aero-order equation could be nearly satisfied with the release
data from the formulations containing higher levels of Ethocel® standard FP premium
polymers.
Table 4.17: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Flurbiprofen consisting of Ethocel® Standard FP Polymer of different viscosity grades. (Mean ± SD of three determinations)
Table 4.18: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple Polymer of different viscosity grades. (Mean ± SD of three determinations)
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-10 9.195±1.172 0.717 0.427±0.124 0.538 0.450± 0.144 0.639 7.568±0.021 0.717 0.001± 0.001 0.998 0.450
F-11 9.170±1.154 0.789 0.374±0. 087 0.701 0.409± 0.115 0.770 7.694±0.110 0.798 0.001± 0.002 0.986 0.482
F-12 10.041±1.770 0.860 0.275±0.017 0.838 0.305± 0.041 0.871 8.582±0.738 0.860 0.127± 0.412 0.937 0.731
Ethocel® Standard 10 PremiumF-13 8.981±1.020 0.720 0.398±0. 104 0.606 0. 445± 0. 140 0. 673 7.360±0.125 0.720 0.00± 0.0009 0.993 0.416
F-14 9.141±1.133 0.749 0.396±0.103 0.703 0. 435± 0.133 0.741 7.571±0.023 0.749 0.001± 0.001 0.998 0.451
F-15 9.806±1.604 0.821 0.326±0.053 0.749 0.346±0. 070 0.806 8.364±0.584 0.821 0.020± 0.058 0.979 0.643
Ethocel® Standard 100 Premium
F-16 9.399±1.316 0.698 0.453±0. 143 0.570 0. 490± 0. 172 0. 650 7.503±0.024 0.698 0.000± 0.0005 0.989 0.382
F-17 9.408±1.322 0.717 0.471±0.156 0.579 0. 491± 0. 173 0. 669 7.597±0.041 0.717 0.00± 0.0006 0.993 0.402
F-18 9.493±1.382 0.807 0.348±0.069 0.725 0.368±0. 086 0.786 8.111±0.405 0. 807 0.007± 0.018 0.990 0.590
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7FP Premium F-1 8.096±0.395 0.909 0.258±0.005 0.820 0.298± 0.036 0.884 7.360±0.125 0.909 0.005± 0.012 0. 986 0.599
F-2 7.975±0.309 0.978 0.169±0.057 0.822 0.205± 0.028 0.917 7.543±0.003 0.978 0.139± 0.359 0. 967 0.784
F-3 5.137±1.697 0.943 0.088±0.114 0.693 0.121± 0.088 0.803 5.718±1.286 0.943 0.307± 0.643 0. 992 0.793
Ethocel® Standard 10 FP PremiumF-4 7.985±0.316 0.920 0.258±0.005 0.818 0.300±0. 037 0. 883 7.252±0.201 0.920 0.004± 0.007 0.996 0.576
F-5 8.279±0.524 0.928 0.224±0.018 0.828 0.259±0. 009 0. 888 7.573±0.025 0.928 0.030± 0.069 0.995 0.698
F-6 5.780±1.242 0.952 0.120±0.091 0.675 0.151±0. 067 0. 804 6.269±0.896 0.952 0.135± 0.271 0.984 0.785
Ethocel® Standard 100 FP Premium
F-7 8.543±0.710 0.877 0.306±0.039 0.812 0.349±0. 072 0.858 7.449±0.062 0. 877 0.001± 0.002 0.996 0.519
F-8 8.615±0.762 0.923 0.250±0.0003 0.796 0.280±0. 023 0.878 7.786±0.176 0.923 0.021± 0.054 0.968 0.671
F-9 2.403±3.630 0.034 1.250±0.707 0.031 1.183±0.662 0.003 1.567±4.221 0.034 0.00± 1.354 0.671 0.013
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Table 4.19: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Flurbiprofen consisting of Ethocel® Standard FP Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient Starch
Table 4.20: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient Starch
D:P W =k1t
k1±S D r1
(100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7FP Premium F-19 2.924±3.261 0.097 1.133±0.624 0.001 1.110±0.611 0. 008 1.906±3.981 0.097 0.00± 1.060 0.827 0.022
F-20 3.778±2.658 0.182 1.031±0.552 0.029 1.045±0.565 0.077 2.533±3.538 0.182 0.00± 2.533 0.801 0.036
F-21 4.502±2.146 0. 278 0.980±0. 515 0.049 0.992±0. 527 0. 127 3.032±3.186 0.278 0.00± 1.387 0.907 0. 053
Ethocel® Standard 10 FP PremiumF-22 3.023±3.191 0. 114 1.317±0. 754 0.030 1.169±0.652 0.0004 2.031±3.893 0.114 0.00± 1.290 0.706 0. 024
F-23 4.108±2.424 0.215 1.056±0.569 0.032 1.049±0.567 0.091 2.783±3.362 0.215 0.00± 4.839 0.815 0.043
F-24 3.355±2.957 0.169 1.097±0.599 0.012 1.086±0.594 0.054 2.238±3.747 0.169 0.00± 4.337 0.828 0.031
Ethocel® Standard 100 FP Premium
F-25 3.766±2.666 0.240 1.031±0. 552 0.043 1.037±0.559 0.107 2.529±3.541 0.240 0.00± 1.527 0.877 0. 042
F-26 3.066±3.161 0.100 1.113±0.610 0.0005 1.100±0.603 0.011 2.036±3.890 0.100 0.00± 3.028 0.731 0.024
F-27 4.031±2.478 0.152 1.151±0. 643 0.001 1.093±0.599 0.018 2.719±3.407 0.152 0.00± 4.518 0.738 0. 037
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-28 2.847±3.316 0.100 1.236±0.697 0.013 1.153±0.641 0. 001 1.879±4.000 0.100 0.00±6.280 0.754 0.023
F-29 2.607±3.486 0.143 1.071±0.580 0.019 1.090±0.596 0.054 1.719±4.114 0.143 0.00±3.824 0.858 0.022
F-30 3.705±2.709 0.193 1.034±0. 554 0.016 1.042±0.562 0.065 2.469±3.584 0.193 0.00±1.660 0.865 0.037
Ethocel® Standard 10 PremiumF-31 2.076±3.861 0.021 1.154±0.639 0.021 1.142±0.633 0.002 1.315±4.400 0.021 0.00±4.797 0.781 0.010
F-32 3.037±3.182 0.087 1.194±0.667 0.008 1.138±0. 630 0.002 2.014±3.905 0.087 0.00± 1.854 0.713 0.022
F-33 3.245±3.035 0.108 1.112±0. 609 0.0005 1.094±0. 599 0.012 2.159±3.803 0.108 0.00± 5.436 0.733 0.026
Ethocel® Standard 100 Premium
F-34 2.206±3.769 0.033 1.159±0.643 0.14 1.144±0.634 0.0003 1.426±4.321 0.033 0.00±9.790 0.710 0.012
F-35 1.520±4.254 0.002 1.329±0.763 0.064 1.238±0. 701 0.025 0.945±4.661 0.002 0.00±4.50 3 0.717 0.005
F-36 3.471±2.875 0.134 1.225±0. 689 0.009 1.130±0. 625 0.006 2.319±3.689 0.134 0.00± 6.237 0.752 0.031
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 150
Table 4.21: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Flurbiprofen consisting of Ethocel® Standard FP Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient CMC
Table 4.22: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient CMC
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-37 2.837±3.323 0. 063 1.200±0. 671 0.009 1.150± 0. 639 0.0006 1.848±4.022 0.063 0.00± 7.147 0.747 0.019
F-38 1.487±4.278 0. 024 1.295±0.738 0.013 1.226± 0. 693 0.0009 0.920±4.679 0.024 0.00±1.241 0.861 0.007
F-39 2.957±3.238 0. 093 1.277±0. 726 0.018 1.166± 0. 650 0.0005 1.937±3.960 0.093 0.00± 6.803 0.790 0.022
