DOMPERIDONE AND I - Pakistan Research Repository

FORMULATION DEVELOPMENT AND IN-VITRO,

IN-VIVO EVALUATION OF FAST DISPERSIBLE

TABLETS OF PROKINETIC AGENTS; DOMPERIDONE

AND ITOPRIDE HCL

PhD Thesis

By AMJAD KHAN

DEPARTMENT OF PHARMACY

UNIVERSITY OF PESHAWAR, PAKISTAN

(2014)

FORMULATION DEVELOPMENT AND IN-VITRO,

IN-VIVO EVALUATION OF FAST DISPERSIBLE

TABLETS OF PROKINETIC AGENTS;

DOMPERIDONE AND ITOPRIDE HCL

AMJAD KHAN

THIS THESIS SUBMITTED TO THE UNIVERSITY OF PESHAWAR IN

PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE

OF DOCTOR OF PHILOSOPHY IN PHARMACY

DEPARTMENT OF PHARMACY

UNIVERSITY OF PESHAWAR, PAKISTAN

DEPARTMENT OF PHARMACY UNIVERSITY OF PESHAWAR

CERTIFICATE OF APPROVAL

It is certified that this thesis entitled “Formulation Development and In-Vitro, In-Vivo Evaluation of Fast Dispersible Tablets of Prokinetic Agents; Domperidone and Itopride HCl” submitted by Mr. Amjad Khan is hereby approved and recommended as partial fulfillment for the award of degree of “Doctor of Philosophy in Pharmacy”.

Meritorious Prof. Dr. Zafar Iqbal _________________ Research supervisor

Associate Prof. Dr. Waqar Ahmad __________________ Chairman Department of Pharmacy University of Malakand

External Examiner

TABLE OF CONTENTS

i

1. Introduction ........................................................................................................................... 1

1.1 Gastro Esophageal Reflux Disease ............................................................................ 1

1.1.1 Pathophysiology of GERD ........................................................................................... 1

1.1.2 Symptoms of GERD ..................................................................................................... 2

1.1.3 Treatment of GERD...................................................................................................... 3

1.2 Prokinetic Agents ........................................................................................................ 3

1.2.1 Mechanism of Action of Prokinetic Agents ................................................................. 4

1.3 Domperidone ............................................................................................................... 6

1.3.1 Physicochemical Properties of Domperidone ........................................................... 6

1.3.2 Chemistry of Domperidone....................................................................................... 6

1.3.3 Pharmacokinetics of Domperidone ........................................................................... 7

1.3.3.1 Dose of Domperidone ........................................................................................... 7

1.3.3.2 Absorption and Bio-availability ............................................................................ 7

1.3.3.3 Distribution............................................................................................................ 7

1.3.3.4 Excretion ............................................................................................................... 7

1.3.3.5 Metabolism ............................................................................................................ 8

1.3.4 Mechanism of Action of Domperidone .................................................................... 8

1.3.5 Indications of Domperidone .................................................................................. 9

1.3.6 Side Effects ........................................................................................................... 9

1.4 Itopride Hydrochloride ............................................................................................ 10

1.4.1 Physicochemical Properties .................................................................................... 10

1.4.2 Chemistry of Itopride HCl ...................................................................................... 10

1.4.3 Pharmacokinetics of Itopride HCl .......................................................................... 11

1.4.3.1 Dose of Itopride HCl ........................................................................................... 11

1.4.3.2 Absorption and Bio availability .......................................................................... 11

TABLE OF CONTENTS

ii

1.4.3.3 Distribution.......................................................................................................... 11

1.4.3.4 Excretion ............................................................................................................. 12

1.4.3.5 Metabolism .......................................................................................................... 12

1.4.4 Mechanism of Action .............................................................................................. 12

1.4.5 Indications ........................................................................................................... 13

1.4.6 Side Effects ......................................................................................................... 13

1.5 Fast Dispersible Tablets ........................................................................................... 14

1.5.1 Orally Disintegrating Tablets .................................................................................. 16

1.5.1.1 Advantages of Orally Disintegrating Tablets ...................................................... 18

1.5.1.2 Problems in Formulation of Orally Disintegrating Tablets ................................ 20

Rapid Disintegration ................................................................................................................ 20 Taste of Active Pharmaceutical Ingredient (API) .................................................................... 21 Physicochemical Properties of Drug ....................................................................................... 21 Mechanical Strength and Porosity of Tablets .......................................................................... 22 Moisture Sensitivity .................................................................................................................. 22

1.5.1.3 Methods of Manufacturing of ODTs ................................................................... 23

Freeze Drying ........................................................................................................................... 23 Molding….….. .......................................................................................................................... 25 Compaction…. .......................................................................................................................... 26 Cotton Candy Process .............................................................................................................. 28 Post Compression Processing .................................................................................................. 29

1.5.2 Effervescent Tablets ................................................................................................ 32

1.5.2.1 Fundamentals of Effervescence Reaction ........................................................... 32

1.5.2.2 Reaction Between Acid and Base to Cause Effervescence ................................. 33

1.5.2.3 Advantages of Effervescent Tablets .................................................................... 35

1.5.2.4 Limitations of Effervescent Tablets .................................................................... 36

1.5.2.5 Preparation of Effervescent Tablets .................................................................... 36

Wet Granulation ....................................................................................................................... 38 Dry Granulation ....................................................................................................................... 39 Direct Compression .................................................................................................................. 39

TABLE OF CONTENTS

iii

1.5.2.6 Compression of Effervescent Tablets ................................................................. 40

1.6 Taste Masking ........................................................................................................... 41

1.6.1 Physiology of Taste................................................................................................. 41

1.6.2 Chemistry of Taste .................................................................................................. 42

1.6.3 Factors to be Considered During Taste Masking Process ...................................... 43

1.6.4 Reduction and Elimination of Bitter Taste ............................................................. 43

1.6.5 Taste Masking Techniques ..................................................................................... 44

1.6.5.1 Addition of Sweeteners and Flavors ................................................................... 45

1.6.5.2 Coating of Drug Particles .................................................................................... 46

1.6.5.3 Micro-encapsulation ............................................................................................ 46

1.6.5.4 Inclusion Complexes ........................................................................................... 48

1.6.5.5 Molecular Complexes of Drug With Other Chemicals ....................................... 49

1.6.5.6 Solid Dispersion .................................................................................................. 49

1.6.5.7 Drug Resin Complexes........................................................................................ 50

1.6.5.8 Formation of Salts or Derivatives ....................................................................... 51

1.7 Aims and Objectives of the Study ........................................................................... 52

1.8 Hypothesis ................................................................................................................. 53

2. Experimental ........................................................................................................................ 54

2.1 Material ..................................................................................................................... 54

2.2 Instrumentation ........................................................................................................ 55

2.3 Study Design .............................................................................................................. 57

2.4 Pre Formulation Studies .......................................................................................... 61

2.4.1 Drug Excipients Compatibility ............................................................................... 61

2.4.1.1 Sample Preparation ............................................................................................. 61

2.4.1.2 Determination of Drug Content ........................................................................... 63

TABLE OF CONTENTS

iv

2.4.1.3 FTIR Spectra ....................................................................................................... 64

2.4.1.4 Evaluation of Physical Consistency of Samples ................................................. 64

2.4.2 Characterization of Drugs and Excipients using SeDeM and SeDeM-ODT Experts

System….. ............................................................................................................................... 65

2.4.2.1 Determination of Basic Parameters ..................................................................... 65

2.4.2.2 Conversion of Experimental Values to “r” Values ............................................. 72

2.4.2.3 Graphical Presentation of SeDeM/ SeDeM-ODT Results .................................. 74

2.4.2.4 Calculation of Index of Good Compressibility and Bucco Dipersibility ............ 75

2.4.3 Development and Validation of U.V Visible Spectrophotometric Method of

Analysis…............................................................................................................................... 77

2.4.3.1 Preparation of Stock Solution ............................................................................. 77

2.4.3.2 Selection of Wavelength of Maximum Absorbance (λ max) ................................ 77

2.4.3.3 Validation of UV Visible Spectrophotometric Method of Analysis ................... 78

Specificity and Selectivity of the Method ................................................................................... 78 Precision of the Method ............................................................................................................. 78 Linearity of the Method .............................................................................................................. 79 Stability of Solutions .................................................................................................................. 79

2.4.4 Development and Validation of HPLC/UV Method of Analysis for Simultaneous

Determination of Domperidone and Itopride HCl .................................................................. 80

2.4.4.1 Preparation of Stock Solution ............................................................................. 80

2.4.4.2 Sample Preparation ............................................................................................. 80

Plasma Sample ......................................................................................................................... 80 Liquid-liquid Extraction ........................................................................................................... 81

2.4.4.3 Optimization of Chromatographic Condition ..................................................... 83

Selection of Stationery Phase ................................................................................................... 83 Selection of Mobile Phase ........................................................................................................ 83 Selection of Mobile Phase Flow Rate ....................................................................................... 84 Selection of Column Oven Temperature .................................................................................. 84 Selection of Detector Wavelength ............................................................................................ 84 Selection of Internal Standard (I.S.) ......................................................................................... 85

TABLE OF CONTENTS

v

2.4.4.4 Validation of the HPLC-UV Method of Analysis ............................................... 85

Specificity / Selectivity .............................................................................................................. 85 Accuracy of the Method ............................................................................................................ 86 Sensitivity of Method ................................................................................................................ 86 Linearity of Method .................................................................................................................. 87 Precision of the Method ........................................................................................................... 87 Stability of Solutions ................................................................................................................. 89 Statistical Interpretation and Correlation of Data ................................................................... 89

2.5 Taste Masking of Itopride HCl................................................................................ 90

2.5.1 Determination of Taste Threshold of Itopride HCl ................................................. 90

2.5.2 Taste Masking Techniques ..................................................................................... 91

2.5.2.1 Taste Masking of Itopride HCl by Granulation Technique ................................. 91

2.5.2.2 Taste Masking of Itopride HCl by Micro Encapsulation .................................... 93

2.5.2.3 Taste Masking of Itopride HCl by Solid Dispersion ........................................... 96

2.5.3 Taste Evaluation of Taste Masked Itopride Hydrochloride .................................. 100

2.5.3.1 Taste Evaluation by Spectrophotometric Method ............................................. 100

2.5.3.2 Taste Evaluation by Human Subjects (Panel Testing) ...................................... 100

2.6 Preliminary Study................................................................................................... 102

2.6.1 Determination of Per Tablet Quantity of Taste Making Agents in Orally

Disintegrating Tablets….. ..................................................................................................... 102

2.6.2 Determination of Per Tablet Quantity of Taste Making Agent in Effervescent

Tablets…….. ......................................................................................................................... 103

2.6.3 Pulverization of Acid Moieties and Surface Passivation of Sodium Bicarbonate 105

2.6.4 Selection of Acid to Base Ratio for Effervescence Reaction ............................... 105

2.6.5 Determination of Per Tablet Quantity of Effervescent Pair .................................. 106

2.7 Preparation of Powder Blend ................................................................................ 107

2.8 Tablet Preparation ................................................................................................. 109

TABLE OF CONTENTS

vi

2.8.1 Preparation of Orally Disintegrating Tablets of Domperidone using Super

Disintegrants….. ................................................................................................................... 109

2.8.2 Preparation of Orally Disintegrating Tablets of Domperidone by Sublimation

Technique…. ......................................................................................................................... 110

2.8.3 Preparation of Effervescent Tablets of Domperidone .......................................... 112

2.8.4 Preparation of Orally Disintegrating Tablets of Itopride HCl using Super

Disintegrants ......................................................................................................................... 114

2.8.5 Preparation of Orally Disintegrating Tablets of Itopride HCl by Sublimation

Technique .............................................................................................................................. 115

2.8.6 Preparation of Effervescent Tablets of Itopride HCl ............................................ 117

2.9 In vitro Evaluation .................................................................................................. 119

2.9.1 Pre Compression Evaluation (Powder Blend Evaluation) .................................... 119

2.9.2 Post Compression Evaluation ............................................................................... 120

2.9.2.1 Physical Parameters of Tablets ......................................................................... 120

Thickness of the Tablets ......................................................................................................... 120 Weight Variation of Tablets ................................................................................................... 120 Wetting Time of Tablets .......................................................................................................... 121 Mouth Feel of Tablets ............................................................................................................. 121 Drug Content of Tablets ......................................................................................................... 122

2.9.2.2 Mechanical Properties of Tablets ...................................................................... 123

Crushing Strength of Tablets .................................................................................................. 123 Tensile Strength of Tablets ..................................................................................................... 123 Specific Crushing Strength of Tablets .................................................................................... 124 Friability of Tablets ................................................................................................................ 124

2.9.2.3 Disintegration Behavior of Tablets ................................................................... 125

Disintegration Time ................................................................................................................ 125 Oral Disintegration Time ....................................................................................................... 125 Effervescence Time of Tablets ................................................................................................ 126

2.9.2.4 In vitro Drug Release (Dissolution Rate) .......................................................... 126

2.9.3 Parametric Study ................................................................................................... 128

2.9.3.1 Moisture Treatments of Orally Disintegrating Tablets ..................................... 128

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vii

2.9.3.2 Compression Force Profile of Orally Disintegrating Tablets ............................ 128

2.9.3.3 Study of Effect of Different Parameters on Rate of Effervescence Reaction ... 129

Effect of Tablet Dimension on Effervescence Time ................................................................ 129 Effect of Disintegrants on Effervescence Time ....................................................................... 130 Effect of Tablet Compressibility on Effervescence Time ........................................................ 130

2.9.4 In vivo Evaluation of Optimal Formulations of Fast Dispersible Tablets ............ 131

2.9.4.1 Pharmacokinetic Evaluation of Fast Dispersible Tablets .................................. 131

Study Design for Pharmacokinetic Evaluation of Fast Dispersible Tablets .......................... 131 Animal Handling .................................................................................................................... 132 Drug Administration ............................................................................................................... 132 Blood Sampling ...................................................................................................................... 133 Analysis of Blood Samples ..................................................................................................... 133 Determination of Pharmacokinetic Parameters ..................................................................... 133

2.9.4.2 Clinical Evaluation ............................................................................................ 134

Patients Inclusion Criteria ..................................................................................................... 134 Patients Exclusion Criteria .................................................................................................... 134 Drug Administration ............................................................................................................... 135 Patient’s Response Evaluation ............................................................................................... 137 Statistical Analysis ................................................................................................................. 140

3. Results and Discussion ...................................................................................................... 141

3.1 Drug Excipients Compatibility .............................................................................. 141

3.1.1 Drug Excipients Compatibility of Domperidone .................................................. 142

3.1.1.1 Domperidone Content ....................................................................................... 142

3.1.1.2 Evaluation of Infra Red Spectra ........................................................................ 144

3.1.1.3 Physical Consistency of Samples ...................................................................... 145

3.1.2 Study of Itopride HCl Excipients Compatibility .................................................. 145

3.1.2.1 Itopride HCl Content ......................................................................................... 145

3.1.2.2 Evaluation of Infra Red Spectra ........................................................................ 148

3.1.2.3 Physical Consistency of the Samples ................................................................ 149

TABLE OF CONTENTS

viii

3.2 Characterization of Drug and Excipients According to SeDeM-ODT Experts

System... ................................................................................................................................. 150

3.2.1 Characterization of APIs as per SeDeM-ODT Experts System ............................ 150

3.2.1.1 Characterization of Domperidone as per SeDeM-ODT Experts System .......... 150

3.2.1.2 Characterization of Itopride HCl as per SeDeM-ODT Experts System ............ 153

3.2.1.3 Characterization of Taste Masked Itopride HCl as per SeDeM-ODT Experts

System…… ........................................................................................................................ 154

3.2.2 Characterization of Excipients as per SeDeM-ODT Experts System ................... 156

3.2.2.1 Characterization of Diluents .............................................................................. 157

3.2.2.2 Characterization of Disintegrants ...................................................................... 158

3.2.2.3 Characterization of Effervescent Excipients ..................................................... 162

3.3 Development and Validation of U.V. Visible Spectrophotometric Method of

Analysis for Domperidone ................................................................................................... 165

3.3.1 Preparation of Solutions ........................................................................................ 165

3.3.1.1 Preparation of Stock solution ................................................................................ 165

3.3.1.2 Preparation of Dilutions ........................................................................................ 165

3.3.2 Selection of Wavelength of Maximum Absorbance (λmax) ................................... 165

3.3.3 Validation of UV Visible Spectrophotometric Method of Analysis of

Domperidone......................................................................................................................... 166

3.3.3.1 Linearity ............................................................................................................ 167

3.3.3.2 Stability of Solution .......................................................................................... 168

3.3.3.3 Specificity and Selectivity ................................................................................. 168

3.3.3.4 Precision of the Method .................................................................................... 168

3.4 Development and Validation of U.V. Visible Spectrophotometric Method of

Analysis for Itopride HCl ....................................................................................................... 170

