Design, Formulation and Evaluation of Controlled Release Tablets …prr.hec.gov.pk/jspui/bitstream/123456789/1229/1/2410S.pdf · 2018-07-23 · Design, Formulation and Evaluation

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


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


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


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


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


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


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


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


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


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


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


in-vitro in-vivo correlation of FLB market formulation…………………….175


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


simple standard premium polymer and HPMC……………………………..074


standard premium polymer and CMC………………………………………074


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


Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xvii








Table 4.9: Hardness, Friability, Weight variation, Drug content Thickness and Diameter

of the prepared tablets expressed as Mean ± SD…………………………..127















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


Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xviii


Release matrices of Flurbiprofen consisting of Ethocel® Standard Simple

Polymer. (Mean ± SD of three determinations)…………………………….148



of Different viscosity grades. (Mean ± SD of three determinations) and co-

excipient Starch…………………………………………………..…………149



Polymer of Different viscosity grades. (Mean ± SD of three determinations)

and co-excipient Starch……………………………………………………..149




excipient CMC. …………………………………………………….………150




and co-excipient CMC…………………………………………….………..150




excipient HPMC…………………………………………………………….151




and coexcipient HPMC……………………………………………………..151


Release Flurbiprofen 200 mg simple and 100 mg solid dispersion tablets

consisting of Ethocel® Standard 7 FP Polymer……………………………..152


Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xix


Release matrices of Diclofenac Sodium consisting of Ethocel® Standard FP

Polymer. (Mean ± SD of three determinations) ……………………………152


Release matrices of Diclofenac Sodium consisting of Ethocel® Standard

Simple Polymer of Different viscosity grades. (Mean ± SD of three

determinations) …………………………………………………….……….152




and co-excipient Starch …………………………………………………….153




determinations) and co-excipient Starch……………………………………153




and co-excipient CMC ……………………………………………………..154




determinations) and co-excipient CMC……………………………………154




and co-excipient HPMC…………………………………………………….155


Faculty of Pharmacy, Gomal University, Dera Ismail Khan, KPK, Pakistan. xx




determinations) and coexcipient HPMC……………………………………155


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


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.


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



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



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).



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).



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.



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).



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).



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).



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



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).



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.,



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



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.



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



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



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).



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



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



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



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.



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



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



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.



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



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.,



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).



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



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).



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



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



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).



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.



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



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



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



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



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



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



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.



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.



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



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



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



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



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).



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).



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


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-



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



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.



(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.



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.



(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.



(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.



(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



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.



(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.



(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.



(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



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.



(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



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.



(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


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



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).



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).



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



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.



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.



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.



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



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


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


F-4 10:1 100 10 --- 89 --- 1

F-5 10:2 100 20 --- 79 --- 1

F-6 10:3 100 30 --- 69 --- 1


F-7 10:1 100 10 --- 89 --- 1

F-8 10:2 100 20 --- 79 --- 1

F-9 10:3 100 30 --- 69 --- 1



Table 3.3: Composition of FLB/DCL-Na 100 mg matrix tablets containing Ethocel® simple

standard premium polymer


Lactose Co-

excipients Mg.St.

FP Simple


F-10 10:1 100 --- 10 89 --- 1

F-11 10:2 100 --- 20 79 --- 1

F-12 10:3 100 --- 30 69 --- 1


F-13 10:1 100 --- 10 89 --- 1

F-14 10:2 100 --- 20 79 --- 1

F-15 10:3 100 --- 30 69 --- 1


F-16 10:1 100 --- 10 89 --- 1

F-17 10:2 100 --- 20 79 --- 1

F-18 10:3 100 --- 30 69 --- 1


standard premium polymer and HPMC


Lactose Co-

excipient HPMC

Mg. St. FP Simple


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


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


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




standard premium polymer and HPMC


Lactose Co-

excipient HPMC

Mg. St. FP Simple


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


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


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


standard premium polymer and CMC


Lactose Co-

excipient CMC

Mg. St. FP Simple


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


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




standard premium polymer and CMC


Lactose Co-

excipient CMC

Mg. St. FP Simple


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


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


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


Lactose Co-

excipient Starch

Mg. St. FP Simple


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


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


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



Table 3.9: Composition of each of FLB and DCL-Na 100 mg matrix tablets containing

Ethocel® simple standard premium polymer and Starch


Lactose Co-

excipient Starch

Mg. St. FP Simple


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


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


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 ---



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).



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



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



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



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.



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 ”.



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



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)



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



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



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,



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.



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).



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



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



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.

Controlled Release Tablets of Selected NSAIDs Chapter 4….Results & Discussion


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



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



Figure 4.3: Diclofenac Sodium particle size distribution though laser scattering

Figure 4.4: Ethocel® 7 FP particle size distribution though laser scattering



Figure 4.5: Ethocel® 7 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



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



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.



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



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



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.



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.



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.



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).



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


Formulation

Bulk Density (g/cm3)

Tapped Density (g/cm3) Hausner’s Ratio

Angle of Repose (θ)

Compressibility Index (%)


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




Formulation

Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index

(%)


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


Formulation

Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index (%)


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




Formulation

Bulk Density (g/cm3) Tapped Density (g/cm3) Hausner’s Ratio Angle of Repose (θ) Compressibility Index

(%)


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


Formulation



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




Formulation



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


Formulation



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



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



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,



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



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



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



A B

B



B

C



C

C



D

D



E

E



E

F



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



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)



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.



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.



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



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



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


Formulation

Thickness (mm) Diameter (mm) Hardness (kg) Friability (%) Weight Variation

(mg) Content Uniformity (%)

FLB DCL-

Na FLB

DCL-Na

FLB DCL-


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


Formulation



FLB DCL-

Na FLB

DCL-Na

FLB DCL-


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




Formulation



FLB DCL-

Na FLB

DCL-Na

FLB DCL-


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



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




Formulation



FLB DCL-

Na FLB

DCL-Na

FLB DCL-


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


Formulation



FLB DCL-

Na FLB

DCL-Na

FLB DCL-


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



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



FLB DCL-

Na FLB

DCL-Na

FLB DCL-


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).



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



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)



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



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



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.



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.



Figure 4.31: FLB release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below) with partial replacement of HPMC



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.



Figure 4.33: FLB release profiles from matrix tablets containing Eethocel® 7 FP (upper) and

simple standard premium (below) with partial replacement of CMC



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.



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.



Figure 4.35: FLB release profiles from matrix tablets containing Ethocel® 7 FP (upper) and simple standard premium (below) with partial replacement of Starch



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



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



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).



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



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


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



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


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


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


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


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



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


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


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


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


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



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


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


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


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


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


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



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


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


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


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


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


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



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


n

k5 ± SD r5 n


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


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


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


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



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


n k5 ± SD r5 n


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


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


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


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


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


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



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


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


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


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


n k5 ± SD r5 n


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


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


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



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


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



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



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



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



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.



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



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.



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



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



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



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



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



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)



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.



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



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



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



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.



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.




in-vitro in-vivo correlation of FLB test formulation


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



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.


in-vitro in-vivo correlation of DCL-Na test formulation


in-vitro in-vivo correlation of DCL-Na market formulation



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


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


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


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


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


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