Ethocel® Standard 10 PremiumF-40 2.788±3.358 0. 084 1.173±0.652 0. 003 1.138±0. 630 0.004 1.841±4.027 0. 084 0.00± 6.331 0.760 0.020
F-41 3.274±3.014 0.162 1.013±0.539 0.008 1.023± 0. 555 0.044 2.180±3.788 0.162 0.00± 7.286 0.763 0.035
F-42 1.808±4.050 0. 025 1.333±0. 76 0.042 1.230± 0. 695 0.007 1.151±4.515 0.025 0.00± 2.319 0.740 0.0097
Ethocel® Standard 100 Premium
F-43 2.228±3.754 0. 005 1.243±0. 702 0.068 1.191± 0. 668 0.023 1.44±4.308 0.005 0.00± 1.076 0.547 0. 08
F-44 2.403±3.630 0.034 1.250±0.707 0.031 1.183± 0. 662 0.003 1.567±4.221 0.034 0.00± 1.354 0.671 0.013
F-45 2.284±3.714 0. 013 1.420±0.827 0.090 1.257± 0.714 0.029 1.488±4.278 0.013 0.00±4.545 0.586 0.010
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-46 2.330±3.681 0.023 1.259±0. 713 0.031 1.191± 0. 668 0.005 1.494±4.273 0.023 0. 000±6.994 0. 729 0.011
F-47 2.364±3.658 0.029 1.328±0.762 0.049 1.222± 0.689 0.008 1.549±4.238 0.029 0. 000±7.592 0. 619 0.012
F-48 2.475±3.579 0.066 1.312±0. 751 0.031 1.189± 0. 666 0.001 1.601±4.198 0.066 0. 000± 8.410 0. 743 0.016
Ethocel® Standard 10 PremiumF-49 2.358±3.661 0.041 1.313±0. 751 0.022 1.221±0.689 0.0008 1.553±4.231 0.041 0. 000± 5.339 0.642 0.013
F-50 1.675±4.145 0.007 1.356±0.782 0.143 1.256± 0.714 0.085 1.046±4.590 0.007 0. 000± 2.332 0.512 0.001
F-51 1.569±4.220 0.006 1.450±0.848 0.086 1.278± 0.729 0.033 0.987±4.631 0.006 0. 000± 2.874 0. 715 0.006
Ethocel® Standard 100 Premium
F-52 1.888±3.997 0.0005 1.333±0.765 0.129 1.240± 0.702 0.066 1.201±4.480 0.0005 0. 000±1.240 0.511 0.004
F-53 1.582±4.211 0.009 1.399±0.812 0.171 1.276± 0.728 0.105 0.990±4.629 0.009 0. 000±1.215 0.498 0.001
F-54 2.284±3.714 0.013 1.420±0.827 0.090 1.257± 0.714 0.029 1.488±4.278 0.013 0. 000±4.545 0.586 0.010
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 151
Table 4.23: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Flurbiprofen consisting of Ethocel® Standard FP Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient HPMC
Table 4.24: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple Polymer of different viscosity grades. (Mean ± SD of three determinations) and coexcipient HPMC
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7FP Premium F-55 8.549±0.715 0.857 0.341±0.064 0.873 0.389± 0.1009 0.841 7.265±0.192 0.857 0. 00± 0.0008 0. 998 0.456
F-56 8.055±0.366 0.962 0.185±0.045 0.835 0.219± 0.019 0.910 7.573±0.025 0.962 0.093±0.230 0.971 0.776
F-57 5.979±1.101 0.962 1.118±0.093 0.751 0. 151± 0.066 0.851 6.425±0.786 0.862 0.170±0.370 0.990 0.799
Ethocel® Standard 10 FP PremiumF-58 6.341±0.845 0.953 0.238±0.008 0.830 0.295±0. 034 0.892 6.171±0.966 0. 953 0. 001± 0.001 0.994 0.490
F-59 8.507±0.685 0.920 0.241±0.006 0.859 0.276± 0.021 0.907 7.727±0.133 0.920 0. 020±0.047 0.989 0.677
F-60 6.844±0.490 0.958 0.180±0.049 0.808 0.216± 0.021 0.884 6.839±0.494 0.958 0. 027±0.059 0.992 0.697
Ethocel® Standard 100 FP Premium
F-61 7.663±0.089 0.884 0.316±0.046 0.732 0.358± 0.079 0.812 6.867±0.473 0.884 0.000±0.0009 0.987 0.473
F-62 8.607±0.756 0.887 0.276±0.018 0.832 0.313± 0.047 0.877 7.666±0.090 0.887 0.006±0.013 0.986 0.600
F-63 7.125±0.291 0.953 0.195±0.039 0.788 0.226± 0.014 0.873 7.021±0.265 0.953 0.028±0.064 0.984 0.703
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-64 2.413±3.623 0.176 1.105±0.604 0.017 1.105± 0.607 0.059 1.572±4.218 0.176 0.00±7.089 0.911 0.024
F-65 3.497±2.856 0.714 0.737±0.344 0.523 0.819± 0.404 0.623 2.840±3.322 0.714 0.00±3.122 0.995 0.104
F-66 4.556±2.107 0.741 0.685±0.307 0.566 0.763± 0.365 0.670 3.634±2.760 0.741 0.00±3.769 0.987 0.130
Ethocel® Standard 10 PremiumF-67 2.306±3.698 0.160 1.114±0.610 0.033 1.120±0.618 0.071 1.532±4.247 0.160 0.00±6.906 0.831 0.020
F-68 3.200±4.066 0. 002 0.795±0.385 0.429 0.874± 0.444 0.510 2.494±3.566 0.602 0.00±6.552 0.981 0. 081
F-69 4.160±2.388 0.621 0.789±0.381 0.379 0.846± 0.424 0.504 3.215±3.056 0.621 0.00±5.292 0.996 0.101
Ethocel® Standard 100 Premium
F-70 2.043±3.884 0.044 1.305±0.745 0.020 1.214± 0.684 0.0006 1.308±4.404 0.044 0.00± 7.290 0.796 0.012
F-71 3.523±2.838 0.439 0.919±0.472 0.217 0.961± 0.505 0.306 2.510±3.555 0.439 0.00±1.704 0.994 0.061
F-72 4.013±2.491 0.440 0.900±0.459 0.194 0.940±0.490 0.300 2.858±3.308 0.440 0.00±8.057 0.995 0.068
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 152
Table 4.25: Different kinetic models applied to determine the release profiles of Controlled Release Flurbiprofen 200 mg simple and 100 mg solid dispersions tablets consisting of Ethocel® Standard 7 FP Polymer
Table 4.26: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP Polymer of different viscosity grades. (Mean ± SD of three determinations)
Table 4.27: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium consisting of Ethocel® Standard Simple Polymer of different viscosity grades. (Mean ± SD of three determinations)
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n
k5 ± SD r5 n
F-73 6.030±1.065 0.982 0.128±0.086 0.771 0.176±0.049 0.874 6.101±1.016 0.982 0. 023±0.050 0.974 0.616
F-74 5.161±1.688 0.952 0.099±0.116 0.660 0.130± 0.095 0.805 5.748±1.279 0.949 0.156± 0.333 0.978 0.748
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7FP Premium F-1 8.361±0.582 0.894 0.286±0.025 0.835 0.328± 0.057 0.882 7.419±0.083 0.894 0. 002± 0.005 0.993 0.550
F-2 8.077±0.381 0.976 0.188±0. 043 0.851 0.227± 0.013 0.930 7.557±0.014 0.976 0.056± 0.143 0.961 0.721
F-3 5.159±1.681 0.944 0.096±0.109 0.668 0.131± 0.081 0.792 5.739±1.271 0.944 0.156± 0.327 0.989 0.741
Ethocel® Standard 10 FP PremiumF-4 8.148±0.431 0.915 0.273±0. 016 0.812 0.313±0. 047 0. 883 7.340±0.139 0.915 0.003± 0.006 0.996 0.565