3.4.1 Preparation of Solutions ........................................................................................ 170

TABLE OF CONTENTS

ix

3.4.1.1 Preparation of Stock Solution ............................................................................... 170

3.4.1.2 Preparation of Dilutions ........................................................................................ 170

3.4.2 Selection of Wavelength of Maximum Absorbance (λmax) ................................... 170

3.4.3 Validation of UV Visible Spectrophotometric Method of Analysis of Itopride

HCl…….. .............................................................................................................................. 171

3.4.3.1 Linearity of the Method ..................................................................................... 171

3.4.3.2 Stability of Solution .......................................................................................... 173

3.4.3.3 Specificity and Selectivity ................................................................................. 173

3.4.3.4 Precision ............................................................................................................ 173

3.5 Development and Validation of HPLC-UV Method for Simultaneous Analysis

of Domperidone and Itopride HCl .................................................................................... 175

3.5.1 Solution Preparation .......................................................................................... 175

3.5.2 Extraction Solvent Selection ............................................................................. 175

3.5.3 Optimization of Experimental Conditions ........................................................ 176

3.5.3.1 Selection of Stationery Phase ............................................................................ 176

3.5.3.2 Selection of Mobile Phase ................................................................................. 177

3.5.3.3 Selection of Mobile Phase Flow Rate ............................................................... 179

3.5.3.4 Selection of Column Oven Temperature ........................................................... 180

3.5.3.5 Selection of pH of Mobile Phase ....................................................................... 181

3.5.3.6 Selection of Detector Wavelength ..................................................................... 182

3.5.3.7 Selection of Internal Standard ........................................................................... 183

3.5.4 Validation of the HPLC-UV Method of Analysis ............................................. 183

3.5.4.1 Linearity of The Method ................................................................................... 185

3.5.4.2 Accuracy of the Method .................................................................................... 186

3.5.4.3 Precision of the Method .................................................................................... 186

3.5.4.4 Stability of Solutions ......................................................................................... 187

TABLE OF CONTENTS

x

3.5.4.5 Sensitivity of the Method .................................................................................. 188

3.6 Preliminary Study................................................................................................... 189

3.6.1 Determination of Quantity of Taste Making Agents per Tablet in ODTs ............ 189

3.6.2 Determination of Quantity of Taste Making Agent per Tablet in Effervescent

Tablets.… .............................................................................................................................. 191

3.6.3 Selection of Acid to Base Ratio of Effervescent Tablets ...................................... 192

3.6.4 Determination of Quantity of Effervescent Pair per Tablet .................................. 193

3.7 Taste Masking of Itopride HCl.............................................................................. 194

3.7.1 Determination of Taste Threshold of Itopride HCl ............................................... 194

3.7.2 Taste Masking of Itopride HCl by Granulation Technique .................................. 195

3.7.3 Taste Masking of Itopride HCl by Solid Dispersion Technique ........................... 199

3.7.3.1 Solid Dispersions of Itopride HCl Prepared with Poly Ethylene Glycol .......... 199

3.7.3.2 Preparation of Solid Dispersions of Itopride HCl Using Cetostearyl Alcohol . 202

3.7.3.3 Solid Dispersions of Itopride HCl Prepared Using HPMC and PVP ................ 204

3.7.4 Taste Masking of Itopride HCl by Microencapsulation Technique ...................... 206

3.8 In-vitro Evaluation of the Fast Dispersible Tablets ............................................ 210

3.8.1 Pre Compression Evaluation ................................................................................. 210

3.8.1.1 Pre Compression Evaluation of ODTs of Domperidone Prepared using Super

Disintegrant ........................................................................................................................ 210

3.8.1.2 Pre Compression Evaluation of ODTs of Domperidone Prepared by Sublimation

Technique ........................................................................................................................... 212

3.8.1.3 Pre Compression Evaluation of Effervescent Formulations of Domperidone .. 214

3.8.1.4 Pre Compression Evaluation of ODTs Formulations of Itopride HCl Prepared

using Super Disintegrants .................................................................................................. 216

3.8.1.5 Pre Compression Evaluation of ODTs of Itopride HCl Prepared by Sublimation

Technique ........................................................................................................................... 217

TABLE OF CONTENTS

xi

3.5.1.1 Pre Compression Evaluation of Effervescent Formulations of Itopride HCl .... 220

3.8.2 Tablet Evaluation .................................................................................................. 222

3.8.2.1 Tablets Evaluation of ODTs of Domperidone Prepared using Super

Disintegrants… .................................................................................................................. 222

Physical Characteristics of ODTs of Domperidone Prepared using Super Disintegrants ..... 222 Mechanical Strength of ODTs of Domperidone Prepared using Super Disintegrants ........... 224 Disintegration Behavior of ODTs of Domperidone Prepared using Super Disintegrants ...... 225 In-vitro Drug Release from ODTs of Domperidone Prepared using Super Disintegrants ..... 226

3.8.2.2 Post Compression Evaluation of ODTs of Domperidone Prepared by

Sublimation Technique ...................................................................................................... 228

Sublimation of Sublimating Agents from ODTs of Domperidone Prepared by Sublimation Technique…… .......................................................................................................................... 228 Physical Characteristics of ODTs of Domperidone Prepared by Sublimation Technique ..... 232 Mechanical Strength of ODTs of Domperidone Prepared by Sublimation Technique ........... 233 Disintegration Behavior of ODTs of Domperidone Prepared by Sublimation Technique ...... 236 In-vitro Drug Release From Orally Disintegrating Tablets of Domperidone Prepared by Sublimation Technique…… ..................................................................................................... 240

3.8.2.3 Evaluation of Effervescent Tablets of Domperidone ........................................ 243

Physical Characteristics of Effervescent Tablets of Domperidone ......................................... 243 Mechanical Strength of Effervescent Tablets of Domperidone ............................................... 244 Disintegration Behavior of Effervescent Tablets of Domperidone .......................................... 246

3.8.2.4 Tablet Evaluation of ODTs of Itopride HCl Prepared using Super

Disintegrants… .................................................................................................................. 248

Physical Characteristics of ODTs of Itopride HCl Prepared using Super Disintegrants ....... 248 Mechanical Strength of ODTs of Itopride HCl Prepared using Super Disintegrants ............. 249 Disintegration Behavior of ODTs of Itopride HCl Prepared using Super Disintegrants ....... 250 In-vitro Drug Release from ODTs of Itopride HCl prepared using Super Disintegrants ........ 251

3.8.2.5 Tablet Evaluation of ODTs of Itopride HCl Prepared by Sublimation

Technique….. ..................................................................................................................... 253

Sublimation of Sublimating Agents from ODTs of Itopride HCl ............................................. 253 Physical Characteristics of ODTs of Itopride HCl Prepared by Sublimation Technique ....... 256 Mechanical Strength of ODTs of Itopride HCl Prepared by Sublimation Technique ............. 257 Disintegration Behavior of ODTs of Itopride HCl Prepared by Sublimation Technique ....... 259 In-vitro Drug Release of ODTs of Itopride HCl Prepared by Sublimation Technique ........... 260

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xii

3.8.2.6 Evaluation of Effervescent Tablets of Itopride HCl .......................................... 262

Physical Characteristics of Effervescent Tablets of Itopride HCl ........................................... 262 Mechanical Strength of Effervescent Tablets of Itopride HCl ................................................. 263 Disintegration Behavior of Effervescent Tablets of Itopride HCl ........................................... 265

3.9 Selection of Optimal Formulations ....................................................................... 267

3.10 Parametric Study .................................................................................................... 270

3.10.1 Orally Disintegrating Tablets ................................................................................ 270

3.10.1.1 Moisture Treatment of ODTs ............................................................................ 270

3.10.1.2 Compression Force Profile of ODTs ................................................................. 273

3.10.2 Effect of Various Parameters on Effervescence Reaction .................................... 274

3.10.2.1 Effect of Surface Area of the Tablet ................................................................. 274

3.10.2.2 Effect of Disintegrants on Effervescence Time ................................................ 279

3.10.2.3 Effect of Tablet Compressibility on Effervescence Reaction ........................... 279

3.11 In-vivo Evaluation ................................................................................................... 281

3.11.1 Pharmacokinetic Evaluation ................................................................................. 281

3.11.1.1 Pharmacokinetic Evaluation of Fast Dispersible Tablets of Domperidone .......... 281

3.11.1.2 Pharmacokinetic Evaluation of Fast Dispersible Tablets of Itopride HCl ............ 283

3.11.2 Clinical Evaluation of Orally Disintegrating Tablets of Domperidone ................ 286

3.11.2.1 Patients Acceptance and Onset of Action ......................................................... 286

3.11.2.2 Evaluation of Emesis Control ........................................................................... 288

Complete Emesis Control ....................................................................................................... 289 Major Emesis Control ............................................................................................................ 290 Partial Emesis Control ........................................................................................................... 291 Treatment Failure ................................................................................................................... 291

3.11.2.3 Nausea Control .................................................................................................. 293

3.11.2.4 Conclusion of Clinical Trials ............................................................................ 295

4. Conclusion .......................................................................................................................... 296

5. References........................................................................................................................... 299

xiii

DEDICATED

To My Father

Ghulam Nabi,

A strong support for me throughout my life

LIST OF TABLES

xiv

Table 1.1: List of Marketed Orally Disintegrating Tablets

Table-1.2: Limitations of Various Methods of Manufacturing of ODTs

Table-2.1: Composition of Samples Used for Drug Excipients Compatibility

Table-2.2: Basic Parameters, Limits and Applied Factors of SeDeM-ODT Experts System

Table-2.3: Formulation of Taste Masked Itopride HCl Prepared by Granulation Technique

Table-2.4: Composition of Taste Masked Itopride HCl Prepared by Microencapsulation

Technique

Table-2.5: Composition of Taste Masked Itopride HCl Prepared by Solid Dispersion Technique

Table-2.6: Formulation of Placebo Tablets for Determination of Quantity of Taste Making

Agents in Orally Disintegrating Tablets

Table-2.7: Composition of Placebo Tablets for Determination of Quantity of Taste Making

Agents in Effervescent Tablets

Table-2.8: Formulation of Orally Disintegrating Tablets of Domperidone Prepared using Super

Disintegrant

Table–2.9: Formulation of Orally Disintegrating Tablets of Domperidone Prepared by

Sublimation Technique

Table-2.10: Formulations of Effervescent Tablets of Domperidone

Table-2.11: Formulation of Orally Disintegrating Tablets of Itopride HCl Prepared using Super

Disintegrant

Table-2.12: Formulations of Orally Disintegrating Tablets of Itopride HCl Prepared by


Table-2.13: Formulations of Effervescent Tablets of Itopride HCl

Table-2.14: Schedule for Administration of Test Products to the Patients for Anti Emetic

Response Evaluation

LIST OF TABLES

xv

Table-2.15: Questionnaire to be completed by the Patient after Two Day Study

Table-2.16: Daily Diary Card for Patient to Record Number of Emetic Episodes and Nausea

Table-3.1: Results of Compatibility Study of Domperidone

Table-3.2: Result of Compatibility Study of Itopride HCl with Excipients Used in Formulation

of Fast Dispersible Tablets (ODTs and Effervescent Tablet)

Table-3.3: Results of Compatibility Study of Itopride HCl with Excipients Used for Taste

Masking

Table-3.4: The “r” Values of APIs Calculated as per SeDeM-ODT Experts System

Table-3.5: Mean Incidence Factor of APIs Calculated on the Basis of SeDeM-ODT Experts

System

Table-3.6: Various Indices for APIs Calculated on the Basis of SeDeM/SeDeM-ODT Experts

System

Table-3.7: The “r” Values of Excipients Calculated as per SeDeM-ODT Experts System

Table-3.8: Mean Incidence Factors of Excipients Calculated on the Basis SeDeM-ODT Experts

System

Table-3.9: Various Indices for Excipients as per SeDeM-ODT Expert System

Table-3.10: Validation Parameters of UV Visible Spectrophotmetric Method of Analysis of

Domperidone

Table-3.11: Intra Day and Inter Day studies of UV Visible Spectrophotmetric Method of

Analysis of Domperidone

Table-3.12: Validation Parameters of UV Visible Spectrophotometric Method of Analysis of

Itopride HCl

Table-3.13: Intra Day and Inter Day studies of UV Visible Spectrophotmetric Method of

Analysis of Itopride HCl

LIST OF TABLES

xvi

Table-3.14: Percent Recovery of Domperidone and Itopride HCl from Human Plasma with

Different Extraction Solvents

Table-3.15: Various Parameters of HPLC Column used for Analysis of Domperidone and

Itopride HCl

Table-3.16: Separation of Domperidone and Itopride HCl using Various Solvents in Different

Ratios as a Mobile phase

Table-3.17: Validation Parameters of HPLC-UV Method of Analysis of Domperidone and

Itopride HCl

Table-3.18: Inter day and Intra Day Studies

Table-3.19: Volunteers Response about Taste of Placebo Tablets Containing Different

Quantities of Taste Making Agents (Sweetener and Flavoring Agent)

Table-3.20: Volunteers Response about Taste of Placebo Effervescent Tablets Containing

Different Quantities of Taste Making Agents

Table-3.21: Taste Response and UV Absorbance of Various Solutions of Itopride HCl Prepared

in Water

Table-3.22: Spectrophotometric Taste Evaluation of Taste masked Itopride HCl prepared by

Granulation Technique

Table-3.23: Volunteers Response about Taste Masked Itopride HCl Prepared by Granulation

Technique

Table-3.24: Spectrophotometric Evaluation of Taste Masked Itopride HCl Prepared by Solid

Dispersion Technique

Table-3.25: Volunteers Response about Taste Masked Itopride HCl Prepared by Solid


Table-3.26: Spectrophotometric Evaluation of Taste Masked Itopride HCl Prepared by Micro-

encapsulation Technique

LIST OF TABLES

xvii

Table-3.27: Volunteers Response about Taste Masked Micro-capsules of Itopride HCl

Table-3.28: Physical properties of Pre compressed Formulations of ODTs of Domperidone

Prepared using Super Disintegrants

Table-3.29: Physical properties of Pre compressed Formulations of ODTs of Domperidone

Prepared by Sublimation Technique

Table-3.30: Physical properties of Pre compressed Formulations of Effervescent Tablets of

Domperidone

Table-3.31: Physical properties of Pre compressed Formulations of ODTs of Itopride HCl

Prepared using Super Disintegrant

Table-3.32: Physical properties of Pre compressed Formulations of ODTs of Itopride HCl


Table-3.33: Physical properties of Pre compressed Formulations of Effervescent Tablets of

Itopride HCl

Table-3.34: Physical Parameters of ODTs of Domperidone Prepared using Super Disintegrants

Table-3.35: Mechanical Strength of ODTs of Domperidone Prepared using Super Disintegrant

Table-3.36: Comparison of Tablet Weight of ODTs of Domperidone before and after

Sublimation of Sublimating Agents

Table-3.37: Physical Parameters of ODTs of Domperidone Prepared by Sublimation Technique

Table-3.38: Mechanical Properties of ODTs of Domperidone Prepared by Sublimation

Technique, Before and After Sublimation of Sublimating Agents

Table-3.39: Disintegration Time and Oral Disintegration Time of ODTs of Domperidone


Table-3.40: Physical Characteristics of Effervescent Tablets of Domperidone

Table-3.41: Mechanical Strength of Effervescent Domperidone Tablets

LIST OF TABLES

xviii

Table-3.42: Physical Characteristics of ODTs of Itopride HCl Prepared using Super

Disintegrants

Table-3.43: Mechanical Properties of ODTs of Itopride HCl Prepared using Super Disintegrants

Table-3.44: Disintegration Behavior of ODTs of Itopride HCl Prepared using Super

Disintegrants

Table-3.45: Comparison of Tablet Weight of ODTs of Itopride HCl before and after Sublimation

of Sublimating Agents

Table-3.46: Physical Characteristics of ODTs of Itopride HCl Prepared using Super

Disintegrants

Table-3.47: Mechanical Strength of ODTs of ItoprideHCl Prepared by Sublimation Technique

Table-3.48: Disintegration Behavior of ODTs of Itopride HCl Prepared using Super

Disintegrants

Table-3.49: Physical Characteristics of Effervescent Tablets of Itopride HCl

Table-3.50: Mechanical Strength of Effervescent Tablets of Itopride HCl

Table-3.51: Ratio of Crushing Strength to Disintegration Time of ODTs of Domperidone and

Itopride HCl Prepared by Sublimation Technique

Table-3.52: Ratio of Disintegration Time to Crushing Strength of ODTs Prepared using Super

Disintegrants

Table-3.53: Ratio of crushing strength to Effervescence Time of Effervescent Tablets of

Domperidone and Itopride HCl

Tabe-3.54: Effect of Moisture Treatment on Optimal formulations of ODTs of Domperidone

Table-3.55: Effect of Crushing Strength on Tablet Disintegration Time and Friability

Table-3.56: Comparison between Mechanical Properties of Large (13mm) and Small (10mm)

Sized Effervescent Tablets

LIST OF TABLES

xix

Table-3.57: Effect of Tablet Size on Effervescence Time of the Effervescent Tablets of

Domperidone

Table-3.58: Effect of Tablet Compressibility on Effervescence Time of Optimal Formulation of

Effervescent Tablets of Domperidone

Table-3.59: Pharmacokinetics Parameters of Domperidone Determined in Healthy Rabbits after

Administration of Fast Dispersible Tablets and Conventional Tablets of Domperidone

(10 mg)

Table-3.60: Pharmacokinetics Parameters of Itopride HCl Determined in Healthy Rabbits after

Administration of Fast Dispersible Tablets and Conventional Tablets of Itopride HCl

(50 mg)

Table-3.61: Control of Emesis with ODTs, Conventional Tablets of Domperidone (10 mg) and

Placebo ODTs in Cancer Patients

LIST OF FIGURES

xx

Figure 1.1: Mechanism of Action of Prokinetic Agents

Figure 1.2: Structural Formula of Domperidone

Figure 1.3: Structure Formula of Itopride HCl

Figure 1.4: Oral Drug Delivery System

Figure 1.5: Challenges in Formulation of Orally Disintegrating Tablets

Figure 1.6: Methods of Preparation of Orally Disintegrating Tablets

Figure 1.7: Methods of Preparation of Effervescent Tablets

Figure 1.8: Schematic Presentation of Taste Masking Techniques

Figure 1.9: Formation of Inclusion Complex of Cyclodextrin and Drug

Figure 1.10: Formation of Drug Resin Complex (Drug Resinate) of Basic and Acidic Drugs

Figure 2.1: Schematic Presentation of Study Design for “Formulation Development and In-vitro,

In vivo Evaluation of Fast Dispersible Tablets of Prokinetic Agents, Domperidone

and Itopride HCl”

Figure 2.2: SeDeM-ODT Diagram and SeDeM Diagram

Figure 2.3: Schematic Presentation of Extraction Procedure

Figure 2.4: Preparation of Microcapsules for Taste Masking of Itopride HCl

Figure 2.5: Preparation of Solid Dispersion for Taste Masking of Itopride HCl by Solvent

Fusion Technique

Figure 2.6: Tablet Preparation by Direct Compression

Figure 3.1: FTIR Spectra of Domperidone and All the Excipients Used in Formulation of ODTs

and Effervescent Tablets of Domperidone, Before Subjecting to Stress Conditions

LIST OF FIGURES

xxi

Figure 3.2: FTIR Spectra of Itopride HCl and Excipients Used in Formulation of Fast

Dispersible Tablets (ODTs and Effervescent Tablets), Before Subjecting to Stress

Conditions

Figure 3.3: FTIR Spectra of Itopride HCl and Excipients Used for Taste Masking of Itopride

HCl before Subjecting to Stress Conditions

Figure 3.4: SeDeM-ODT and SeDeM Diagrams of Domperidone, Itopride HCl and Taste

Masked Itopride HCl

Figure 3.5: SeDeM-ODT and SeDeM Diagrams of the Diluents (Micro Crystalline Cellulose

and Tablettose-80) Used in Formulation of Fast Dispersible Tablets (ODTs and

Effervescent Tablets)

Figure 3.6: SeDeM-ODT and SeDeM Diagrams of Disintegrants Used in Formulation of Fast

Dispersible Tablets (ODTs and Effervescent Tablets)

Figure 3.7: SeDeM Diagrams of Effervescent Excipients Used in Formulation of Effervescent

Tablet of Pro Kinetic Agents

Figure 3.8: UV Absorbance of Domperidone Solution in Methanol (10µg/ml)

Figure 3.9: UV Absorbance of Itopride HCl Solution in Water (10 µg/ml)

Figure 3.10: Effect of Acetonitrile Ratio in Mobile Phase on Elution of Different Analytes

Figure 3.11: Effect of Mobile Phase Flow rate on Elution of Different Analytes

Figure 3.12: Effect of Column Oven Temperature on Elution of Domperidone and Itopride HCl

Figure 3.13: Effect of Various pH of Mobile Phase on Elution of Different Analytes

Figure 3.14: Effect of Detector Wavelength on Elution of Domperidone and Itopride HCl

Figure 3.15: Representative Chromatograms of Standard Solutions and Spiked Plasma Samples

of Internal Standard, Domperidone and Itopride HCl.

Figure 3.16: RP-HPLC Chromatograms of Standard Solutions of Itopride HCl and

Domperidone and Internal standard (Tenofavir)

LIST OF FIGURES

xxii

Figure 3.17: Calibration Curve of Domperidone and Itopride HCl Standard Solutions and

Spiked Plasma Samples

Figure 3.18: Chromatograms Representing LOD and LLOQ Value of Domperidone and Itopride

HCl

Figure 3.19: Comparison of UV Absorbance of Unit Dose of Solid Dispersions of PVP K-30

and PVP K-90 in 3 ml Test Media at 220 nm

Figure 3.20: Disintegration Time and Oral Disintegration Time of ODTs of Domperidone

Prepared Using Super Disintegrants

Figure 3.21: In-vitroDrug Release from ODTs of Domperidone Prepared Using Super

Disintegrant.

Figure 3.22: Sublimation Rate from ODTs of Domperidone Prepared by Sublimation Technique

Containing Different Concentrations of Menthol as Sublimating Agent

Figure 3.23: Sublimation rate from ODTs of Domperidone Prepared by Sublimation Technique

Containing Different Concentrations of Ammonium Bicarbonate as Sublimating

Agent

Figure 3.24: Comparison of Crushing Strength of ODTs of Domperidone after Sublimation of

Menthol and Ammonium Bicarbonate

Figure 3.25: Comparison of In-vitro Disintegration Time and Oral Disintegration Time of ODTs

of Domperidone Prepared by Sublimation Technique

Figure 3.26: Comparison of Disintegration Time of ODTs of Domperidone Containing Different

Concentrations of Sublimating Agents

Figure 3.27: In-vitro Drug Release from ODTs of Domperidone Prepared by Sublimation

Technique Containing Menthol as Sublimating Agent

Figure 3.28: In-vitro Drug Release from ODTs of Domperidone Prepared by Sublimation

Technique Containing Ammonium Bicarbonate as Sublimating Agent

LIST OF FIGURES

xxiii

Figure 3.29: Effervescence Time of Effervescent Tablet of Domperidone (10 mg)

Figure 3.30: Comparison of Effervescence Time with Different Effervescent Pairs and Varying

Concentration of Disintegrant

Figure 3.31: In-vitro Drug Release from ODTs of Itopride HCl Prepared Using Super

Disintegrants in Different Concentrations

Figure 3.32: Sublimation Rate from ODTs of Itopride HCl Prepared by Sublimation Technique

Containing Different Concentrations of Ammonium Bicarbonate

Figure 3.33: Sublimation Rate from ODTs of Itopride HCl Prepared by Sublimation Technique

Containing Different Concentrations of Menthol

Figure 3.34: In-vitro Drug Release from ODTs of Itopride HCl Prepared by Sublimation

Technique Containing Ammonium Bicarbonate as Sublimating Agent


Technique Containing Menthol as Sublimating Agent

Figure 3.36: Effervescence Time of Effervescent Tablets of Itopride HCl Containing Different

Combinations of Effervescent Pair and Disintegrants

Figure-3.37: Effervescence Time of Large Sized (13.00 mm) and Small Sized (10.00 mm)

Effervescent Tablets

Figure 3.38: Plasma Concentration (ng/ml) of Domperidone at Various Time Intervals in

Healthy Male Rabbits after Administration of ODTs, Effervescent Tablets and

Conventional Tablets of Domperidone (10 mg)

Figure 3.39: Plasma Concentration (ng/ml) of Itopride HCl at Various Time Intervals in Healthy

Male Rabbits after Administration of ODTs, Effervescent Tablets and

Conventional Tablets of Itopride HCl (50 mg)

Figure 3.40: Distribution of Emetic Episodes on Day-1 and Day-2 of Anti Cancer

Chemotherapy

LIST OF FIGURES

xxiv

Figure 3.41: Emesis Control with ODTs of Domperidone, Conventional Tablets of

Domperidone and Placebo ODTs

Figure 3.42: Control of Nausea with ODTs and Motillium (Conventional tablets of

Domperidone) on Day-1 and Day-2, Following Anti Cancer Chemotherapy

Figure 3.43: Comparison of Control of Nausea with ODTs and Conventional Tablets of

Domperidone

LIST OF ABBRIVIATIONS

xxv

Ach Acetyl choline Ach E Acetyl choline Esterase API Active Pharmaceutical Ingredient AUC Area Under Curve cCNa Cross linked Carboxy Methyl Cellulose Sodium Cmax Peak Plasma Concentration cAMP Cyclic Adinosine Mono Phosphate CTZ Chemo Receptor Triger Zone D2 Dopamine type-2 receptor DMP Domperidone Fig Figure GERD Gastro Esophageal Reflux Disease GIT Gastro Intestinal Tract HPMC Hydroxy Propylmethyl Cellulose Hr Hour i.e. That is I.S. Internal Standard ITP.HCl Itopride Hydrochloride IUPAC International Union of Pure and Applied Chemistry LOD Limit of Detection LLOQ Lower Limit of Quantification Min Minutes Ml Milliliter MRT Mean Residence Time Nm Nanometer ODT Orally Disintegrating Tablets PEG Polyethylene Glycol PK Pharmacokinetic RPM Revolution Per Minute RSD Relative Standard Deviation S/N Signal to Noise Ratio S.D. Standard Deviation Tmax Time to Achieved Cmax U.V. Ultra Violet Vd Volume of Distribution 5-HT 5 Hydroxy Treptamine

ACKNOWLEDGMENTS

xxvi

First of all many thanks to Almighty Allah for His uncountable blessings bestowed upon

me and helped me to accomplish such a tedious job successfully. My research work would not

have been possible without the help, support, and guidance of many peoples to whom I want to

convey my deepest gratitude.

First and foremost, I wish to thank my parents, my brothers, my sisters, my wife and

whole of my family who supported me and prayed for me throughout my research work.

I would like to thank my research supervisor Meritorious Prof. Dr. Zafar Iqbal,

B. Pharm., M. Pharm. (Pak.), PhD., Post Doc. (UK), from the core of my heart for his guidance,

encouragement, critical evaluation, and confidence that he gave me to grow as a scientist

throughout my professional career.

I am grateful to Prof. Dr. Muhammad Saeed (Chairman Department of Pharmacy),

Prof. Dr. Jamshaid Ali Khan, Prof. Dr. Fazal Subhan, and Asst. Prof. Dr. Amirzada Khan

for their moral and moral support.

I am thankful to whole of my research group and laboratory fellows Dr. Fazli Nasir, Dr.

Abad Khan, Dr. Imran Khan, Dr. Yasir Shah, Dr. Latif Ahmed, Mr. Muhammad Ibrahim

(Deputy Secretary (Drugs), K.P, Mr. Ismail, Mr. Amanullah and Mr. Zia Ullah for their

support and help. It was a pleasure to have you as colleagues and friends.

I would like to thank management of Ferozsons Laboratories Pvt. Ltd, Nowshera,

Pakistan, for provision of the facility to carryout bulk of the study. I wish to thank Mr. Zahir

Rehman (B. Pharm, M. Phill), Mr. Dilshad Khan (B. Pharm, M. Pharm), Mr. Sohail

Haider (B. Pharm), Mr. Tahir Jamal Babar (M Sc Chemistry), Mr. Hafiz Irshad Ullah

ACKNOWLEDGMENTS

xxvii

(Pharm D), and Mr. Imran Khan (B. Pharm) for their technical guidance and moral support. I

would thank whole of the production department of Ferzsons Laboratories Ltd, Nowshera,

espacially Mr. Tahmeed Ullah for their valuable help during tablet preparation.

I am cordially thanked to Mr. Qaiser Khan (Getz Pharma, Pakistan) and Mr.

Khurram (Getz Pharma, Pakistan) for their unconditioned help in conducting clinical studies.

I am also thankful to the Higher Education Commision, Pakistan for promoting the

culture of higher education and research and for its funding to carry out the study.

AMJAD KHAN

ABSTRACT

xxviii

Oral drug delivery system is the most preferred route of drug administration due to ease

of administration; handling, longer shelf-life compared with the other dosage form and cost

effectiveness. The drug release from the Fast Dispersible Tablets is rapid compared with the

conventional tablets. These tablets can be grouped as; I) Orally Disintegrating Tablets 2)

Effervescent Tablets.

Prokinetic drugs enhance gastric emptying, prevent reflux of gastric content and relieve

the symptoms of dyspepsia. Prokinetic drugs are commonly used for treatment of various GIT

diseases like Gastro Esophageal Relux Disease, Functional Dyspepsia and Diabetic Gastroparisis

and for control of emesis of varyying etiology. Prokinetic drugs have motility enhancing effect

on upper part of GIT, whereas no clinically significant effects on motility of large intestine have

been reported. While taking prokinetic drugs, dose of drugs with inhibitory effects on GIT

motility should be reduced without increasing dose of prokinetic drugs as higher doses bear the

risk of iatrogenic inhibition of gastric motility.

In the present study, Orally Disintegrating Tablets and Effervescent Tablets of

Domperidone and Itopride HCl, prokinetic drugs, were formulated and evaluated. The project

was accompolished in three steps;

i. Pre formulation studies

ii. Development of formulations

iii. Evaluation of the formulations.

Pre formulation studies included drug excipients compatibility study, characterization

of drug and excipients as per SeDeM and SeDeM-ODT experts system and development of

ABSTRACT

xxix

method of UV-Visible Spectrophotometric and RP-HPLC methods analysis for Domperidone

and Itopride HCl.

Binary mixture approach was applied for drug excipients compatibility study using 1g

of each material. Samples were prepared in 1:1 with and without moisture and subjected to stress

conditions (75 ± 5% R.H and 45 ± 2 oC) for 90 days. Each sample was evaluated for drug

content (using HPLC method of analysis), physical state and FTIR spectra. Suitability of the both

APIs and excipients for preparation of fast dispersible tablets by direct compression was

determined on the basis of SeDeM/SeDeM-ODT profile. Basic parameters were determined for

each powder according to the official and reported methods. Experimental values were converted

to “r” values by applying specific factors and Index of Good Compressibility and Bucco

dispersibility (IGCB) was calculated according to SeDeM-ODT experts system.

Two types of methods analysis (UV Visible Spectrophotometric method and HPLC

method) were developed and validated for each drug. HPLC method of analysis was developed

for simultaneous determination of domperidone and itopride HCl using water and acetonitrile

(65:35) as mobile phase. pH of the water was adjusted to 3.00 with O-phosphoric acid and

Tenofavir was used as internal standard.

The taste of Itopride HCl is bitter and prior to formulation as Fast Dispersible Tablets

taste of the drug was masked using different excipients (Eudragit, HPMC, PVP, PEG and

Cetostearyl alcohol). Taste masking was carried out by granulation technique, solid dispersion

technique and micro encapsulation technique.

Orally disintegrating tablets were prepared by direct compression by using super

disintegrants and sublimation method.

ABSTRACT

xxx

Cross carmellose sodium and sodium starch glycolate were used as disintegrant alone

and in combination with starch maize. Menthol and ammonium bicarbonate were used in

different concentrations as sublimating agents and heat was applied for sublimation.

ODTs of domperidone were compressed on 10.00 mm oval shallow concave punches

by adjusting the compression weight to 200 mg. Taste masked ODTs of itoprideHCl were

compressed on 10.50 mm round shallow concave punches (compression weight was 350 mg).

Effervescent tablets of both drugs (Domperidone and Itopride HCl) were compressed on 13.00

mm round flat punches under compression weight of 650 mg.

Prior to compression bulk density, tapped density, Carr’s index, Hausner ratio, angle of

repose and flow ability of powder blends for all the formulations were evaluated.

Tablets were subjected to in-vitro and in-vivo evaluation. In-vitro evaluation included

determination of the physical characteristics; mechanical strength, disintegration behavior and

in-vitro drug release. In-vivo evaluation comprised of preclinical evaluation (pharmacokinetic

evaluation) and clinical evaluation.

The in-vivo drug release and pharmacokinetics were studied in healthy male rabbits and

clinical evaluation was carried out in patients taking anti cancer chemotherapy. Clinical

evaluation was carried out in the hospital under the supervision of the physician following the

approval from the Health Regulatory Authorities and Hospital Ethical Committee.