F-5 8.265±0.514 0. 932 0.229±0.014 0.860 0.263±0.011 0.911 7.602±0.045 0.932 0.028± 0.066 0.999 0.695
F-6 5.768±1.250 0.960 0.120±0.091 0.707 0.157±0. 063 0.832 6.117±1.004 0.960 0.101± 0.226 0.984 0.785
Ethocel® Standard 100 FP Premium
F-7 8.597±0.749 0. 876 0.321±0.050 0.812 0.361±0.081 0.863 7.454±0.058 0.876 0.001± 0.002 0.998 0.507
F-8 8.800±0.893 0. 916 0.270±0. 013 0.784 0.294±0.033 0.877 7.894±0.252 0.916 0.017± 0.045 0.961 0.657
F-9 6.846±0.488 0.965 0.165±0.060 0.733 1.194±0.036 0.849 6.953±0.413 0.965 0.053±0.112 0.981 0.740
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-10 9.192±1.169 0.714 0.491±0.170 0.472 0.494± 0.175 0.617 7.516±0.015 0.714 0.000± 0.0006 0. 990 0.407
F-11 9.066±1.081 0.756 0.422±0. 12 1 0.639 0.446± 0.141 0.725 7.588±0.035 0.756 0.001± 0.001 0. 984 0.449
F-12 9.927±1.689 0.839 0.314±0.045 0.754 0.335± 0.063 0.818 8.438±0.636 0.839 0.025± 0.072 0. 974 0.654
Ethocel® Standard 10 PremiumF-13 9.199±1.175 0.713 0.443±0. 136 0.560 0.477± 0.163 0.649 7.458±0.056 0.713 0.00± 0.0007 0.986 0.397
F-14 9.117±1.117 0.752 0.418±0.118 0.650 0. 450± 0.144 0.723 7.528±0.007 0.752 0.00± 0.001 0. 991 0.432
F-15 9.859±1.642 0.814 0.331±0.057 0.737 0.354±0.076 0.794 8.350±0.574 0.814 0.016± 0.047 0. 976 0.623
Ethocel® Standard 100 Premium
F-16 9.436±1.342 0. 693 0.483±0.164 0.529 0.510± 0.186 0.631 7.490±0.033 0.693 0.00± 0.0003 0.992 0.370
F-17 9.408±1.322 0.715 0.496±0.174 0.553 0.504± 0.182 0.662 7.600±0.044 0.715 0.00± 0.0005 0. 994 0.399
F-18 9.530±1.409 0.803 0.368±0.083 0.692 0.380±0. 094 0.770 8.107±0.402 0. 803 0.006± 0.013 0. 996 0.578
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 153
Table 4.28: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient Starch
Table 4.29: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium consisting of Ethocel® Standard Simple Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient Starch
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n
k5 ± SD r5 n
Ethocel® Standard 7 Premium
F-28 2.231±3.752 0.066 1.178±0.656 0.005 1.150±0.638 0.002 1.454±4.301 0.066 0.00±6.365 0.747 0.015
F-29 2.364±3.657 0.107 1.141±0.629 0.004 1.134±0.627 0.027 1.543±4.238 0.107 0.00±3.529 0.837 0.018
F-30 3.573±2.802 0.133 1.094±0. 597 0.0007 1.080±0.589 0.025 2.401±3.362 0.133 0.00±1.578 0.728 0.310
Ethocel® Standard 10 Premium
F-31 2.138±3.817 0.028 1.250±0.706 0.034 1.186±0.664 0.004 1.377±4.356 0.028 0.00±3.506 0.706 0.011
F-32 2.985±3.218 0.719 1.302±0.744 0.032 1.183±0.662 0.0003 1.982±3.928 0.071 0.00±1.184 0.673 0.020
F-33 2.900±3.278 0.102 1.252±0.708 0.010 1.164±0.649 0.003 1.928±3.966 0.102 0.00±7.169 0.735 0.022
Ethocel® Standard 100 Premium
F-34 3.115±3.126 0.086 1.286±0.732 0.018 1.179±0.659 0.0007 2.074±3.863 0.086 0.00±1.571 0.689 0.022
F-35 1.450±4.303 0.001 1.385±0.802 0.106 1.270±0.723 0.059 0.902±4.691 0.001 0.00±2.497 0.633 0.002
F-36 3.346±2.963 0.116 1.263±0.716 0.012 1.156±0. 634 0.004 2.240±3.746 0.116 0.00±3.819 0.718 0.027
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7FP Premium F-19 2.563±3.517 0.117 1.237±0.697 0.001 1.166±0.650 0.011 1.675±4.145 0.117 0.00± 9.696 0.858 0.021
F-20 3.622±2.768 0.186 1.123±0.617 0.014 1.094±0.599 0.062 2.436±3.607 0.186 0.00±8.746 0.805 0.035
F-21 4.078±2.445 0.294 1.006±0. 534 0.074 1.015±0. 544 0.155 2.759±3.379 0. 294 0.00±3.421 0.909 0.049
thocel® Standard 10 FP PremiumF-22 2.708±3.414 0.066 1.309±0. 748 0.031 1.193±0.669 0.0008 1.789±4.065 0.066 0.00±3.418 0.745 0.018
F-23 3.751±2.677 0.165 1.095±0.597 0.008 1.078±0.588 0.048 2.523±3.545 0.165 0.00± 1.883 0.774 0.035
F-24 3.119±3.123 0.187 1.205±0.675 0.003 1.137±0.630 0.064 2.083±3.857 0.187 0.00±8.919 0.848 0.029
zthocel® Standard 100 FP Premium
F-25 3.709±2.706 0.228 1.076±0.584 0.029 1.062±0.577 0.090 2.496±3.565 0.228 0.00±1.072 0.854 0.040
F-26 2.770±3.370 0.098 1.183±0.660 0.004 1.137±0.630 0.005 1.832±4.034 0.098 0.00± 6.032 0.744 0.022
F-27 3.701±2.712 0.152 1.200±0.671 0.002 1.118±0.616 0.016 2.491±3.568 0.152 0.00±1.323 0.749 0.034
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 154
Table 4.30: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient CMC
Table 4.31: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium consisting of Ethocel® Standard Simple Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient CMC
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-37 2.653±3.453 0.064 1.221±0.686 0.012 1.164± 0.649 0.0005 1.750±4.092 0.064 0.00±3.694 0.693 0.017
F-38 2.693±3.425 0. 071 1.273±0.723 0.018 1.184± 0.663 0.0001 1.783±4.069 0.071 0.00±3.305 0.695 0.018
F-39 2.477±3.577 0. 071 1.264±0.716 0.016 1.183± 0.662 0.0002 1.629±4.178 0.071 0.00± 1.191 0.721 0.017
Ethocel® Standard 10 PremiumF-40 2.435±3.607 0.037 1.275±0.724 0.032 1.196±0.671 0.002 1.598±4.200 0.037 0.00±1.315 0.646 0.013
F-41 3.145±3.105 0.155 1.073±0.582 0.003 1.069± 0.581 0.035 2.096±3.847 0.155 0.00± 3.243 0.768 0.031
F-42 1.496±4.271 0.016 1.426±0.831 0.065 1.270± 0.72 4 0.018 0.937±4.667 0.016 0.00±1.181 0.740 0.007
Ethocel® Standard 100 Premium
F-43 2.056±3.875 0. 001 1.388±0.804 0.115 1.258± 0.715 0.049 1.327±4.391 0.001 0.00± 1.868 0.530 0.006
F-44 2.143±3.814 0.012 1.366±0.789 0.074 1.242± 0.704 0.022 1.390±4.346 0.012 0.00±2.427 0.604 0.009
F-45 2.641±3.462 0.051 1.259±0.713 0.024 1.182± 0.661 0.0005 1.741±4.099 0.051 0.00±3.389 0.658 0.016
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-46 2.166±3.798 0.007 1.423±0. 829 0.106 1.265± 0.720 0.040 1.407±4.334 0.007 0.00±2.559 0.558 0.008
F-47 2.364±3.685 0.017 1.426±0.831 0.090 1.253± 0.712 0.027 1.542±4.239 0.017 0.00±6.634 0.601 0.011
F-48 2.167±3.797 0. 025 1.274±0.723 0.035 1.202± 0.675 0.005 1.406±4.335 0.025 0.00± 3.588 0.670 0.011
Ethocel® Standard 10 PremiumF-49 1.477±4.096 0.001 1.376±0.796 0.134 1.258±0.715 0.075 1.104±4.549 0.001 0.00±3.993 0.539 0.003
F-50 1.504±4.266 0.016 1.404±0.813 0.187 1.280± 0.731 0.119 0.936±4.668 0.016 0.00±7.256 0.480 0.0005
F-51 1.221±4.466 0.020 1.463±0.857 0.146 1.304± 0.748 0.103 0.732±4.812 0.020 0.00± 2.171 0.655 9.551
Ethocel® Standard 100 Premium
F-52 1.730±4.106 0.001 1.493±0.878 0.168 1.305± 0.748 0.096 1.100±4.552 0.001 0.00±1.824 0.506 0.003
F-53 1.434±4.315 0.017 1.470±0.862 0.190 1.308± 0.751 0.126 0.887±4.702 0.017 0.00±2.063 0.511 0.0004
F-54 2.093±3.849 0.004 1.464±0.858 0.119 1.281± 0.731 0.050 1.356±4.371 0.004 0.00±1.527 0.549 0.007
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Table 4.32: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP Polymer of different viscosity grades. (Mean ± SD of three determinations) and co-excipient HPMC
Table 4.33: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium consisting of Ethocel® Standard Simple Polymer of different viscosity grades. (Mean ± SD of three determinations) and coexcipient HPMC
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n
k5 ± SD r5 n
Ethocel® Standard 7FP Premium
F-55 8.303±0.541 0.942 0.259±0.006 0.736 0.277± 0.022 0.882 7.616±0.055 0.942 0.013± 0.031 0. 972 0.656
F-56 8.105±0.401 0.972 0.196±0.038 0.876 0.237± 0.006 0.948 7.546±0.005 0.972 0.025±0.058 0.974 0.688
F-57 6.061±1.043 0.959 0.128±0.086 0.739 0.163± 0.059 0.843 6.476±0.750 0.959 0.085±0.172 0.987 0.755
Ethocel® Standard 10 FP Premium
F-58 6.453±0.766 0.954 0.253±0.002 0.805 0.308±0. 034 0.882 6.215±0.935 0.954 0.00± 0.001 0.995 0.476
F-59 8.605±0.754 0.918 0.255±0.003 0.849 0.288±0.029 0.904 7.754±0.153 0.918 0.014±0.033 0.988 0.651
F-60 8.605±0.754 0.918 0.255±0.003 0.849 0.288± 0.029 0.904 7.754±0.153 0.918 0.014±0.033 0.988 0.651
Ethocel® Standard 100 FP Premium
F-61 7.571±0.023 0.884 0.320±0.049 0.749 0.367± 0.085 0.821 6.760±0.549 0.884 0.000±0.0007 0.991 0.455
F-62 8.636±0.777 0.886 0.299±0.034 0.807 0.331± 0.059 0.868 7.672±0.094 0.886 0.004±0.008 0.984 0.577
F-63 7.164±0.264 0.954 0.204±0.032 0.782 0.234± 0.008 0.871 7.035±0.355 0.954 0.022±0.049 0.978 0.685
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n k5 ± SD r5 n
Ethocel® Standard 7 Premium F-64 2.145±3.813 0.075 1.215±0.682 0.005 1.167± 0.651 0.002 1.395±4.343 0.075 0.00±2.572 0.755 0.016
F-65 3.156±3.096 0.651 0.777±0.372 0.465 0.857± 0.432 0.553 2.523±3.546 0.651 0.00±7.973 0.974 0.088
F-66 3.797±2.644 0.653 0.761±0.361 0.403 0.832± 0.414 0.523 2.981±3.221 0.653 0.00±3.230 0.994 0.101
Ethocel® Standard 10 PremiumF-67 2.050±3.879 0.042 1.210±0.678 0.018 1.167±0.651 0.0004 1.322±4.395 0.042 0.00±2.597 0.730 0.012
F-68 3.380±2.939 0.416 0.978±0.514 0.170 1.000±0.533 0.272 2.366±3.656 0.416 0.00±5.154 0.980 0.05
F-69 3.428±2.905 0.535 0.900±0.459 0.326 0.951± 0.498 0.435 2.535±3.537 2.535 0.00±2.087 0.958 0.064
Ethocel® Standard 100 Premium
F-70 2.015±3.905 0.068 1.337±0.768 0.011 1.228± 0.694 0.0004 1.298±4.411 0.068 0.00± 3.632 0.817 0.013
F-71 3.380±2.939 0.416 0.978±0.514 0.170 0.1000± 0.533 0.272 2.366±3.656 0.416 0.00±51.154 0.980 0.055
F-72 3.513±2.845 0.404 0.945±0.491 0.165 0.979±0.518 0.263 2.462±3.588 0.404 0.00±1.154 0.986 0.057
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Table 4.34: Different kinetic models applied to determine the release profiles of Controlled Release matrices of Diclofenac Sodium solid dispersions consisting of Ethocel® Standard 7 FP Polymer
4.15. Testing Polymer hydration or water uptake
Swelling of matrix depends upon the rate of penetration of dissolution medium into the
polymer matrix (Liew et al., 2006). The result of water uptake test is given as the % weight
change as shown in the figures 4.39 and 4.40. The swelling behavior of selected FLB and
DCL-Na formulations, F-1-9 (with Ethocel® viscosity grades 7, 10 & 100, D:P ratio 10:1,
10:2 & 10:3) and F-73 (solid dispersions tablets), containing Ethocel® standard 7 FP
polymers, prepared by direct compression technique, was studied. It could be observed that
the selected matrix tablets absorbed water from the external medium and swelled up. The
figure below characterizes out the study of the effect of Ethocel® polymer on the matrix
swelling. It could be observed that the water uptake by the polymer matrix started from the
placement of the tablet into the dissolution medium (S Kamel et al., 2008) The surface layer
swelled, formed a gel and as a result the tablets increased in size. This hydrated swelled layer,
then, dissolved and eroded slowly and a new layer formed with the exposure of core material
to the dissolution medium. This process continued until the matrix tablet dissolved and
eroded completely (Wan et al., 1993), normally it took 6 hrs of the experiment. During the
first 2 hrs a hysteresis mechanism was observed and the water rapidly entered the matrix
through metastable pores to swell it up (García-González et al., 1993). It could also be
observed that, as Ethocel® is a hydrophobic polymer and the tendency for swellability
declined with presence of a cross-linked polymer structure. The morphological changes of
D:P W =k1t
k1±S D r1 (100-w) =ln100-k2t
k2±SD r2
(100-w)1/3=1001/3-k3t k3±SD r3
W=k4t1/2
k4±SD r4 Mt / M∞=k5 t
n
k5 ± SD r5 n
F-73 6.833±0.497 0.995 0.147±0.072 0.858 0.196±0.035 0.941 6.672±0.611 0.995 0. 028±0.063 0.988 0.653
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swelled matrix tablets captured at various time points are also in good agreement with
swelling behavior of the polymer as shown in the figure 4.41.