UV visible spectrophotometric method of analysis was accurate and specific for both

drugs (Domperidone and Itopride HCl). Methods of analysis were quiet linear for both drugs,

ABSTRACT

xxxi

having R2 values of 0.998 for domperidone and 0.999 for itopride HCl. Regression equations

were 0.039 x + 0.051 and 0.068 x + 0.0168 for domperidone and itopride HCl, respectively.

HPLC-UV method of analysis for simultaneous determination of domperidone and

itopride HCl using tinofavir as internal standard was developed and validated. The method had

LLOQ values of 10 ng/ml and 15 ng/ml for domperidone and itopride HCl, respectively. The

method was applied for drug excipients compatibility study and in-vivo analysis of both drugs.

The excipients intended to be used in formulation of Fast Dispersible Tablets were

found compatible with both drugs. Drug content, physical consistency and FTIR spectra of all

the samples remained un-affected by exposure to stress conditions (45 ± 5 oC and 75 ± 5% R.H)

for 90 days.

On the basis of SeDeM experts system, both the APIs were found deficient in most of

parameters required for direct compression. Taste masking of itopride HCl improved most of the

parameters, making it suitable for direct compression. Microcrystalline cellulose and Tablettose-

80 were used as diluents in combination. In combination both the excipients resulted in a diluents

system with all the characteristics required for direct compression.

Itopride HCl is a bitter tasting drug with taste threshold of 80µg/ml. Different

excipients and methods were used for the taste masking of the itopride HCl, however the best

results were obtained using HPMC processed by granulation technique. Drug release was

retarded below its taste threshold in 1:3 (drug to polymer ratio). Granulation technique was rapid

and simple technique of taste masking without any advanced machinery involvement.

ABSTRACT

xxxii

At pre-compression level, all formulations exhibited good rheological characteristics;

the angle of repose, flow ability, Hausner ratio and Carr’s index were found within the range of

better flow for all the formulations.

Orally disintegrating tablets with better mechanical strength and rapid disintegration

were obtained by sublimation technique and using super disintegrants. Compared with the

sublimation technique, mechanical strength of the tablets prepared using super disintegrants was

higher.

Higher peak plasma concentration was achieved with both types of Fast Dispersible

Tablets (ODTs and Effervescent Tablets) in rabbits compared to conventional tablets. Rate of

absorption was higher with both the fast dispersible tablets as Tmax was achieved very quickly.

The clinical evaluation showed the effective control of the emesis by ODTs in patients

undergoing chemotherapy compared with the conventional tablets and better patient compliance.

Almost all the patients enrolled in the study preferred to take ODTs in comparison with

the conventional tablets due to ease of administration, better taste and mouth feel.

The present studies showed the good mechanical strength and drug release behavior of

the ODTs. The in-vivo drug release and pharmacokinetic data in the rabbits also support the

appropriate drug release from the ODTs. The better patient’s compliance and control of the

emesis by the ODTs compared with the conventional tablets showed that the ODTs can play an

effective role in the control of emesis.

CHAPTER-1 INTRODUCTION

1

1. Introduction

1.1 Gastro Esophageal Reflux Disease

Gastro esophageal reflux disease (GERD) is one of the most prevalent upper

gastrointestinal disorders in clinical practice. GERD has a prevalence of 8 – 20% [1-2] and is a

chronic disease with relapsing symptoms, requiring lifelong treatment in 25 – 50% of patients [2-

3]. Main symptoms of GERD are heartburn and/or acid regurgitation [4]. It can substantially

impair the quality of life [5], generates substantial health related costs for patients, providers and

society and reduces work productivity. Only 20 – 30 % of the patients with reflux symptoms

consult a physician. Patients with GERD can be classified [2] into three main groups;

Non Erosive Reflux Disease

Erosive Esophageal Disorder

Barrett’s Esophagitis

1.1.1 Pathophysiology of GERD

The pathophysiology of GERD involves contact of the esophagus with noxious

substances in refluxed gastric juice [6-7] and can occur in one of two general ways:

a. When contact time between epithelium and gastric contents is so prolonged that gastric

juice damages the healthy esophageal epithelium [8]


2

b. Gastric reflexate is of such a high potency that can damage the epithelium or esophageal

epithelium is so much sensitive to gastric reflexate

1.1.2 Symptoms of GERD

Symptoms of GERD depend upon age of the patients. In children the symptoms appear

during the first months of life and improve up to 12 – 24 months in 80% of the cases. In case of

adults symptoms may be a continuation from childhood or appear later. They are persistent

usually requiring treatment [2, 9].

Main symptoms are persistent heartburn and acid regurgitation [10], chest pain,

hoarseness in the morning, and dysphagia [11]. GERD can also cause a dry cough and bad

breathe [1].

The clinical manifestations may be:

Specific, such as rumination, vomits, regurgitations

Related to esophagitis, such as pain, anemia, and bleeding

Respiratory, such as bronchospasm and repeated pneumonia

Otorhinolaryngological, such as laryngitis, sinusitis, otitis


3

1.1.3 Treatment of GERD

GERD is mainly considered to be a hypo motility disorder. By improving GIT motility,

GERD patients especially those with nonerosive disease and delayed gastric emptying, can be

effectively treated. There are 2 main strategies that have been applied for the treatment of GERD

[2]. These are;

a. Decrease in gastric acid secretion and its volume by using

i. H2- receptor antagonists

ii. Proton-pump inhibitors

b. Increase in acid clearance by improving GIT motility using prokinetic agents

1.2 Prokinetic Agents

Prokinetic agents are the drugs that act by enhancing acetylcholine effect at muscarinic

nerve endings in GIT. They increase tone of lower esophageal sphincter, relaxes pyloric

sphincter and increases peristalsis resulting in emptying of upper GIT [6].


4

1.2.1 Mechanism of Action of Prokinetic Agents

GIT motility is mainly controlled by acetylcholine and dopamine having stimulatory

and inhibitory effect respectively [6, 12].

a. Acetylcholine is released from enteric nerve endings causes contraction of smooth

muscles through M3 receptors present on smooth muscle layer throughout the gut.

b. Dopamine is present in significant amounts in the gastrointestinal tract and has several

inhibitory effects on gastrointestinal motility, including reduction of lower esophageal

sphincter tone and intragastric pressure via D2 receptors.

Prokinetic agents regulate the gastric motility by;

a. Antagonizing dopamine effect at D2 receptors

Pro kinetic agents inhibit dopamine receptors at chemoreceptor trigger zone. Stimulation

CTZ by chemotherapeutic agents and/or presence of nauseating agents GIT initiates

vomiting reflux. By blockade of dopamine receptor at CTZ message to vomiting center is

blocked resulting in prevention of nausea and vomiting.

b. Increasing stimulatory effect of acetylcholine by blocking its metabolizing enzyme

acetylcholine esterase [13].


5

Mechanism of action of prokinetic agents is presented in Fig-1.1.

Figure 1.1: Mechanism of Action of Prokinetic Agents


6

1.3 Domperidone

1.3.1 Physicochemical Properties of Domperidone

Domperidone (DMP) is structurally related to butyrophenones. It is stable hygroscopic

solid which is incompatible with strong oxidizing agents [14].

1.3.2 Chemistry of Domperidone

Domperidone is chemically 6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl) propyl]

piperidin-4-yl]-1H benzimidazol-2-one [15]. Its molecular formula is C22H24ClN5O2 with

corresponding molecular weight 425.911 g/mol.

Figure 1.2: Structural Formula of Domperidone

Domperidone is water insoluble and slightly soluble in ethanol (96 %) and in methanol

[15]. pKa value of domperidone is 7.9.


7

1.3.3 Pharmacokinetics of Domperidone

1.3.3.1 Dose of Domperidone

Adults; 10 – 20 mg, four times a day (Maximum adult dose is 20 mg, 4 times a day)

Children; 0.300 mg/kg, three times a day [16]

1.3.3.2 Absorption and Bio-availability

Following oral administration, absorption of domperidone is very fast and is 46.5%. Its

Volume of distribution of is 5.71/kg [16]

1.3.3.3 Distribution

Plasma protein binding is 91 – 93%. It does not cross the blood brain barrier. Very low

concentration has been observed in milk.

1.3.3.4 Excretion

Domperidone is mainly excreted through renal route (>30%). It can be excreted in very

low percentage in breast milk.


8

1.3.3.5 Metabolism

After oral administration plasma half-life of domperidone is 7.50 hours. It undergoes

first-pass and gut-wall metabolism and almost 85% is metabolized pre systemically.

Hydroxylation and oxidative N-dealkylation are main metabolic pathways and hydroxyl

domperidone and 2, 3-dihydro-2-Oxo-1-H-benzimidazol-1-propionic acid are its two main

metabolites.

1.3.4 Mechanism of Action of Domperidone

Domperidone is a dopamine antagonist having strong affinity for D2 and D3 receptors

of Dopamine. The main action of domperidone is to regulate gastrointestinal motility by

improving gastric emptying and peristalsis. Prokinetic properties of domperidone are due to

peripheral dopamine receptor blocking action. Its anti-emetic action is because of dopamine

receptors blocking activity at gastric level and CTZ level [17-18]. Domperidone regulate the

gastric motility;

By antagonizing effect of Dopamine on D2 receptors

By increasing stimulatory effect of acetylcholine by blocking its metabolizing

enzyme acetylcholine esterase

Domperidone inhibits dopamine receptors at the chemoreceptor trigger zone.

Presences of an irritant in the stomach or nauseating agents present in the blood

(chemo therapeutic agents) stimulate the chemoreceptor trigger zone. Stimulation of

CTZ initiates vomiting reflux via signaling vomiting center in the brain. By


9

blockade of dopamine receptor at CTZ message to vomiting center is not send

resulting in prevention of nausea and vomiting [19].

1.3.5 Indications of Domperidone

Delayed gastric emptying, Gastro esophageal reflux disorders [16], Dyspepsia, Reflux

esophagitis, Non ulcer dyspepsia, Gastric distention, Nausea, Vomiting due to Chemotherapeutic

agents Migraine [18] and Gastric discomfort [19]are the main indications for domperidone.

1.3.6 Side Effects

Domperidone is extremely well tolerated as it does not cross the blood-brain barrier and

neuropsychiatric and extra pyramidal side effects are rare [16]. Headache, dizziness, dry mouth

nervousness, flushing, irritability and leg cramps are commonly observed side effects [13].

Symptoms of overdose may include drowsiness, dizziness, confusion, twitching,

muscle rigidity, and irregular heartbeat.


10

1.4 Itopride Hydrochloride

1.4.1 Physicochemical Properties

Itopride HCl (ITP.HCl) is a white to off white crystalline powder

1.4.2 Chemistry of Itopride HCl

ItoprideHCl is chemically N-[4-[2-(dimethylamino) ethoxy]-benzyl]-3, 4-

dimethoxybenzamide-HCl [20]. Its molecular formula is C20H26N2O4-HCl and molecular weight

is 394.9 g/mol. Structure formula of itopride HCl is shown in Fig 1.3

Figure 1.3: Structure Formula of Itopride HCl

Itopride HCl is freely water soluble having a bitter taste. Its pKa value is 8.72 and

melting point in the range of 191 – 195 oC [21].


11

1.4.3 Pharmacokinetics of Itopride HCl

1.4.3.1 Dose of Itopride HCl

The recommended dose for adult patients is 150mg daily in divided doses [22]. One

tablet (50 mg), taken orally three times a day, before meals [12]. However food has no effect on

its absorption.

1.4.3.2 Absorption and Bio availability

Itopride HCl is completely absorbed from G.I.T. and undergoes first pass metabolism.

Its relative bioavailability is 60% [23]. Food has no effect on its bioavailability. Maximum

plasma concentration (0.28µg/ml) is achieved within 0.50 – 0.75 hours of a single 50 mg dose.

Linear pharmacokinetics is observed after multiple doses of 50 – 200 mg t.d.s, with minimal

accumulation in the body [24].

1.4.3.3 Distribution

Itopride HCl is 96% bound to plasma protein mainly to albumin. Less than 15% is

bound to alpha-1-acid glycoprotein [24].


12

1.4.3.4 Excretion

After administering therapeutic doses of itopride hydrochloride, only 3.7% is excreted

as itopride while 75.4% is excreted as its N-oxide metabolite [24].

1.4.3.5 Metabolism

Itopride HCl is extensively metabolized in the liver by Flavin dependent mono-

oxygenase (FMO3). Efficiency of FMO3 is genetically controlled having two polymorphic forms.

Recessive polymorphs have low levels of FMO3 and subsequently slow metabolism of itopride

hydrochloride resulting in high blood level and vice versa for dominant one.

Primary metabolite of itopride hydrochloride is an N - oxide metabolite formed by

oxidation of tertiary amine N-dimethyl group [21].

1.4.4 Mechanism of Action

Itopride HCl activates gastrointestinal propulsive motility due to it;

Dopamine D2 antagonizing activity [22]

Acetyl cholinesterase inhibitory activity [25]

Itopride, by virtue of its dopamine D2 receptor antagonism, remove the inhibitory

effects on Ach release. It inhibits the enzyme AchE which prevents the degradation of Ach. The

net effect is an increase in Ach concentration, which in turn, promotes gastric motility, increases


13

the lower esophageal sphincter pressure, accelerates gastric emptying and improves gastro-

duodenal coordination [20, 25].

1.4.5 Indications

Typically, itopride is indicated in the treatment of GI symptoms caused by reduced GI

motility [20, 22]. Dyspepsia of a non-ulcer type (gastric fullness and discomfort), anorexia,

heartburn regurgitation, bloating, nausea and vomiting

1.4.6 Side Effects

Side effects commonly observed with itopride HCl therapy are Anaphylactic reaction,

Leucopenia, Thrombocytopenia, Increased Prolactin level, Gynecomastia, Dizziness, Headache,

Tremors Diarrhea, Skin rashes and itching, Increased ALT (SGPT) level.


14

1.5 Fast Dispersible Tablets

Fast dispersible tablets disperse quickly compared with conventional tablets. There are

two subgroups of fast dispersible tablets;

Fast dispersible tablets that rapidly disperse or dissolve after administration (Orally

disintegrating tablets)

Fast dispersible tablets that are dispersed or dissolved before administration

(Effervescent tablets)

Schematic presentation of various types of oral solid drug delivery system is presented in Fig

1.4.


15

Figure 1.4: Oral Drug Delivery System


16

1.5.1 Orally Disintegrating Tablets

Orally Disintegrating Tablets (ODTs) are unit solid dosage form that disintegrates

and/or dissolves rapidly in the saliva and ingested without need of any liquid vehicle.

European pharmacopoeia [26] states, “orally disintegrating tablets are solid dosage

forms that are placed in the mouth, rapidly disintegrate or dissolve upon contact with the saliva

and then easily swallowed without the need for water”

The United States Food and Drug Administration Center for Drug Evaluation and

Research [27] defines an ODT as a “medicated dosage form, which disintegrates rapidly, usually

within seconds, when placed upon the tongue”.

The wide range of nomenclature used for orally disintegrating tablets include “fast-

dissolve”, “fast-melt”, “rapidly disintegrating”, “quick-melt”, “quick-dissolve”, “crunch-melt”,

“bite-dispersible”, “mouth-dissolve”, and oro dispersible.

Main theme of the ODTs is to combine the benefit of a compact solid dosage form

(stability and ease of handling and administration) and liquid dosage form (ingestible) into a

single one.

A survey showed that 50% of the population suffered from problem of dysphagia

resulting in high incidence of noncompliance and ineffective therapy [28]. It is difficult for most

of the patients, especially pediatric and geriatric patients, to swallow a whole tablet. Compared to

conventional tablets, ODTs disintegrate in oral cavity, easily swallowed overcoming the problem

of dysphagia and results in improved patient’s compliance [29].


17

Dissolution rate and absorption are rate limiting steps for bioavailability of drug from

oral solid dosage forms (Tablets and Capsules) [30]. Aqueous solubility of drug directly affects

its dissolution rate [31] from dosage form. Greater the drug solubility, higher will be its

dissolution rate and more drug will be available at the site of absorption. Quick disintegration of

ODTs results in exposure of individual drug particles to the dissolution medium. This causes a

larger liquid/solid contact resulting in an improved dissolution rate.

With improving patient compliance, ODTs can also potentially increase bioavailability

of poorly water soluble drugs by improving their dissolution rate [32]. ODTs avoid the need of

gastric disintegration; facilitate pre gastric absorption resulting in quick onset of action. It is of

importance in case of drugs used for producing quick onset of action [33] e.g. anti-allergic, anti-

pyretic, analgesics etc.

ODTs have a potential to increase the market life of a product having many commercial

reasons. At the end of patent life, formulating a drug into a novel dosage form can extend the life

of the patent and market.


18

1.5.1.1 Advantages of Orally Disintegrating Tablets

Orally disintegrating tablets have advantages of both oral liquid and solid dosage form.

Some of the advantages of ODTs [27, 34-40] are;

ODTs are very stable like conventional solid dosage forms

ODTs provide accurate dose as drug is administered as unit dose

ODTs are light in weight and have small pack size making them easy to carry

ODTs are easy to handle and administer

ODTs are better tasting and palatable without any risk of suffocation

ODTs are patient friendly having better taste, without any need of chewing and water

for administration

ODTs are advantageous for pediatric patients, geriatric patients, bedridden patients

and those having no access to water

ODTs can extend the life cycle of the drugs near to expiry of their patents by

providing a new dosage form

There is the possibility of increased bio availability due to possible pre gastric

absorption


19

Table 1.1: List of Marketed Orally Disintegrating Tablets

Brand Name Included API Indications Used Technology

Tab. Claritin Redi Loratadine Antihistamine

Freeze Drying

Tab. Feldene Melt Piroxicam NSAID

Tab. Maxalt-MLT Rizatriptan Migraine

Tab. Pepcid ODT Famotidine H2-Antagonist

Resperdal M-Tab Resperidone Schizophrenia

Tab. Zubrin Tepoxalin Dog NSAID

Klonopin Wafers Clonazepam Anxiety/Panic

Dimetapp ND Loratidine Anti Histamine

Imodium Instant Melts Loperamide Anti diarrheal

Propulsid Cisapride GI Prokinetic

Ralivia Flash Dose Tramadol Pain

Cotton Candy

Zolpidem ODT Zolpidem Insomnia

Fluoxitin ODT Fluoxitin Depression


20

1.5.1.2 Problems in Formulation of Orally Disintegrating Tablets

Due to its novelty compared with conventional tablet, there are certain challenges for

formulation development of ODTs. Most common challenges are summarized in Fig 1.5.

Figure 1.5: Challenges in Formulation of Orally Disintegrating Tablets

Rapid Disintegration

“Rapid disintegration” refers to disintegration of tablets in less than 1 min, but ODTs

are preferred to have disintegrated as soon as possible [41]. ODTs are desired to disintegrate in

the oral cavity using saliva as disintegration medium. Therefore ODTs should disintegrate


21

rapidly in minimum available fluid. Grittiness should not be observed and the resultant

dispersion should be smooth with good mouth feel [42].

Disintegration of ODTs is controlled by tablet porosity. By increasing tablet porosity

fluid penetration to the core of the tablet is increased which produces an internal pressure to

disintegrate the tablet [43]. By increasing tablet porosity its mechanical strength is reduced due

to void spaces between the particles [44]. A lot of work is required to balance mechanical

strength of ODTs and their rapid disintegration.

Taste of Active Pharmaceutical Ingredient (API)

ODTs disintegrate in the oral cavity which is the main site for taste perception.

Anything coming in contact with taste buds, located in oral cavity, is sensed for its taste [35].

Use of ODT technology for an obnoxious and bitter tasting drug is a challenge. Bitter taste of the

drug should be properly masked making it acceptable for patients.

Physicochemical Properties of Drug

Physicochemical properties like drug solubility, particle size, crystal morphology,

hygroscopicity and compressibility affect tablet disintegration behavior and its mechanical

strength [45]. For the ideal ODTs, physicochemical properties of drug should significantly not

affect tablet properties. Technology used for development of ODTs should have the capability to

accommodate the unique properties of drug such that final tablet remains unaffected. Work is


22

needed to be done on physicochemical characterization of the material and establishment of their

relation to the tablet characteristics.

Mechanical Strength and Porosity of Tablets

Mechanical strength of the tablet is related to the compactness of tablet core [46]. To

get tablet of sufficient mechanical strength, porosity of the tablet is reduced. With the increase in

compactness and decrease in porosity, disintegration time of the tablet prolonged as water cannot

penetrate the tablet core [45, 47]. Mechanical properties are of the tablets are compromised to

achieve a rapidly disintegrating porous structure.

ODTs have low mechanical strength and are easily damaged during transportation and

handling by the patients [47]. Especially the ODTs prepared by lyophilization are much more

friable. An ideal ODT should have a balance between mechanical strength and disintegration

behavior of the tablets.

Moisture Sensitivity

Water soluble or highly porous excipients absorb water faster resulting in rapid

disintegration of tablet [48]. Porous network and water soluble excipients render ODTs

susceptible to environment of higher humidity.


23

1.5.1.3 Methods of Manufacturing of ODTs

Various methods used for preparation of ODTs are presented as under;

Figure 1.6: Methods of Preparation of Orally Disintegrating Tablets

Freeze Drying

Freeze drying is the process of solvent removal from frozen solution or dispersion drug

and structure forming excipients. Drug excipients solution/dispersion is filled into the blister

cavities, frozen and freeze dried to get ODTs [38-39]. The resulting tablets are highly porous,


24

rapidly disintegrate (≈3 seconds) and have an excellent mouth feel. The tablets are sealed in

special blister packaging to provide extra protection [29]. Early ODTs were manufactured by

freeze-drying technique.

When placed on the tongue, ODTs prepared by freeze drying disintegrate instantaneously

and release the drug into oral cavity [49]. Most common patented technologies developed on the

basis freeze-drying technique are Zydis, Quick solve, Lyoc and Nano crystal technology

Freeze drying is a costly process and requires specialized equipments. Manufacturing

process is expensive. Stability problems arise at high temperature and relative humidity [50].

Method can be applied to chemically stable drug having a small particle size preferably

below 50 micron. High doses of water soluble drugs usually above 60mg are difficult to be

achieved [51]. A rigid structure is necessary for support of the tablet matrix. Highly water

soluble drugs form eutectic mixture and cannot be frozen to form rigid supporting structure [52].

Due to the reason the method cannot be applied for water soluble drugs having dose above

60mg.

ODTs prepared by this method are more sensitive to moisture. Exposure to atmospheric

humidity above 45% can cause serious damage to dosage form [53]. Multi layer packaging is

applied for protection from environmental effects. Any damage to the packaging can result in

loss of integrity. Patient will have to peel off these multiple layers before use. Wet or sweaty

hand can lead to collapse of dosage form.


25

Molding

Molding is the second largest method of manufacturing used for ODTs. This method

has two types;

Compression molding

Heat molding

Compression molding

The method of compression molding involves molding of tablets under reduced

pressure following wet massing. Wet tablets molded under reduced pressure are dried in the air

to get final ODTs [29, 34]. Main ingredients of the formulation are water soluble and commonly

used solvents are ethanol, water or their mixture

The resulting tablets have low disintegration time and mechanical strength due to

highly porous structure. Manufacturing processes developed on the basis of compression

molding technology are mostly patented [52]. ODTs prepared by the technique have low

mechanical strength and are not very much resistant to handling during processing and handling.

Chances of tablet erosion and edging are maximal during processing.

Heat Molding

Heat molding technique involves preparation of ODTs from molten matrix containing

dissolved or dispersed drug [29, 42]. Drug Solution or dispersion governs the properties of

tablets like disintegration time, drug dissolution rate and mouth feel [35].


26

A patent has been registered by Novartis, Switzerland, [54] for a method of molding in

which drug solution or dispersion was filled to molds and solvent was removed by heating,

vacuum or microwave radiations.

Compaction

Preparation of ODTs by conventional tablet compression machine is much attractive as

the process is simple, economical and highly robust [29, 55]. Modifications have been adopted

for preparation of ODTs using conventional tablet press.

A. Pre Compression Modifications

i. Melt granulation [42], spray drying [56], or flash-heating [29] has been applied in

modified form at pre compression level

ii. Excipients with high water solubility and water absorbing properties have been used

as main ingredients of ODTs

B. Post compression Modifications

Tablets are subjected to various treatments like sublimation [57-58], sintering and

moisture treatment [59]


27

Methods of granulation used for preparation of ODTs are:

Melt Granulation

Low melting point waxy materials are used for melt granulation. Granules are prepared

by standard hot melt granulation procedure using hot melt extruder, blended with other

ingredients and compressed. The resulting tablets have good mechanical strength but their

disintegration time is higher (more than one minute [49]). PEG-6-Stearate has been used for the

preparation of granules by melt granulation technique [56]. PEG-6-Stearate is a waxy material

having melting point in the range of 33 – 37 oC and an HLB value of 9.0.

Preparation of granules by melt granulation technique requires specialized machinery

and material with low melting point. Resultant tablets are very costly compared with

conventional tablets.

Main drawback of the technique is use of the waxy material which makes the product

unstable at elevated temperature. Waxy materials are hydrophobic in nature the resultant tablets

have relatively higher disintegration time. Compression of granules having low melting point

waxy material can lead to a number of problems like sticking and low dissolution rate of drug

from tablets.

Spray Drying

Spray drying is a fast way of solvent removal for the preparation of porous particles.

During spray drying solvents remove quickly producing porous particles with larger surface area

[29, 34]. Taste masking can be achieved by spray drying active material with the saccharides,


28

sweetening agents and flavors. To further improve disintegration, effervescent agents have been

included in the spray dried mixture [35].

Spray drying is an advanced technique for preparation of porous granules. Spray drying

is a multi-step process involving solution preparation and solvent removal. Large quantity of

solvent is required for preparation drug solution/dispersion which has to be removed. Heat is

produced during spray drying which renders the technique unsuitable for thermo labile drugs.

Preparation of ODTs of water insoluble drugs having large dose is very difficult by the

technique. As large quantity of organic solvents will be required for solution preparation and

heat generated during spray drying will further limit its use.

Cotton Candy Process

The cotton candy process is also known as shear form or flash dose technology. In this

process drug is flash melted with sacharide and polysaccharide and subjected to centrifugal force

using gradient temperature [27]. As a result floss like crystalline structure with large surface area

is formed enabling rapid disintegration [45]. Then mixed with other excipients and compressed

into tablets. Two systems have been used to prepare shear form floss with self-binding

properties. These are:

UniFloss System

Dual Floss System

Main advantages of the process are rapid disintegration of tablets and applicability of

technique for larger doses.


29

Cotton candy process is specialized and multi-step process. The application of

centrifugal force and temperature gradient in the range of 180 – 250 oC renders the process

unsuitable for thermo labile substances.

Post Compression Processing

Orally disintegrating tablets have been prepared using following post compression processing;

Humidity Treatment

Humidity treatment of compressed tablets with low mechanical strength results in an

increase in their mechanical strength. Tablets are compressed at low mechanical strength,

exposed to the environment of high humidity and are subsequently dried. At high humidity,

moisture is adsorbed on the particle surface and causes liquid bridges to develop which on drying

convert into solid bridges. Humidification and subsequent drying change the crystalline state of

the sugar resulting in increased tablet strength [60].

Sintering

Sintering is a complex process of bonding and partial fusion of particles using pressure

and heat. Tablets are compressed at low compression force and heated for enough time until

binding agent is melted to produce intra tablet bonds. The product is welded in a shape together


30

after solidification of binding agent at ambient temperature. Usually heating is carried out at 50 –

100 oC for 3 – 45 min. These tablets have a disintegration time of 3 – 60 sec.

Main ingredients of the formulation are diluents (bulking agent), structure agent and

binders. Both the components (structure agent and bulking agent) are dissolved in a suitable

solvent and sprayed dried to get beads of low-density. Binding agents and active ingredient can

be incorporated into the formulation by the following ways;

Dry blending with spray dried or dispersed granulated product

By dissolving with bulking agent and spray drying into granules

All the powders are compressed into tablets at lower compression force, heated and

solidified to get final ODTs.

Sintering process results in ODTs having low disintegration time, relatively better

mechanical strength and can be applied for a varying degree of doses. As high temperature is

applied, care must be taken during processing of heat labile drugs.


31

Table-1.2: Limitations of Various Methods of Manufacturing of ODTs

Freeze Drying Technique

i. Technical process requiring specialized equipments

ii. Very expensive

iii. Suitable only for low dose

iv. ODTs prepared by this technique are unstable at higher humidity

v. ODTs have very low mechanical strength

vi. Highly moisture resistant packaging is required

Molding Technique

i. Process is patent protected

ii. ODTs have low mechanical strength

iii. Heat molding is unsuitable for thermo labile drugs

iv. Stability problem

v. High cost of preparation

Cotton Candy Process

i. Specialized and multi step process

ii. Specialized equipments are required

iii. Unsuitable for thermo labile drugs

Compaction

Melt Granulation

i. Specialized equipments are used

ii. Low melting point excipients are used

iii. Low dissolution rate due to waxy excipients

iv. Costly process

Spray Drying

i. Specialized equipments are required

ii. Large quantity of solvent is needed

iii. Unsuitable for thermo labile drugs

iv. Cannot be applied for large doses of water insoluble drugs


32

1.5.2 Effervescent Tablets

Effervescent tablets are uncoated tablets containing acid and base substances which

react in the presence of water releasing carbon dioxide [61]. They are dissolved or dispersed in

water before administration to the patients.

U.S. FDA defines effervescent tablets as tablets that are dissolved or dispersed in water

before administration [62].

Effervescent tablets are an alternative dosage for the patients with dysphagia, pediatric

and geriatric population. Effervescent tablets are easy to take and gentle on the stomach. As the

drug is dissolved or dispersed in water, disintegration step before drug absorption is omitted [63]

and are considered to be fast acting.

1.5.2.1 Fundamentals of Effervescence Reaction

Effervescence reaction occurs between soluble organic acids and alkali metal

carbonates and bicarbonates in the presence of water [64]. These substances do not react in dry

state, water acts as catalyst for the reaction resulting in formation of respective salt and carbon

dioxide. It is a self-propagated reaction and initiated by even trace amount of water. Water

produced as by product, propagates it further till all the acid and/or base is consumed. Due to the

reason effervescent tablets are considered to be highly moisture sensitive [63] and are processed

in an environment of controlled humidity.


33

Acids used in preparation of effervescent tablets may be obtained from food substances

(naturally occurring acids), acid anhydrides and acid salts [64]. Acid substances used in

formulation of effervescent tablets are citric acid, tartaric acid, ascorbic acid, fumaric acid, malic

acid, adipic acid and succinic acids.

Carbonates and bicarbonates are basic substances used for reaction with acid substances

in effervescent tablets in the form of salts [64]. Sodium bicarbonate, sodium carbonate,

potassium bicarbonate and potassium carbonate, sodium sesquicarbonate, sodium glycine

carbonate, L-lysine carbonate, arginine carbonate, amorphous calcium carbonate and calcium

carbonate are commonly used base substances.

1.5.2.2 Reaction Between Acid and Base to Cause Effervescence

Effervescence reaction is an acid base neutralization reaction resulting in formation of

salt, water and carbon dioxide. Citric acid and tartaric are two commonly used acid in

combination with sodium bicarbonate as a base. The reaction between citric acid and sodium

bicarbonate and tartaric acid and sodium bicarbonate [62, 65] are given as;

H3C6H5O7.H2O + 3 NaHCO3 H2O Na3C6H5O7 + 4H2O + 3CO2

(Citric acid +Sodium bicarbonate) (Sodium citrate +Water +Carbon dioxide)

H2C4H4O6 + 2 NaHCO3 H2O Na2C4H4O6 + 2H2O + 2CO2

(Tartaric acid +Sodium bicarbonate) (Sodium tartarate + Water+ Carbon dioxide)


34

Three molecules of sodium bicarbonate are required to neutralize one molecule of citric

acid and two molecules of sodium bicarbonate to neutralize one molecule of tartaric acid. The

proportion of acids may be varied, as long as the total acidity is maintained and the bicarbonate

neutralized. Ratio of citric acid and tartaric acid to sodium bicarbonate can be calculated as

follows:

Citric acid: Sodium bicarbonate = 1: 1.2 (weight: weight)

Tartaric acid: Sodium bicarbonate = 1:1.12 (weight: weight)

210 gm of CA = 252 gm of NaHCO3

150 mg of TA = 168 gm NaHCO3

Water acts as catalyst for the reactions and once starts, continues till consumes acid

and/or base [64].


35

1.5.2.3 Advantages of Effervescent Tablets

Effervescent tablets have certain advantages [63, 66-67] as under;

Effervescent tablets are larger in size and larger doses of drug can be

accommodated

They are almost water free and are most suitable for moisture sensitive drugs

Effervescent tablets are patient friendly and easy to administer. The drug is

available in a palatable liquid form (dissolved or dispersed) and can be easily

absorbed from GIT

Effervescent tablets are helpful for pediatric patients, geriatric patients and

those having difficulty in swallowing as taken as liquid

Effervescent tablets are dissolved in water to get a buffered solution so gastric

tolerance of the drug can be improved

Drugs administered as effervescent tablets show more consistent and

predictable pharmacokinetics response compared to conventional tablets and

capsules

Absorption of drugs with pH dependent absorption can be improved as the

desired pH can be achieved by proper selection of acids and base quantities in

the formulation


36

1.5.2.4 Limitations of Effervescent Tablets

Effervescent tablets are dispersed in water and administered as liquid. Unpleasant taste of

most of the medicaments makes them difficult to be formulated as effervescent tablets and

requires separate step of taste masking [63]. Effervescent tablets mostly form a fine dispersion

because of the presence of insoluble ingredients in the formulation which is not liked by most of

the patients. Effervescent tablets are relatively costly because of use of special excipients with

low moisture contents and increased manufacturing cost due control of the processing

environment. Effervescent tablets are usually larger in size and require special packing due to

their moisture sensitive nature and low mechanical strength.