Figure 4.39: Plot of % swelling by FLB controlled release tablets as a function of time
Figure 4.40: Plot of % swelling by DCL-Na controlled release tablets as a function of time
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Figure 4.41: Morphology of FLB (A, C, E, and G) and DCL-Na (B, D, F and H) matrix
tablets showing the swelling degree
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4.16. Matrix erosion
The erosion behavior of selected FLB and DCL-Na matrix tablets, F-1-9 (with Ethocel®
viscosity grades 7, 10 & 100, D:P ratio 10:1, 10:2 & 10:3) and F-73 (solid dispersion tablets),
containing Ethocel® standard 7 FP polymers, prepared by direct compression technique, was
studied. The surface layer of the matrix tablets initially hydrated when came in contact with
the dissolution medium to generate and outer viscous gel layer (Sinha Roy and Rohera,
2002). Later matrix bulk hydration, swelling and erosion took place sequentially. It could be
observed that the overall dissolution and release rate of drugs was controlled by the rate of
swelling, diffusion (Colombo et al., 1995) and erosion (Sinha Roy and Rohera, 2002) of the
matrix gel. The result of matrix erosion is shown in the figure 3.39 and 3.40: showing the
amount of polymer eroded and dissolved in the dissolution medium. The selected matrix
tablets containing Ethocel® standard 7 FP polymers, showed a linearity of weight loss and
polymer erosion. It was observed that all the matrix tablets eroded slowly losing about 60%
of their weights after 6 hours, as presented in the figures 4.42 and 4.43.
Figure 4.42: Plot of FLB controlled release matrix erosion
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Figure 4.43: Plot of DCL-Na controlled release matrix erosion
4.17. Testing Dissolution Equivalency
A simple model independent approach that uses a similarity factor, reported by (Shah et al.,
1998), was applied to compare the release profiles both of FLB and DCL-Na test
formulations (F-3) with that of reference tablets (F-3). In general, f 1 up to 15 and f 2 ≥ 50
indicates the similar dissolution profile. For FLB test (F-3) and reference tablets, the
dissimilarity factor (f 1) was found to be 23.88, while the similarity factor (f 2) was found
was found to be 41.44. These results indicate that the dissolution profiles of test and reference
tablets were not similar and were found to be significantly different. For DCL-Na test and
reference formulation the dissimilarity factor (f 1) was found to be 29.87 and the similarity
factor (f 2) 35.21, indicating that there exist significant difference between the two release
profiles, as shown in the figures 4.44 and 4.45.
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Figure 4.44: FLB dissolution equivalency
Figure 4.45: DCL-Na dissolution equivalency
4.18. Effect of aging on the release of FLB and DCL-Na from controlled release matrix tablets.
The effect of six months storage of FLB and DCL-Na selected tablets were studied, at
ambient conditions (temperature 25°C and relative humidity 65%) and accelerated storage
conditions (temperature 40°C and relative humidity 75%). It was observed that the selected
tablets did not reveal any sort of degradation or reduction in the drug contents. All physical
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parameters such as appearance, thickness, diameter, hardness, friability, weight variation,
content uniformity and dissolution profiles were evaluated at 0, 1, 2, 3, 6, 9 and 12 months.
These observations suggested that the physical parameters of FLB and DCL-Na tablets, under
the above said storage conditions, were stable enough to survive the shelf life. Thickness and
diameter ranged from 2.10 ± 0.00 to 2.3 ± 0.3 mm and 4.0 ± 0.4 to 4.8 ± 0.5 mm,
respectively, indicating no significant difference in the average thickness and diameter after
storage both at ambient and accelerated stability conditions. Hardness of FLB and DCL-Na
tablets ranged from 6.6 ± 0.10 to 7.9 ± 0.011 3cmkg , indicating no significant difference
after storage both at ambient and accelerated conditions. Friability ranged from 6.2 ± 0.12 to
8.1 ± 0.02 3cmkg , indicating no significant difference after storage, both for FLB and DCL-
Na test tablets. Weight variation tests for FLB and DCL-Na aged tablets ranged from 200 ±
0.01 to 204 ± 0.04 mg, at ambient and accelerated stability. Content uniformity test both FLB
and DCL-Na aged tablets ranged from 98.05 ± 0.09 to 99.7 ± 0.08%, hence showing no
significant difference after storage. Release profiles of aged FLB and DCL-Na controlled
release matrix tablets shown that FLB stored tablets release FLB ranging from 48.95 to
50.12% and DCL-Na stored tablets release DCL-Na ranging from 50.21 to 51.22%, hence
showing no significant difference was found between the freshly prepared and aged tablets
stored at ambient and accelerated conditions. The observations of FLB and DCL-Na stored
tablet both at ambient and accelerated conditions (0, 1, 2, 3, 6, 9, & 12 months) showed no
significant difference, so the aged tablets were subjected from release studies. The
dissimilarity factor (f 1) for release profiles of FLB and DCL-Na fresh and aged tablets
ranged from 0.010 to 0.190 and 0.011 to 0.020, respectively, while similarity factor (f 2)
ranged from 97.01 to 99.23 and 96.23 to 98.54 for FLB and DCL-Na fresh and aged tablets.
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Hence, it could be evaluated that no significant difference was observed in the release
profiles of both FLB and DCL-Na test tablets, and were found to be similar.