1.5.2.5 Preparation of Effervescent Tablets

Effervescent tablets are prepared by conventional compression tooling making some

extra considerations due to their moisture sensitive nature. Even traces of moisture can start the

reaction between acid and base leading to destruction of the product. There are two sources of

water;

Intrinsic Moisture of the Excipients

Water is present in excipients as water of hydration, chemically bound to the molecules.

They are usually present in a trace amount and don’t take part in effervescence reaction.

However if much water molecules are present they can add to effervescence reaction [62].


37

Environmental Humidity

Most of excipients are hygroscopic in nature. At elevated environmental humidity,

water from atmosphere gets adsorbed on the surface of the excipients and is loosely attached.

Adsorbed water is usually in large amount and readily available for effervescence reaction as

there is no chemical bonds or strong forces of attractions [64].

During processing effervescent tablets materials with minimum moisture are selected

and processing is carried out under controlled conditions of humidity.

The following methods have used for preparation of effervescent tablets;

Figure 1.7: Methods of Preparation of Effervescent Tablets


38

Wet Granulation

Although there are certain disadvantages of wet granulation, it is still used for

manufacturing of effervescent tablets [62]. For preparation of effervescent tablets, wet

granulation has been carried out using both aqueous and organic based binders. Two types of wet

granulation process have been applied;

Single Step Wet Granulation

In single step wet granulation all the components of the formulation except lubricants

are granulated simultaneously. As both components of effervescent pair are granulated so

organic solvents are used as binder to avoid effervescence reaction.

Material exposure to the environment and risk of moisture uptake is high due to the

subsequent process of sizing. Use of organic solvents is main limitation of the process. Organic

solvents are costly having hazardous effects on health of the processor and environment. As heat

cannot be applied for drying of granules prepared with organic solvents, processing time is

significantly increased.

Double Steps Wet Granulation

During double step granulation acid and base components are granulated separately,

using the standard wet granulation technique with water based binders. Both the components are

blended prior to compression. It has minimized the risk associated with organic solvents but


39

number of steps and processing time got doubled. Separate steps of wet massing, drying and

sizing are carried out for each component separately.As water based binders are used, drying

should be applied to the extent of complete water removal.

In another approach one component (acid or base) is granulated and the second is added

in powder form and compressed into tablets. Using this approach productivity can be increased

with cost reduction [63]. Usually acid component is granulated as base is added as such. Most of

the base substances have poor rheological properties and compressibility. Large quantities of

these materials can negatively affect the final blend.

Dry Granulation

Problems associated with wet granulation were overcome by application of dry

granulation for preparation of effervescent tablets. Dry granulation can be carried out by both

slugging method and use of roller compactor [62-63]. As no water is involved in granulation

there are no chances of premature effervescence and product stability is improved. The Major

drawback of dry method is requirement of expensive excipients and expensive machinery like

roller compactors.

Direct Compression

Direct compression is most desirable for effervescent tablet preparation as minimum

number of steps is involved and exposure to the atmosphere is reduced [63]. With proper


40

selection of excipients effervescent tablets can be prepared with enhanced stability by direct

compression.

It is not easy as most of the material lack compressibility and flow characteristics [68].

Acid substances are usually crystalline in nature and should be pulverized to get uniform particle

size. During pulverization a lot of fine particles are produced which can negatively affect flow

and compressibility of the final powder blend. A lot of trials should be carried out to get powder

blend with optimum flow and compressibility making it suitable for direct compression.

1.5.2.6 Compression of Effervescent Tablets

Effervescent tablets are compressed using conventional compression tooling but

difference is there because of the sensitive nature of effervescent tablets.

Effervescent tablets have low moisture content (usually less than 1%) compared with

conventional tablets (up to 3%) and are larger in size. Because of their low moisture content and

larger tablet size, they have low mechanical strength [64]. Dwell time should be increased to get

tablets with optimum mechanical strength.

Effervescent tablets should be processed in an environment of controlled humidity. As

absorption of trace amount of moisture from the atmosphere can cause the self-propagated

effervescence resulting in product destruction [62, 69].


41

1.6 Taste Masking

The ability to respond to dissolved molecules and ions is called taste. Tongue elicits

taste response by detection with taste buds and brain interprets it. Taste buds are cells, clustered

into onion shaped organs. Molecules and ions taken into the mouth reach via a pore on the

tongue surface into the inside the receptor cells [70].

Taste can be classified into four main types that are sweet, salty, bitter and sour. There

are specific taste buds in specified area of tongue [71] for detection of each taste sensation.

Receptors for sweet taste concentrate on the tip of the tongue, for sour taste on both edges of the

tongue while for bitter taste on back of the tongue near the throat

1.6.1 Physiology of Taste

Physiologically taste is a sensory response produced by chemical stimulation of taste

buds. Chemicals from orally ingested medicine dissolve in saliva and enter into the taste buds via

taste pore [72]. They interact with;

Surface protein called taste receptors

Pore like protein called ion channels

Taste receptors in the cells are linked to the G protein triggering system and release

gustducin (a G protein). Gustducin activates phosphodiesterase and changes intracellular second

messengers (cAMP, and IP3). Second messengers cause depolarization of the cells and send

electrical response to the brain [73-74].


42

1.6.2 Chemistry of Taste

Taste stimuli are chemical sensations in the oral cavity triggered by various compounds

of the basic tastes. A wide variety of compounds exhibits same taste, making generalization

difficult.

Sour taste is produced due to hydrogen ions [72] in a concentration dependent manner.

Cationic species are responsible for salty taste [73]. Sodium chloride has typical salty taste.

Various compounds without any similarity produces sweet taste [73]. Sugars and glycerin are the

two main sweet substances and contains poly hydro alcohol (–CH2OH) groups. Saccharin is

intensely sweet but has no hydroxyl group (–OH). Some amino acids like glycine, also exhibit

sweet taste.

The bitter taste of a molecule is associated with Nitro group and its severity depends on

the number of Nitro groups [72]. It is exhibited by a wide range of compounds including salts of

organic and inorganic compounds. Structurally unrelated compounds like esters of aromatic

acids, lactones and sulfur containing aliphatic compounds exhibit bitter taste [75].


43

1.6.3 Factors to be Considered During Taste Masking Process

Following are the different factors [74] that should be considered during a taste

masking process:

Extent of the bitter taste of the active pharmaceutical ingredient

Required drug load

Drug particulate shape and size distribution

Drug solubility and ionic characteristics

Required disintegration and dissolution rate of the finished product

Desired bioavailability

Desired release profile

Required dosage form

1.6.4 Reduction and Elimination of Bitter Taste

Drug available in soluble form in the oral cavity can be tasted by taste receptors. Fast

Dispersible Tablets are either dispersed prior to administration or dispersed in oral cavity,

providing open access of the drug particles to the taste buds. Most of the drugs are bitter in taste

and their taste needs to be masked prior to formulation of fast dispersible tablets. There are two

approaches [76] for taste masking;

Prevention of contact between bitter tasting compound and taste receptors

Reduction in solubility of the drug in the oral cavity


44

Various taste masking techniques have been presented in Fig 1.8

Figure 1.8: Schematic Presentation of Taste Masking Techniques

1.6.5 Taste Masking Techniques

Each compound has specific taste masking requirements and there is no universal

method that can be applied to all types of compounds. Ideally a taste masking technique will

prevent drug release at the initial time point followed by rapid release.

An ideal taste masking method [77] will;

Involve a minimum number of processing steps and fewest types of equipment

Effectively mask the taste with minimum possible excipients

Have no adverse effect on the drug release profile

Require economical and easily available excipients


45

Be cost-effective

Be easily applied at commercial level

The following methods have been applied for taste masking of bitter drugs;

1.6.5.1 Addition of Sweeteners and Flavors

The most simple and convenient way of taste masking is the addition of flavoring agents

and sweeteners.Selection of sweeteners is based on their specific taste and release profile [75].

Sweetening agents may be;

Instant sweeteners

Lingering sweeteners

Sweeteners are used alone or in combination to get the desired sweetness profile.

Flavors are always used in combination with other material to get a desired flavor

profile [74]. Components of flavor combination include specific flavor, coolant and

desensitizers. Flavoring agents may be;

Natural flavors

Nature identical flavoring substances


46

1.6.5.2 Coating of Drug Particles

Coating of drug particles with inert materials (Polymers) produces a physical barrier

between drug particles and taste receptors. Due to the barrier drug particles cannot interact with

taste receptors and sensation is not produced [71, 74]. pH of oral cavity is 7.4. Any polymer

which is insoluble at this pH can coat drug particles and prevent its contact with taste receptors

masking its bitter taste. Polymers having solubility at lower pH but insoluble at higher pH are the

best candidate for taste masking as they will not affect the drug dissolution rate [74]. Various

materials have been reported for their use in taste masking. Some of them are starches, polyvinyl

pyrolidones (povidone) of various molecular weights, gelatin, methylcellulose, hydroxyl

methylcellulose, microcrystalline cellulose and ethyl cellulose.

Bioavailability from orally administered solid dosage form is mainly controlled by

dissolution rate of drug which is directly related to drug solubility. Taste coating alters

dissolution rate of the drug and hence its bioavailability. It is a challenge with taste coating

techniques to prevent drug release for a brief period of time (2 – 5 min) followed by abrupt

release.

1.6.5.3 Micro-encapsulation

Microencapsulation is the process of applying a thin coat to the small particles of

solids, droplets of liquids and dispersions[78]. Bitter tasting drugs are encapsulated to produce

free flowing coated particles which are blended with other excipients and compressed to produce

taste masked tablets [74, 78]. Coacervation-phase separation technique and solvent evaporation


47

techniques are applied for taste masking [79]. Evaporation process is carried out at normal

atmospheric pressure and room temperature. It is a time consuming step requiring up 24 hours

for complete removal of organic solvent [80]. Evaporation of organic solvents has been

accelerated by increasing temperature of continues phase. But increase in temperature results in

outcomes of microencapsulation to a significant level. Yang et al, demonstrated that when

temperature of continues phase was increased from 22 oC to 38 oC encapsulation efficiency and

initial burst release were changed significantly [81]. When pressure is reduced below the

saturated vapor pressure of the solvent at a given temperature, the solvent starts boiling and

emulsified droplets are destroyed by the bubbles produced due to boiling solvent [82].

A lot of formulation difficulties are associated with compression coated particles into

tablets. The major challenge is ability of the coating layer to maintain its integrity under

compression force applied for tablet preparation. Most of the micro particles and coated beads

are de shaped by compression to get tablet having sufficient mechanical strength. Do et al, 2004,

covered the coated particles with a cushioning material which allowed the particles to remain

intact under compression force. Cushioning materials are highly compressible and hydrophilic

material used as diluents. Silicified micro crystalline cellulose has also been applied as diluents

to maintain the integrity of coated particles. Addition of cushioning material and silicified

excipients are of limited use. They are effective only in case of low drug dose. Larger quantity of

cushioning material will be required for larger drug dose resulting in large sized tablet. Larger

quantity of silicified material can produce grittiness in oral cavity which can reduce acceptance.


48

1.6.5.4 Inclusion Complexes

Inclusion complexation is the process of including a drug particle in a cavity of a host

molecule. Complex forming agents usually have cup shaped structure, drug particles get fitted

into the cavity and form stable complexes [75, 83]. Vander Waals forces are responsible for

formation of inclusion complexes. Inclusion complexation masks the bitter taste by;

Decreasing oral solubility of the drug

Decreasing number of drug particles exposed to taste buds in the oral cavity

Beta cyclodextrin is cyclic oligosaccharide derived from starch and is commonly used

as complexing agent. It forms stable complexes in solid and solution form [84]. For preparation

of inclusion complexes of beta cyclodextrin, drug and cyclodextrin dispersion is subjected to

different drying process like spray drying, freeze drying and slow evaporation. All these are

advanced techniques requiring specialized equipments making the process multi step and costly.

The dried complex mostly exhibit poor rheological characteristics needing further processing to

get free flowing granules [85].


49

Figure 1.9: Formation of Inclusion Complex of Cyclodextrin and Drug

1.6.5.5 Molecular Complexes of Drug With Other Chemicals

Molecular drug complexes are prepared by rapid cooling of the hot aqueous solution of

drug and complexing agents [73, 75]. Solubility of drug substances can be reduced by

complexing with other molecules (without formation of inclusion complexes). Decrease drug

solubility results in reduction of its degree of bitterness. Caffeine forms molecular complex with

gentisic acid and its bitter taste gets masked [73].

1.6.5.6 Solid Dispersion

Dispersion of a drug in an inert matrix in the solid state is called solid dispersion [71].

Commonly used matrix forming materials are poly vinyl pyrolidone, polyethylene glycols (of

various molecular weights), and H.P.M.C, mannitol and ethyl cellulose.


50

Solid dispersions are commonly prepared by the following methods;

Melting method

Solvent method

Melting solvent method

This approach usually requires a higher concentration of excipients compared toother

taste masking techniques.

1.6.5.7 Drug Resin Complexes

Ionizable drugs are complexed with ion exchange resins to form an insoluble drug-resin

complex commonly called drug resinate [71]. Drug resinate dissociate into free drug and resin

due to ion exchange reaction in GIT fluids. Ion exchange reaction occurs usually in the acidic

environment of the stomach. The drug is released from resinate into the GIT fluids and is made

available for absorption while resin is excreted as such [71]. Drug resinate are completely

insoluble and taste of even strongly bitter drugs can be masked.

Figure 1.10: Formation of Drug Resin Complex (Drug Resinate) of Basic and Acidic Drugs


51

1.6.5.8 Formation of Salts or Derivatives

Reduction in drug solubility by chemical alteration can result in taste masking. By

forming different salts and derivatives of the drug, its solubility in saliva is reduced. The drug is

not available to interact with taste buds and its taste gets masked [73]. Salts of different drug

have been formed for taste masking are;

Magnesium salt of aspirin

Maleat salt of chlorphenaramine

Alkoxy alkyl carbonates salt of clarithromycine

It is evident from discussion that all the existing techniques of taste masking have

major inconveniences. Most common is additional processing which increases developmental

time of the product. Safety and stability issues can arise with use of extra material for taste

masking. All these techniques increases cost of the product to great extent [86-87]. So there is

need of taste masking techniques that is simple, economical and utilizes commonly used

excipients. It should use simple formulation steps that can be integrated with formulation

development of the final product.


52

1.7 Aims and Objectives of the Study

The main objective of the study was to develop stable formulations of fast

dispersible tablets (Orally Disintegrating Tablets and Effervescent Tablets) of

prokinetic agents (Domperidone and Itopride HCl)

Design and exploration of robust, simple and economical method of manufacturing

for fast dispersible tablets. Current methods of manufacturing used for both types of

fast dispersible tablets are very much complicated multi step requiring specialized

equipments. Specific aim of this study is to develop a simple method of

manufacturing for fast dispersible tablets that better meets the ideal properties like

simplicity, minimum material handling, conventional compression tools and cost

effectiveness.

Taste masking of water soluble bitter tasting drug (Itopride HCl) to get palatable

fast dispersible tablets is another objective of the study. There is need of taste

masking technique that is simple, economical and can be applied for high dose

water soluble drugs by applying simple formulation steps that can be integrated

with formulation development of the final product.


53

1.8 Hypothesis

Orally disintegrating tablets having rapid disintegration and sufficient mechanical

strength can be prepared by conventional methods of tablet preparation

Effervescent tablets prepared by direct compression are more robust, stable and easy to

produce

Better taste masking of high dose water soluble drugs can be achieved by wet granulation

technique

Better patients acceptance can be achieved with Fast Dispersible Tablets compared to

conventional tablets

CHAPTER-2 EXPERIMENTAL

54

2. Experimental

2.1 Material

Domperidone (Ningbo Sansheng Pharmaceuticals Company, China), Itopride

hydrochloride (A.M.I. Life Sciences Pvt. Ltd, India), Tablettose-80 (Molkerei Meggle,

Germany), Microcrystalline cellulose (F.M.C International, Ireland), Sodium starch glycolate

{Primojel} (C.H.P. Carbohydrates, Pirina, Germany), Cross linked carboxy methyl cellulose

sodium {cross carmellose sodium} (F.M.C International, Ire Land), Starch maize (I.C.I,

Pakistan), Citric acid (Merck KGA, Germany), Tartaric acid (Merck KGA, Germany), Sodium

bicarbonate (Merck KGA, Germany ), Colloidal silicon dioxide {Aerosil-200} (F.M.C, Ireland ),

Magnesium stearate (Coin Powder International Company Ltd, Taiwan), Menthol (Hemmer and

Remmer G.M.B.H, Germany), Ammonium bicarbonate and Hydroxy propyl methyl cellulose

(HPMC) (Dow Chemical Company Midland, USA.), Polyvinyl pyrollidone (PVP k-30, PVP k-

90) (I.S.P. Technology, Texas), Mannitol (Shangdong Tianli Pharmaceuticals Company Ltd,

China), Poly ethylene glycol (PEG-4000 and PEG-6000) (I.C.I Chemicals and Polymers,

England), Sucralose (Brother Enterprises Private Limited, Pakistan), Cetostearyl alcohol (Croda

Chemicals Ltd, England), Flavor tuttifruiti (Bush Boake Allen, Pakistan) were used in the study.