4.19. High performance liquid chromatography (HPLC) method development
4.19.1. Preparation of HPLC analytical method
The system suitability parameters were found to be within acceptable limits. An analytical
run time of 8 min was optimized for each drug sample. The retention time of FLB and DCL-
Na under the experimental conditions were found to be 3.2 and 5.9 min as shown in figures
4.46 & 4.47. According to the ICH guidelines parameters such as precision and accuracy,
limit of detection and limit of quantitation and specificity were estimated and evaluated (ICH,
1996, Shah et al., 1992):
4.19.2. Precision and accuracy
The precisions and accuracy of the method developed both for FLB and DCL-Na drugs were
noted as the relative standard deviation (%RSD) and % recovery of the QC samples, as
shown in tables 4.35 and 4.36. The inter-day and intra-day precisions for the three samples
were found to be between 0.001 to 0.027% and 0.004 to 0.030% for FLB and 0.0005 to
0.0053%, and 0.0002 to 0.0006% for DCL-Na, respectively. These values comply with the
acceptance criteria of the ICH guidelines (Shah et al., 1992).
The purity of FLB and DCL-Na peaks was checked all over the study using a PDA detector
and Agilent ChemStation software through examining the UV spectra at four predetermined
points on the eluted drug peak from beginning to end (Krull and Szulc, 1997, Wiberg et al.,
2004). Figures 4.48 and 4.49 are representative example showing FLB and DCL-Na spectra
acquired during FLB and DCL-Na elution. The examined points were 2 upslope points, a
base point and a down-slope point for purity determination, indicating a single component
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and a pure peak. The calibration curves figures 4.50 and 4.51 showed the best linearity of R2
= 0.9996 and 0.9985 for FLB and DCL-Na respectively.
4.19.3. Limit of detection (LOD) and limit of quantitation (LOQ)
LOD and LOQ were estimated to be 0.173 & 0.578 µg/ml for FLB and 6.634 & 22.114 µg/ml
for DCL-Na, respectively.
4.19.4. Specificity
The calibration curves were linear in the range of 5–50 µg/ml (R2 > 0.9996). Percentage (%)
recovery ± % relative standard deviation (RSD) ranged from 97.07 ± 0.008 to 103.66 ± 0.013
and 98.40 ± 3.84 to 103.53 ± 1.59, for FLB and DCL-Na respectively (Tables 4.37 and 4.38).
Table 4.35: FLB Reverse predicted concentrations, % recovery and regression coefficient
(R2)
Set number Nominal concentration (µg/ml)
R2 Slope Intercept 5 10 15 20 30 50
1 5.19 10.00 14.45 19.91 30.07 50.00 0.9998 0.051 1.000
2 5.16 9.82 14.51 19.56 30.47 50.06 0.9996 0.138 1.004
3 5.18 9.81 15.51 19.41 30.62 50.14 0.9995 0.168 1.006
4 5.20 9.84 14.76 19.71 30.54 49.93 0.9997 0.036 1.001
5 5.17 9.87 14.56 19.46 30.40 50.03 0.9989 0.120 1.002
Mean 5.18 9.87 14.56 19.61 30.42 50.03 0.9996 13.375 6.4988
% RSD 0.013 0.005 0.008 0.001 0.001 0.014
% Recovery 103.6 98.72 97.07 98.07 101.4 100.0
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Table 4.36: DCL-Na Reverse predicted concentrations, % recovery and regression
coefficient (R2)
Set number Nominal concentration (µg/ml)
R2 Slope Intercept 5 10 15 20 30 50
1 5.34 9.68 14.50 19.91 30.95 50.00 0.9984 13.481 9.5682
2 4.95 10.11 14.96 19.43 30.26 49.65 0.9995 13.58 5.127
3 5.07 10.31 15.35 19.77 29.55 50.86 0.9984 13.210 3.0877
4 5.29 10.02 14.48 19.71 29.14 49.80 0.9983 13.324 7.0479
5 5.21 9.77 14.51 20.22 29.22 50.32 0.9975 13.280 7.6631
Mean 5.17 9.98 14.76 19.80 29.83 50.13 0.9996 13.375 6.4988
% RSD 1.59 4.39 3.84 0.73 3.40 0.81
% Recovery 103.53 99.80 98.40 99.00 99.43 100.26
Table 4.37: FLB Precision and accuracy data of the QC samples (Results were expressed as
mean values, n = 5)
Nominal concentration (µg/ml)
Intra-day Inter-day
8 25 45 8 25 45
Mean 7.786 25.432 48.982 8.075 25.388 48.187 % RSD 0.0004 0.0006 0.0003 0.0006 0.0003 0.0020
% Recovery 97.843 101.444 99.873 98.982 100.020 99.982
Table 4.38: DCL-Na Precision and accuracy data of the QC samples (Results were expressed
as mean values, n = 5)
Nominal concentration (µg/ml)
Intra-day Inter-day
8 25 45 8 25 45
Mean 7.668 25.611 44.717 7.926 25.001 44.888 % RSD 0.0006 0.0003 0.0002 0.0005 0.0006 0.0053
% Recovery 95.850 102.444 99.371 99.075 100.004 99.751
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Figure 4.46: FLB Representative HPLC chromatograms for FLB in mobile phase
Figure 4.47: DCL-Na Representative HPLC chromatograms for DCL-Na in mobile phase
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Figure 4.48: UV- absorption spectra of the FLB peak from a standard solution
nm220 240 260 280 300 320 340 360 380
Figure 4.49: UV- absorption spectra of the DCL-Na peak from a standard solution
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Figure 4.50: Mean standard HPLC-Calibration Curve for FLB (n=5)
Figure 4.51: Mean standard HPLC-Calibration Curve for DCL-Na (n=5)
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4.20. In-vivo Studies and Pharmacokinetic analysis
The in-vivo studies of the FLB and DCL-Na test and marketed brands were conducted in
albino rabbits. Rabbit has been chosen as the model, since there have been many
bioavailability studies of NSAIDs using this animal as a model (Fara and Myrback, 1990).
FLB and DCL-Na are rapidly absorbed when given as an oral solution, rectal suppository, or
by intramuscular injection. These are absorbed more slowly when given as enteric-coated
tablets, especially when given with food. The orally administered NSAIDs are reported to be
absorbed almost completely, but subjected to first pass metabolism leading to availability of
about 50% of the drug in the systemic circulation (Heyneman et al., 2000). DCL-Na
penetrates synovial fluid where concentration may persist even when plasma concentrations
fall. Diclofenac sodium has also been detected in the breast milk. The terminal plasma half
life of DCL-Na is about 1 to 2 hours, while that of FLB is 3.3 to 3.4 hours. The usual oral
dose for DCL-Na is 75 to 150 mg daily in individual doses, and that of FLB is 50 to 100 mg
after every six hours, to a maximum total daily dose of 300 mg (MARTINDALE, 1996).
Figures 4.52 and 4.53 are typical chromatograms of standard solutions containing 5 µg/ml
FLB and DCL-Na drugs, rabbit plasma spiked with 10 µg/ml of FLB and DCL-Na. The
rabbit plasma was collected from the blood withdrawn 4-hours after oral administration of
FLB and DCL-Na test tablets. The retention times for FLB and DCL-Na drug were noted to
be 3.2 and 5.9 minutes, respectively. The calculated mean % recovery of FLB and DCL-Na
obtained from six aliquot samples was found to be more than 90% at a concentration range of
0.25-10 µg/ml. The standard curves both for FLB and DCL-Na were found to be linear with
linearity (r2) of 0.999 and 0.9991, as shown in the figures 4.54 and 4.55, respectively.