55

2.2 Instrumentation

In this study following instruments were used for preparation and analysis of Fast

Dispersible Tablets of prokinetic drugs (domperidone and itopride HCl) in the pharmaceutical

and biological samples. These are:

Equipments Used for the Preparation of Fast Dispersible Tablets

One of the objectives of the study was to use commonly used in pharmaceutical

manufacturing equipments for preparation of fast dispersible tablets. Equipments used for

preparation of fast dispersible tablets include Digital balance (Libror AEG-120, Schimadzu,

Japan), Sieve shaker with standard meshes (Endicott Ltd, England), Laboratory scale double

cone mixer (Morgan Machinery Ltd), paddle wet mixer (Morgan Machinery Ltd), Hot air drier,

Hot plate with magnetic stirrer, and commercial scale Rotary tablet Compression Machine D3A,

(Manesty, England), Rotary Tablet Compression Machine ZP-19 (S.T.C. China), Rotary

granulator (S.T.C, China).

Instruments Used for Analysis of Fast Dispersible Tablets

Loss on drying was determined using Halogen moisture analyzer (Mettlor Toledo,

Switzer Land). Different glassware like graduated glass cylinder, glass funnel and Petri dish

were used for determination of flow of powder blend.


56

Compressed tablets were evaluated for various compendial and non-compendial

characteristics. Tablet Hardness and Thickness tester, (Pharma Test, Germany), Tablet

Disintegration Tester (Pharma Test, Germany) and Dissolution Testing Apparatus (Pharma Test,

Germany) were used for determination physical parameters of tablets. Double beam UV Visible

spectrophotometer (Shimadzu, Japan) was used for determination of drug content. Friability of

the tablets was determined using double drum Roche Friabilator, (Faisal Engineering, Pakistan).

FTIR Spectrophotometer (Shimadzu, Japan) and Climatic Chamber (Hotpack,

Philadelphia), were used for drug excipients compatibility study.

HPLC Perkin-Elmer HPLC system (Norwalk, USA), consisted of a pump (series 200),

on-line vacuum degasser (series 200), auto-sampler (series 200), Peltier column oven (series

200), linked by a PE Nelson network chromatography interface (NCI) 900 with UV/VIS detector

(series 200). The whole HPLC system was controlled by Perkin-Elmer Total Chrom Workstation

Software (version 6.3.1). UV/Visible spectrophotometer (Lambda 25, Perkin Elmer), Centrifuge

(Centurion Scientific Ltd), Shaking Water Bath B.S.11 Lab Companion (Jelo Tech Korea), pH

meter (Hanna Instruments, USA) and Autoclave HS-60 (Hansuin Medical Co. Ltd Korea).


57

2.3 Study Design

The study was carried out in different phases as;

Phase-1: Pre formulation studies that included;

Selection of Excipients

Excipients were selected on the basis of their compatibility with domperidone and

itopride HCl and suitability for direct compression.

Compatibility of the excipients was determined by drug excipients

compatibility study

Suitability of the excipients for direct compression was determined by

SeDeM-ODT experts system

Development and validation of methods of analysis for the drugs included in the

study (Domperidone and Itopride HCl)

Phase-2: Formulation development, where two types of fast dispersible formulations were

developed for both drugs;

Orally Disintegrating Tablets

Effervescent Tablets


58

Orally disintegrating tablets were prepared by two techniques

Using Super Disintegrant


Itopride HCl is a bitter tasting drug and its taste was masked by following methods:


Solid dispersion Technique

Microencapsulation (Particle coating)

Phase-3: Evaluation of the formulations was carried out in phase-3. Evaluation of the

formulations included;

In-vitro Evaluation

In-vitro evaluation of the formulations was carried out at pre and post compression

levels. At pre-compression level bulk density, tapped density, Hausner ratio, Carr’s Index, flow

ability, angle of repose and loss on drying was evaluated.

Following compression, physico-chemical properties of the tablets were studied that

included;

Physical characteristics (weight variation, physical appearance and tablet

thickness)

Mechanical strength (crushing strength, specific crushing strength, tensile

strength and friability),


59

Disintegration behavior (disintegration time, oral disintegration time and

effervescence time)

In-vitro drug release

In vivo Evaluation

Optimal formulations of fast dispersible tablets (ODTs and Effervescent Tablets) of

both drugs (Domperidone and Itopride HCl) were subjected to pharmacokinetic evaluation in

rabbits and pharmacokinetic parameters were compared with the conventional tablets.

Clinical evaluation was carried out in patients taking anticancer chemotherapy after

approval by the ethical committee of the clinical setup.


60

Figure 2.1: Schematic Presentation of Study Design for “Formulation Development and In-vitro, In vivo Evaluation of Fast

Dispersible Tablets of Prokinetic Agents, Domperidone and Itopride HCl”


61

2.4 Pre Formulation Studies

Pre formulation studies included:

Drug excipients compatibility

Characterization of material as per SeDeM/SeDeM-ODT experts system

Development and validation of methods of analysis for both drug (Domperidone and

Itopride HCl).

2.4.1 Drug Excipients Compatibility

The binary mixture approach was used to study the drug excipients compatibility of

samples. Samples were prepared with and without added moisture (3%) and stored under stress

conditions for 3 months [88]. Physical consistency, drug content and F.T.I.R. spectra were

evaluated at each sampling point.

2.4.1.1 Sample Preparation

Samples were prepared containing only excipients, drug and combination of drug and

excipients (1 g each) as described in Table-2.1. Samples were stored under stress conditions (45

oC and 75% relative humidity) in a climatic chamber for 90 days [88].


62

Table-2.1: Composition of Samples Used for Drug Excipients Compatibility

Sample Sample Composition

D-1 Pure Domperidone

D-2 Excipients intended to be used in the formulation of ODTs of DMP using

the super disintegrant technique

D-3 Domperidone and all excipients intended to be used in the formulation of

ODTs of DMP by super disntegrant technique

D-4 Domperidone and all excipients intended to be used in the formulation of

ODTs of DMP by super disntegrant technique and 3% water

D-5 All the excipients intended to be used in the formulation of ODTs by

sublimation technique

D-6 Domperidone and excipients intended to be used in the formulation of

ODTs by sublimation technique

D-7 DMP and all excipients intended to be used in the formulation of ODTs of

DMP by sublimation technique and 3% water

D-8 All the excipients intended to be used in the formulation of effervescent

tablets of Domperidone

D-9 DMP and all excipients intended to be used in the formulation of

effervescent domperidone tablets

I-1 Pure ItoprideHCl powder

I-2 ITP.HCl and all excipients intended to be used in the formulation of ODTs

of ITP.HCl by super disintegrant technique

I-3 All excipients intended to be used in the formulation of ODTs of ITP.HCl

by super disintegrant technique and 3% water

I-4 ITP.HCl and all excipients intended to be used in the formulation of ODTs

of ITP.HCl by sublimation technique

I-5 All excipients intended to be used in the formulation of ODTs of ITP.HCl

by sublimation technique + ITP.HCl + 3% Water

I-6 ITP.HCl and excipients intended to be used for taste masking of ITP.HCl by

granulation technique


63

I-7 ITP.HCl, all excipients intended to be used in taste masking of ITP.HCl by

granulation technique and 3% purified water

I-8 All excipients intended to be used in formulation of solid dispersion in 1:1

I-9 All excipients intended to be used in formulation of solid dispersion for

taste masking blended with ITP.HCl in 1:1

I-10 ITP.HCl, all excipients intended to be used in formulation of solid

dispersion and 3% Water

I-11 ITP.HCl and all excipients intended to be used in the formulation of

effervescent tablets of ITP.HCl in 1:1

DMP: Domperidone ITP.HCl: Itopride HCl

2.4.1.2 Determination of Drug Content

Drug contents of the samples containing drug (Domperidone or Itopride HCl) were

determined using HPLC method, developed for simultaneous determination of the two drugs.

Standard solution (2µg/ml) of each drug and same concentration of sample solution was

prepared in mobile phase. Both the sample solution and standard solution were analyzed under

same chromatographic conditions. Percent drug content was calculated on the basis of peak area

of the two samples using the following equation:

%Drugcontent

x100 -------------- Eq-2.1

Where

A sample = Peak area of sample solution

A standard = Peak area of standard solution

Analysis was performed in triplicate and results were presented as Mean ± S.D. (n = 3).


64

2.4.1.3 FTIR Spectra

The F.T.I.R. spectrum of samples was recorded using FTIR spectrophotometer (F.T.I.R

Prestige, Shimadzu, Japan) equipped with IR Solutions version 1.10 software.

KBr pellet method was used for sample preparation. Sample (2% w/w) was mixed with

KBr and pulverized. Pulverized sample was loaded into sample holder and pressed to form a

compact mass. Spectra were recorded in 400 – 4000 cm -1 spectral region at resolution of 8 cm-1.

All the spectra were recorded in absorbance mode.

2.4.1.4 Evaluation of Physical Consistency of Samples

The samples were visually inspected for any change in color and consistency. Changes

in physical appearance indicate physical or chemical interaction with excipients.


65

2.4.2 Characterization of Drugs and Excipients Using SeDeM and SeDeM-ODT

Experts System

SeDeM and SeDeM-ODT expert systems are pre formulation tools for determination of

suitability of drugs and excipients for direct compression and bucco dispersibility [89]. Material

intended to be used in the formulation of ODTs were evaluated using SeDeM-ODT and for

effervescent tablets as per SeDeM expert system.

2.4.2.1 Determination of Basic Parameters

Basic 15 parameters of the SeDeM-ODT expert system were determined according to

their respective pharmacopoeial and reported methods [89-90] as under;

Bulk Density (Da)

Bulk density of the powder was determined according to U.S.P.32/N.F.27, using

graduated glass cylinder [91-92]. Bulk density was calculated using following equation:

Da --------------Eq-2.2

Where

Da = Bulk density of powder (g/ml)

W = Weight of powder (g)

Va = bulk volume of powder (ml)

All determinations were made in triplicate and their mean values were used for further

calculations.


66

Tapped Density (Dc)

Tapped volume of the powder was determined in triplicate using cylinder method [91,

93]. Briefly, the glass cylinder containing weighed material was tapped manually against the

hard surface of laboratory table. After 100 taps, volume of the powder was observed and

continued till no more reduction in volume of the powder was observed. It was measured as

tapped volume (Vc).

From mean tapped volume and weight of powder, tapped density was calculated using

the following equation;

Dc --------------Eq-2.3

Where

Dc = Tapped density of powder (g/ml)

Wg = Weight of powder (g)

Vc = Tapped volume (ml)

Inter-Particle Porosity (Ie)

Values of bulk density and tapped density were used for calculation of inter-particle

porosity using the following equation;

Ie

-------------- Eq-2.4


67

Where

Ie = Inter particle porosity

Dc = Tapped density (g/ml)

Da = Bulk density (g/ml)

Carr’s Index (IC)

Carr’s index was calculated from the values of bulk density and tapped density [91,

94]using following equation:

C. I. x100 -------------- Eq-2.5

Where

C.I. = Carr’s index of the powder (%)

Dc = Tapped density of the powder (g/ml)

Da = Bulk density of the powder (g/ml)

Cohesion Index (Icd)

Powder under test was compressed into tablet using maximum compression force

without capping and lamination. The mean crushing strength of these tablets (n = 10) was

determined using digital tablet hardness tester (Pharma Test, Germany) representing cohesion

index of the material [95].


68

Hausner Ratio (IH)

Hausner ratio was calculated from the values of mean bulk density and tapped density

[91-92, 94] using the following equation:

Hr -------------- Eq-2.6

Where

Hr = Hausner ratio of the powder

Dc = Tapped density of the powder (g/ml)

Da = Bulk density of the powder (g/ml)

Angle of Repose (α)

Angle of repose was determined (n = 3) by funnel method [91, 96]. The test powder

was allowed to flow from a glass funnel fitted at the height of 3 cm from table surface and angle

of repose was determined using equation-2.7.

∝ tan -------------- Eq-2.7

Where

α = Angle of repose of powder (o)

H = Height of the cone formed by powder (cm)

r = Radius of the base of cone formed by powder (cm)


69

Flowability (t")

Flow ability was determined by measuring the time “T” required for the powder (100g)

to flow through the orifice of a glass funnel fitted at the height of 3 cm from table surface. The

equation-2.8 was applied to calculate the flowability of the material [97].

t" -------------- Eq-2.8

Where

t"= Flow ability of the powder (g/sec)

W = Weight of the powder (g)

T = Time (sec) required for powder to flow through the orifice

Loss on Drying (%HR)

Loss on drying was determined gravimetrically according to USP, [91, 98] using a

halogen moisture analyzer (Mettlor Toledo, Switzer Land). Powder (1g) was loaded into the pan

of moisture analyzer, heated for 5 min at 100 oC and noted the value of percent loss. The

moisture content of the material was determined in triplicate and their average was taken.

Hygroscopicity (%H)

Hygroscopicity was measured by placing the accurately weighed amount of powder in

climatic chamber at 75% ± 5% relative humidity for 24 hrs at room temperature. The material


70

was analyzed after 24 hrs for their percent weight gain by reweighing [95]. Hygroscopicity of the

powder based on the percent gain in weight was calculated by equation-2.9.

Percentweightgain x100 -------------- Eq-2.9

Where

Wb = Initial weight of powder (g)

Wa = Weight of powder after moisture treatment (g)

Particle Size Distribution (%Pf)

Sieve shaker fitted with standard sieves of pore size 850, 600, 425, 300 and 250 µm

(Endecott, England) was used for particle size distribution. Powder (100g) was loaded on the top

sieve, and vibrated the sieve shaker for 10 min. Percent amount of powder retained over each

sieve was calculated using equation-2.10 [97, 99].

Percentpowderretained

x100-------Eq-2.10

Homogeneity Index (I )

Homogeneity index was determined according to European pharmacopoeia [97].

Powder (100 g) was loaded to a sieve shaker fitted with sieves of 850,500, 425, 300, 250 and 50


71

µm pore size and vibrated for 10 min. Percent amount of powder retained over each sieve and

that passed through a 50 µm sieve were calculated. Homogeneity index of the material was

calculated using the following equation;

Iθ ∆

-------------- Eq-2.11

Where

Iθ = Relative homogeneity index

Fm1 = Percentage of particles in the majority range

Effervescence Test

Effervescence test was determined as per official monograph (USP-35/NF-30). Powder

was compressed into tablets under maximum pressure without any capping and lamination. One

tablet was placed in a beaker containing 200 ml of purified water at ambient temperature. Time

taken by the tablet to disperse completely was taken as its effervescence time.

Disintegration Time with Disk

The powder was compressed under maximum pressure without any capping and

lamination and subjected to determination of disintegration time using USP disintegration

1: ∆Fmn was calculated on the basis of equation proposed by Sune-Negre et al, 2008.


72

apparatus. Six tablets were selected for each material and their disintegration time with disk was

determined using de-ionized water as a medium at 37 ± 2 oC [100]. Mean of six determinations

was taken as disintegration time.

Disintegration Time without Disk

Disintegration time was determined as described in the previous section without any

disk [100].

2.4.2.2 Conversion of Experimental Values to “r” Values

Experimental values of the powder were converted into “r” values by applying specific

factors, as given in Table-2.2. SeDeM/ SeDeM-ODT diagram were constructed on the basis of

“r” values. Values of “r” ranged 0 – 10 and 5 was minimum acceptable value.