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Figure 4.52: A representative chromatogram of FLB extracted from rabbit plasma withdrawn
4 hours after oral administration of FLB test tablets
Figure 4.53: A representative chromatogram of DCL-Na extracted from rabbit plasma
withdrawn 4 hours after oral administration of DCL-Na test tablets
Figure 4.54: FLB standard curve in plasma
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Figure 4.55: DCL-Na standard curve in plasma
Figure 4.56 shows the mean plasma concentration versus time profiles of FLB and DCL-Na
test and reference tablets, in-vivo. The pharmacokinetic studies of FLB and DCL-Na test
tablets indicated that the concentration of drugs were observable up to 42 hours, while those
of market brand tablets up to 30 hours. The release data of test tablets of both drugs showed
desired controlled in-vivo release profiles. Pharmacokinetic parameters computed from
plasma level time curve, using a compartmental kinetic approach, are presented in table 4.57.
The extension in half-life (t1/2) and time required achieving maximum concentration (Tmax) of
test formulations of both drugs was observed which was indicative of drug release occurring
at slower rate for prolonged period of time. These findings suggest that the need to take these
drugs in three or four divided doses could be eliminated. The overall pharmacokinetic
parameters of FLB and DCL-Na drugs are discussed separately below. Statistical software
SPSS-14 was used to evaluate the treatment effect of test and reference tablets. The ‘P’ value
obtained by t-test is given with each pharmacokinetic parameter.
The peak plasma concentration (Cmax) for controlled release FLB test formulation was found
to be 237.66 ± 1.98 μg/ml and time to attain the peak concentration (Tmax) was 4.63 ± 0.24
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hrs. Tmax was extended to 4.6 ± 0.24 in test formulation from 3.43 ± 0.05 in commercial
formulation, with a statistical difference of (P<0.05). Area under the curve was found to be
83501.7 ± 2.61 µg.hr/ml, which was approximately 2.5% higher than that observed for
commercial preparation 33563.3±4.21 µg.hr/ml, the statistical difference found was (P<0.01),
indicating two highly different values. Extended Tmax and higher area under the curve in test
formulation is indicative of controlled release of FLB test formulation. This controlled
release was further supported by a higher value of half-life (10.48±0.02 vs. 6.13±0.11 hours,
with P<0.05), lower clearance (0.004 vs. 0.62 ml/min, with highly significant difference
P<0.01). The drug from test formulation persisted longer as indicated by its mean residence
time (MRT) (15.12±1.19 vs. 8.80±1.62 hours, with a significant difference of P<0.05), which
also indicate prolonged stay of drug in the body. Although, continuous release was seen in-
vitro, the minor peak fluctuations in the plasma concentration–time curves were observed.
Controlled release dosage forms capable of steady release of the drug over prolonged periods
may therefore prove beneficial to overcome such variability due to erratic bioavailability of
the drug.
Figure 4.56: Comparative serum concentration-time profiles of FLB test and reference
tablets, following oral administration to rabbit
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The peak plasma concentration (Cmax) for controlled release DCL-Na test formulation was
found to be 123.29±1.22 μg/ml and time to attain the peak concentration (Tmax) was
4.24±0.23 hours. Tmax was extended to 4.24±0.23 in test formulation from 2.93±0.05 in
commercial formulation, indicating a significant difference P<0.05. Area under the curve was
found to be 39900.3±2.52 µg/ml, which was approximately 2.5% higher than that observed
for commercial preparation 6867.55±1.09 µg.hr/ml, with a highest difference of P<0.01.
Extended Tmax and higher area under the curve in test formulation is indicative of controlled
release of FLB test formulation. This controlled release was further supported by a higher
value of half-life (10.22±0.12 vs. 3.29±0.05 hours, with highest difference of P<0.01), lower
clearance (0.111 vs. 0.470 ml/min, with significant difference of P<0.05). The drug from test
formulation persisted longer as indicated by its mean residence time (MRT) (14.71±1.02 vs.
4.69±0.26 hours, with significant difference of P<0.05), which also indicate prolonged stay of
drug in the body. Although, continuous release was seen in-vitro, the minor peak fluctuations
in the plasma concentration–time curves were observed. DCL-Na in vitro in vivo comparison
of two sustained release formulations have been done by investigated by (Su et al., 2003) and
a significant difference was observed in the area under the plasma concentration-time curve
(AUC0-24) and Cmax. Controlled release dosage forms capable of steady release of the drug
over prolonged periods may therefore prove beneficial to overcome such variability due to
erratic bioavailability of the drug. The results are shown in figure 4.57.
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Figure 4.57: Comparative serum concentration-time profiles of DCL-Na test and reference
tablets, following oral administration to rabbit
4.21. In-vitro In-vivo Correlation
The in-vitro release data of FLB test formulation was observed to be related with the in-vivo
parameter, area under the curve, at respective time points. Under the FDA guideline, different
levels of correlations between in-vivo and in-vitro parameters, such as A, B, C, D & E have
been introduced to achieve in-vitro in-vivo correlation (FDA, 1997). To achieve a best in-
vitro in-vivo correlation of FLB test and market tablets, the percent drug released in-vitro (Fr)
was plotted against percent drug absorbed in-vivo (Fa) (Wagner and Nelson, 1964), as shown
in figures 4.58 and 4.59. As indicated by r2 value of 0.9777 for FLB test tablet, the correlation
was found to be high. These results showed that the test formulation was suitable enough to
be used for further therapeutic evaluation. However, the market brand also showed
appropriate correlation, and gave the linearity of R2=0.876.
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 175
Figure 4.58: Percent drug absorbed (Pa) plotted against percent drug released (Pa) to show
in-vitro in-vivo correlation of FLB test formulation
Figure 4.59: Percent drug absorbed (Pa) plotted against percent drug released (Pa) to show
in-vitro in-vivo correlation of FLB market formulation
The in-vitro release data of DCL-Na test formulation was also observed to be related with the
in-vivo parameter area under the curve at respective time points. Under the FDA guideline,
different levels of correlations between in-vivo and in-vitro parameters, such as A, B, C, D &
E have been introduced to achieve in-vitro in-vivo correlation (FDA, 1997). To achieve a best
in-vitro in-vivo correlation of DCL-Na test tablets, the percent drug release in-vitro (Fr) was
plotted against percent drug absorbed in-vivo (Fa) (Wagner and Nelson, 1964), as shown in
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 176
figures 4.58 and 4.59. As indicated by R2 value of 0.9883 for DCL-Na test tablet, the
correlation was found to be high. These results showed that the test formulation was suitable
enough to be used for further therapeutic evaluation. However, the market brand also showed
appropriate correlation, and gave the linearity below 0.850.
Figure 4.60: Percent drug absorbed (Pa) plotted against percent drug released (Pa) to show
in-vitro in-vivo correlation of DCL-Na test formulation
Figure 4.61: Percent drug absorbed (Pa) plotted against percent drug released (Pa) to show
in-vitro in-vivo correlation of DCL-Na market formulation
Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 177
Table 4.57: Various pharmacokinetic parameters determined for 200 mg FLB and 100 mg
DCL-Na controlled release matrix tablets, following oral administration to rabbits
Pharmacokinetic Parameter Calculated for Test Tablets Reference Tablets
Flurbiprofen
Half Life t1/2 (hours) 10.48±0.02 6.13±0.11
Time of maximum plasma concentration Tmax (hours) 4.63±0.24 3.43±1.11
Maximum plasma concentration Cmax (μg/ml) 237.66±1.98 246.24±2.81
Area under the curve AUC0 (μg.hour/ml) 4882.19±3.45 3202.12±3.28
Area under the curve AUC0-inf (μg.hour/ml) 83501.7±2.61 33563.3±4.21
Mean residence time MRT 0-48hrs (hours) 15.12±1.19 8.80±1.62
Clearance (Cl) (ml/min) 0.004±0.02 0.62±0.18
Diclofenac Sodium
Half Life t1/2 (hours) 10.22±0.12 3.29±0.05
Time of maximum plasma concentration Tmax (hours) 4.24±0.23 2.93±0.05
Maximum plasma concentration Cmax (μg/ml) 123.29±1.22 117.89±1.29
Area under the curve AUC0 (μg.hour/ml) 2421.39±2.43 1033.47±2.61
Area under the curve AUC0-inf (μg.hour/ml) 39900.3±2.52 6867.55±1.09
Mean residence time MRT 0-48hrs (hours) 14.71±1.02 4.69±0.26
Clearance (Cl) (ml/min) 0.11±0.03 0.47±0.81
Controlled Release Tablets of Selected NSAIDs Chapter 5….Conclusion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 178
5. CONCLUSION
The controlled release matrix tablets of flurbiprofen and didclofenac sodium were
successfully developed using different grades of Ethocel® polymer and different drug to
polymers ratios. Direct compression technique was used to manufacture the matrix tablets of
model drugs. Ethocel® polymers with lower viscosity grades were more compressible than
their counterparts with higher viscosity grades. Moreover, particle size and concentration of
the polymer, rather than viscosity grades, are found to be the rate determining factors in
controlling the release of FLB and DCL-Na from the matrix tablets. Ethocel® FP polymers
with fine particles extended the release rates of the drugs more efficiently that conventional
granular forms of the Ethocel®. The release mechanism of drugs from the matrix tablets was
found to be changeable, depending mainly on the particle size and amount of the polymer
used. Effect of different co-excipients like starch, CMC and HPMC was also evaluated.
Ethocel® 7 FP polymer with drug to polymer ratio 10:3 showed the most desired pH
independent zero-order release kinetics. It was found that, among the co-excipients, only
HPMC prolonged the release rate up to certain extent, while starch and CMC caused burst
effect and disintegrated the tablet soon after the dissolution run. Swelling and erosion studies
were found to be good in agreement with the drug release mechanism, and it was observed
that polymer concentration, polymer particle size, diffusion, swelling and erosion were the
main factors involved in the drug release mechanism from the matrix tablets. Validation and
method development studies gave the shorter time run and the best linearity both for FLB and
DCL-Na drugs. Single oral doses of 200 mg FLB and 100 mg DCL-Na controlled release test
tablets fairly desired therapeutic serum level-time curves up to 42 hours without fluctuations.
Stable and constant drug absorption and a delayed Tmax values were found, indicating reduced
side effects. The prolonged mean retention time of the single dose of each of FLB and DCL-
Na indicated the use of a single controlled release tablet once-a-day.
Controlled Release Tablets of Selected NSAIDs Chapter 5….Conclusion
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 179
FUTURE PROSPECTS
Rheumatoid arthritis, ankylosing spondilitis, osteoarthritis and soft tissues disorders such as
sprains and strains are wide spread causing physical stability especially in adults. There could
be found a huge market for drugs those relieve pain, swelling and inflammation. Furbiprofen
and Diclofenac Sodium have been found effective and safe drugs for the above mentioned
disorders. Controlled release drug delivery systems of FLB and DCL-Na with the most
suitable and biocompatible excipients, using novel and innovative techniques, would be
recommended to achieve the desired therapeutic response. Human studies would be
conducted to find out the pharmacokinetic parameters and therapeutic inferences of the
prepared tablet in different clinical settings.
Controlled Release Tablets of Selected NSAIDs List of Publications
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 180
LISTOFPUBLICATIONS
1. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, Hamdy Abdelkader, Raid
Alany, Abid Hussain and Nauman Rahim Khan. 2011. Physicochemical
characterization and in-vitro evaluation of flurbiprofen oral controlled release matrix
tablets: Role ether derivative polymer Ethocel®. African Journal of Pharmacy and
Pharmacology, 5(7), 862-873.
2. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, Nauman. Rahim Khan, Abid
Hussain, Waqas Rabbani. 2011. Effect of ether Derivative Cellulose Polymers on
Hydration, Erosion and Release Kinetics of Diclofenac Sodium Matrix Tablets.
Archives of Pharmacy Practice, 2(3), 123-128.
3. Muhammad Akhlaq, Gul. Majid Khan, Abdul Wahab, Abid Hussain, Arshad Khan,
Asif Nawaz and Hamdy Abdelkader. 2011. A Simple High-Performance Liquid
Chromatographic Practical Approach for Determination of Flurbiprofen. Journal of
Advanced Pharmaceutical technology and Research, 2(3), 151-155.
4. Muhammad Akhlaq, Gul Majid Khan, Abdul Wahab, and Asif Nawaz. 2011.
Formulation and in-vitro evaluation of flurbiprofen controlled release matrix tablets
using cellulose derivative polymers. Pakistan Journal of Pharmacy, 21-23(1 & 2), 3-9.
5. Abdul Wahab, Gul Majid Khan, and Muhammad Akhlaq. 2011. Formulation and
Evaluation of Controlled Release Matrices of Ketoprofen and Influence of Different
Co-Excipients on the Release Mechanism. Die Pharmazie, 2011. 66, 677-683.
6. Nauman Rahim Khan, Gul. Majid Khan, Abdul Wahab, Muhammad Akhlaq, and,
Abid Hussain. 2011. Formulation, and Physical, in-vitro and ex-vivo evaluation of
Controlled Release Tablets of Selected NSAIDs List of Publications
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 181
transdermal ibuprofen hydrogels containing turpentine oil as penetration enhancer.
Die Pharmazie. 66, 1-44.
7. Abdul Wahab, Gul Majid Khan, Muhammad Akhlaq and Abid Hussain. 2011.
Innovative Transdermal Dermal Drug Delivery System and Technology: A review of
Current Trends with Futuristic Prospective. Gomal University Journal of Research.
26(2): 25-32.
8. Asif Nawaz, Gul Majid Khan, Muhammad Akhlaq and Abid Hussain. 2011.
Curcumin: A natural product of biological importance. Gomal University Journal of
Research, 27(1), 7-14.
9. Paper presented in IPCE (International Pharmacy Conference and Exhibition) 2011,
Lahore, Abdul Wahab, Muhammad Akhlaq, Nauman Rahim Khan, Abid Hussain,.
and Gul Majid Khan. 2011. Development and evaluation of controlled release
matrices of Ibuprofen using ethylcellulose polymer and investigating the effect of co-
excipients on its release mechanism.
10. Abdul Wahab, Muhammad Akhlaq and Gul Majid Khan. 2011. Pre-formulation
investigation and in-vitro evaluation of directly compressed (Accepted African
Journal of Pharmacy and Pharmacology).
11. Asif Nawaz, Gul Majid Khan, Muhammad Akhlaq, Arshad Khan and Abid Hussain.
2011. Formulation and In-vitro Evaluation of Topically Applied Curcumin Hydrogel.
(Accepted Latin American Journal of Pharmacy).
12. Asif Nawaz, Gul Majid Khan, Muhammad Akhlaq, Arshad Khan, Abid Hussain and
Dayo, A. 2011. Effect of penetration enhancer on in-vitro permeability of Curcumin
patches through rabbit skin. (Submitted AAPS PharmaSciTech).
Controlled Release Tablets of Selected NSAIDs References
Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. 182
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