73

Table-2.2: Basic Parameters, Limits and Applied Factors of SeDeM-ODT Experts System

Factor / Incidence Parameter Symbol Unit Equation Limits Applied factor

Dimension Bulk Density Da g/ml Da = M/Va 0 – 1 10V

Tapped Density Dc g/ml Dc = M/Vc 0 – 1 10V

Compressibility

Inter Particle Porosity Ie – Dc – Da/Dc x Da 0 – 1.2 10V/1.2

Carr' Index Ic % 100 x (Dc – Da)/Dc 0 – 50 V/5

Cohesion Index Icd N Experimental 0 – 200 V/20

Flow ability /

Powder flow

Hausner Ratio IH – Dc/Da 3 – 1 (30 – 10V)/2

Angle of Repose (α) o tan -1(h /r ) 0 – 50 10 – (V/5)

Powder Flow t" S Experimental 0 – 20 10 – (V/2)

Lubricity/ Stability Loss on Drying %HR % Experimental 0 – 10 10 – V

Hygroscopicity %H % Experimental 0 – 20 10 – (V/2)

Lubricity/Dosage Particles < 50 %Pf % Experimental 0 – 50 10 – (V/5)

Homogeneity Index I – Fm /100 + ∆Fmn 0 – 2 x 10–2 500V

Disgregability

Effervescence Time DE min Experimental 0 – 5 (5 – V) x 2

D. Time with Disk DCD min Experimental 0 – 3 (3 – V) x 3.333

D. Time without Disk DSD min Experimental 0 – 3 (3 – V) x 3.333

V: Experimental/ Calculated Value


74

2.4.2.3 Graphical Presentation of SeDeM/ SeDeM-ODT Results

Results of SeDeM and SeDeM-ODT experts system were presented as SeDeM diagram

and SeDeM-ODT diagram respectively built on the basis of basic parameters. Results obtained

from the experimental determination of various parameters were converted to “r” values by

applying specific factors, representing radii of the diagram. A diagram was formed by

connecting radius values with linear segment [89]. The resultant diagram indicated suitability of

the powder for direct compression and buccodispersibility by comparison of their shaded and

non-shaded area. Blank diagrams for both expert systems are given in Fig-2.2.

Figure 2.2: SeDeM-ODT Diagram and SeDeM Diagram

Da; Bulk density %HR; Loss on drying Dc; Tapped density %H; Hygroscopicity Ie; Inter-particle porosity %Pf; Particle size IC; Carr index I ; Homogeneity index ICd; Cohesion index DE; Effervescence test IH; Hausner ratio DCD; Disintegration time with disk Α; Angle of repose DSD; Disintegration time without disk t"; Flow ability


75

According to SeDeM-ODT expert system, 15 parameters were determined for each

drug and excipient while for the SeDeM expert system only 12 parameters were determined and

three parameters governing bucco dispersibility were excluded.

2.4.2.4 Calculation of Index of Good Compressibility and Bucco Dipersibility

Index of Good Compressibility and Bucco dispersibility (I.G.C.B.) determines

suitability of the powder for direct compression and bucco dispersibility. I.G.C.B. value was

calculated for powder as under [89, 101]:

Index of Good Compressibility and Bucco Dispersibility (IGCB)

Good compressibility and bucco dispersibility index were calculated as the product of

parametric index profile and reliability factor using following equation:

I. G. C. B I. P. Px -------------- Eq-2.12

Where

IPP = Parametric Index Profile

f = Reliability Factor

Parametric index profile (I.P.P.) is the mean of “r” values of all the parameters. “r”

values of all the parameters were added and divided by number of parameters to get the


76

meanvalue which was taken as parametric index profile (I.P.P.). Value of acceptability limit of

parametric index profile was I.P.P. ≥ 5

Reliability factor (f) was calculated using following equation;

---------------Eq-2.13

Value of “f” depends upon number of parameters included in the study and has

maximum value of 1. In case of;

15 parameters included in the study,f = 0.971

12 parameters included in the study, f = 0.952

08 parameters included in the study, f = 0.900

Powder intended to be used in formulation of ODTs was characterized according to

SeDeM-ODT experts system and IGCB values were calculated on the basis of 15 parameters. In

case of effervescent tablets, powder was characterized according to SeDeM experts system and

IGC value was calculated on the basis 12 basic parameters. Three parameters for characterization

of disgregability were excluded. Rest of the parametric determinations, applied factors,

acceptable limits and parametric indices were same for both experts systems.


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2.4.3 Development and Validation of U.V Visible Spectrophotometric Method of

Analysis

UV Visible Spectrophotometric method of analysis was developed separately for both

drug and validated as per ICH guidelines [102].

2.4.3.1 Preparation of Stock Solution

Stock solution of each drug (Domperidone and Itopride HCl) was prepared by

dissolving drug (10 mg) in sufficient quantity to get concentration of 100 µg/ml. Methanol was

used as solvent for domperidone and itopride HCl was dissolved in purified water. Stock

solutions were stored for preparation of the dilutions for further use.

2.4.3.2 Selection of Wave Length of Maximum Absorbance (λ max)

Dilute solution of both the drugs were prepared from stock solution in their respective

solvents (Itopride HCl in purified water and Domperidone in analytical grade methanol) having a

concentration of 10µg/ml and were scanned in the range of 200 – 400nm using double beam UV

spectrophotometer (Shimadzu, Japan). The wavelength of maximum absorbance (λ max) was

determined from a scan spectrum of each drug.


78

2.4.3.3 Validation of UV Visible Spectrophotometric Method of Analysis

UV Visible Spectrophotometric method of analysis was validated according to ICH

guidelines [102] as under:

Specificity and Selectivity of the Method

Percent recovery method was applied for determination of specificity of the method. A

solution of each drug having a concentration of 20µg/ml was prepared by dilution of an aliquot

from stock solution with respective solvent. Another duplicate of the solution was prepared

containing commonly used pharmaceutical excipients (Tablettose-80, magnesium stearate, micro

crystalline cellulose). Absorbance of both solutions was measured at their λmax and calculated

their percent recovery [103].

Precision of the Method

Precision of the analytical method was studied by repeatability and intermediate

precision [102-104].

Repeatability of the method was determined by measuring absorbance of the solution

(10µg/ml) six times in triplicate and comparing their mean absorbance.

Intermediate precision was performed both inter day and Intraday. For Intraday

precision, absorbance of the solution was measured in triplicate at an interval of 6 hrs for 24 hrs.

Their mean absorbance was calculated and compared with each other.


79

Inter day precision was determined by analysis of a solution (10µg/ml) for three

consecutive days at an interval of 24 hrs. Absorbance was measured in triplicate each day and

their mean, standard deviation and relative standard deviation were calculated. Mean absorbance

was compared with each other.

Linearity of the Method

Linearity of the method was determined by analyzing response of each drug in

concentration range of 0.1 – 100 µg/ml. Dilute solutions of each drug were prepared in

concentration range of 0.1 – 100 µg/ml and their absorbance was measured at their respective

λmax [102-103]. All the measurements were made in triplicate; their mean and standard deviation

were calculated. Mean absorbance of each solution was plotted against corresponding

concentration and regression analysis was performed for each curve using Microsoft Excel,

2007.

Stability of Solutions

Stability of drug solution was determined by keeping solution for 72 hrs at room

temperature and analyzing it using the same parameters [104]. Absorbance of the solution

(10µg/ml) was measured in triplicate at various time intervals (0, 6, 12, 18, 24, 48 and 72 hrs).

Stability of the solution was evaluated by comparison of results of latter hour absorbance with

that of a freshly prepared solution.


80

2.4.4 Development and Validation of HPLC-UV Method for Simultaneous

Determination of Domperidone and Itopride HCl


Stock solutions of domperidone, itopride HCl and internal standard (Tenofavir) were

prepared in the mobile phase, having a concentration of 1mg/ml each and stored in amber glass

vial at –20 oC. Domperidone is water insoluble and was initially dissolved in minimum amount

of methanol and made up volume with mobile phase. Working solutions (10 ml) were prepared

on the daily basis by dilution with mobile phase.

2.4.4.2 Sample Preparation

Plasma Sample

Blood samples were collected from human volunteer in Heparin tubes and centrifuged

at 4000 RPM for 10 min at 4 oC to separate plasma. Aliquot of plasma (250 µL) was taken in

Eppendorf tube (1.0 mL), Acetonitril (500 µL) was added and vortexed for 2 min. Sample was

centrifuged at 4000 RPM and 4 oC for 10 min and supernatant was collected using posteur

pipette. Plasma sample was spiked with standard solution of both the analytes and internal

standard and vertexed for 1 min.


81

Liquid-liquid Extraction

Plasma (250 µL) was added to an Eppendorf tube, deproteinized with acetonitrile (500

µL) and vortexed for 5 min. The sample was centrifuged at 4000 RPM for 10 min. After

centrifuging, the supernatant was transferred to Eppendorf tube and made volume up to 1.0 ml

with the extraction solvent. Three solvents (Methanol, Acetonitrile and Mobile phase {water:

acetnitrile, 65:35 v/v}) were studied for liquid-liquid extraction. Schematic diagram of extraction

procedure has been presented in Fig 2.3.


82

Figure 2.3: Schematic Presentation of Extraction Procedure for Both Analyes (Domperidone

and Itopride HCl)


83

2.4.4.3 Optimization of Chromatographic Condition

Selection of Stationary Phase

Various reverse phase HPLC columns were tried to select a suitable stationary phase

for simultaneous determination of domperidone and itopride HCl. These columns included:

Hypersil BDS C8 Column (150 mm x 4.6 mm, 5µm)

Discovery HS C18 Column (150 mm × 4.6 mm, 5 µm)

Symmetry C8 Column (150 mm × 3.9 mm, 5 µm)

Symmetry C8 Column (250 mm × 4.6 mm, 5 µm)

Each column was guarded by Perkin Elmer C18 (30 mm x 4.6mm, 10 µm) guard column.

Selection of Mobile Phase

Mobile phase composition was optimized using different ratios of organic solvents

(Acetonitrile and Methanol) and purified water in isocratic mode. Mobile phase showing better

resolution was selected for further analysis.

Following three mobile phase combinations (v/v) were studied for simultaneous

determination of domperidone and itopride HCl:

Acetonitril: Water (25: 75)

Acetonitril: Water (35: 65)

Acetonitril: Methanol: Water (25: 25: 50)


84

pH of the water used in preparation of mobile phase was adjusted to 3.00 with O-

phosphoric acid.

Selection of Mobile Phase Flow Rate

Mobile phase was adjusted at different flow rates within the range of 1.0 – 2.0 mL/min.

Separation of both the drugs, their respective peak area and peak height was studied at different

flow rate. Flow rate that showed better resolution, peak height and peak area was selected.

Selection of Column Oven Temperature

Resolution and elution of different compounds is significantly affected by column oven

temperature. Different column oven temperatures were applied in the range of 30 – 50 oC and

their effect on retention time, peak area, peak height and resolution was observed. The

temperature at which better resolution was obtained was selected for analysis.

Selection of Detector Wave Length

Standard solutions of domperidone and itopride HCl having concentration 2.0 µg/ml

each were prepared in the mobile phase and scanned using UV visible spectrophotometer at a

wavelength range of 200 – 400 nm separately. UV spectra of both the analytes were overlapped

and wavelength at which both the analytes had maximum absorbance was selected as wave

length of detector.


85

Effect of detector wave length on sensitivity was evaluated by analyzing the

compounds at different wave lengths in the close proximity to the selected on. Wave lengths

were studied in the range of 205 – 225 nm.

Selection of Internal Standard (I.S.)

Different compounds (Ciprofloxacin, Tenofavir, Neproxen Sodium and Clopidogril)

were evaluated for use as internal standard. Compound with best recovery and shorter analysis

time was selected as IS.

2.4.4.4 Validation of the HPLC-UV Method of Analysis

Method of analysis used for simultaneous determination of domperidone and itopride

HCl was validated according to ICH guidelines [102]. Method validation is necessary to

challenge the proposed method under various parameters of HPLC and to find out the limits of

allowed variability for different conditions. Following parameters were studied for validation of

the proposed method;

Specificity / Selectivity

Specificity of the method was determined by separate analysis of samples of each

analyte prepared in mobile phase and spiked plasma samples [104].


86

Accuracy of the Method

Percent recovery was used for determination of accuracy of the proposed method [105].

Percent recovery was calculated by spiking the biological sample at three appropriately

nominated concentrations (0.25, 0.50 and 1.00 µg/ml) of both the analytes. Concentration of IS

was kept constant and extraction was made using mobile phase. Sample (20 µL) was injected

into the HPLC system five times (n =5) and percent recovery was calculated using following

equation:

%Recovery B/A x100--------------- Eq-2.14

Where

A = Peak area response ratios of the analytes with respect to IS in the mobile phase

B = Peak area response ratios of the analytes with respect to IS in the spiked biological sample

Sensitivity of Method

Sensitivity of the method was evaluated on the basis of the determination of its limit of

detection (LOD) and lower limit of quantification (LLOQ) for all the studied analytes [102, 104].

Signal to noise ratio (S/N) was determined for each analyte using HPLC software. Limit of

detection (LOD) was the concentration at which signal to noise ratio (S/N) was 3 and lower limit

of quantification (LLOQ) was the concentration at which S/N ratio was 10.


87

Linearity of Method

Linearity of the proposed method was assessed by constructing calibration curve of

each analyte [102-103, 106]. Samples of both analytes were prepared in the mobile phase and

plasma in the concentration range of 20 – 100ng/ml. The ratio of the peak area of each analyte to

the peak area of internal standard was plotted against corresponding concentration. Slope (m),

intercept (b) and correlation coefficient (R2) were calculated from regression equations using

Microsoft Excel 2007.

Precision of the Method

Precision of the method was determined by repeatability and intermediate precision

[103]. Repeatability included both injection repeatability and analysis repeatability.

Injection Repeatability

Samples of appropriate concentration were prepared in mobile phase and injected 5

times, using the same protocols. Various parameters like retention time, peak height and peak

area was measured and mean, standard deviation (SD) and covariance (% RSD) were calculated.

Analysis Repeatability

Five samples of appropriate concentration were prepared in mobile phase and analyzed

separately (n = 5). Results were obtained as repeatability of the recovered amount, expressed by

mean, standard deviation (SD) and covariance (% RSD).


88

Intermediate Precision

Intermediate precision was determined by performing inter day and Intra-day study of

the samples of each analyte. Each sample was analyzed 3 times a day (at eight hour interval) for

3 consecutive days. Amount recovered from each sample was calculated using the following

equation:

C X/Y A/B Cs F ----------------- Eq-2.15

Where

and are peak area response ratios of the analytes with respect to IS in biological

samples and 1:1 mixture, respectively.

and are peak area response ratios of the analytes with respect to IS in 1:1 mixture and

standard samples, respectively

s is the concentration of each analyte in the 1:1 mixture

D is the dilution factor of each biological sample

Standard deviation and covariance were calculated for each sample


89

Stability of Solutions

Samples of all the analytes were stored at different conditions for one week period and

were then analyzed [104]. Samples were stored at:

At 25 oC

At 4 oC

At –20 oC

Percent stability and percent loss were calculated using the following equations;

% / 100------------------------- Eq-2.16

% ‒ 100------------------- Eq-2.17

Where

St = Stability of analyte at time “t”

S0 = Stability at initial time

Statistical Interpretation and Correlation of Data

Various statistical tools such as mean (x̄), standard deviation (SD) and relative standard

deviation (% RSD) was applied for the quantification of analytes.


90

2.5 Taste Masking of Itopride HCl

The taste of itopride HCl is highly bitter that required to be masked prior to formulating

as fast dispersible tablets (Orally Disintegrating Tablets and Effervescent Tablets). Taste

masking of itopride HCl was carried out by different techniques following determination of its

taste threshold.

2.5.1 Determination of Taste Threshold of Itopride HCl

Dilution method and sensory evaluation technique in combination with measurement of

UV absorbance of each solution was applied for the determination of taste threshold [107].

Various solutions of itopride HCl were prepared in purified water PH 7.10 having concentration

within the range of 10 – 200 µg/ml. Absorbance of each solution was measured using double

beam U.V spectrometer (Shimadzu, Japan) at 220 nm in triplicate (n = 3). Each solution (2 ml)

was given to a panel of 24 volunteers (healthy males) having an age range of 30 – 40 years. Each

volunteer was asked to retain the sample in oral cavity for 3 min, spit it and rinse mouth with

water. Response of each volunteer about the taste of solution was recorded. A gap of one hour

was made for second sample as washout time.


91

2.5.2 Taste Masking Techniques

Bitter taste of itopride HCl was masked by following 3 techniques;


Microencapsulation (Particle Coating)

Solid Dispersion Technique

2.5.2.1 Taste Masking of Itopride HCl by Granulation Technique

Water based wet granulation technique was applied for the taste masking of itopride

HCl by granulation technique. Polyvinyl pyrolidone K-30 and hydroxy propyl methyl cellulose

were two polymers used in granulation technique of taste masking. Composition of various

formulations of taste masking by granulation technique is depicted in Table-2.3.

Drug, polymer, micro crystalline cellulose and cross carmellose sodium were sifted

through mesh number 20 and dry mixed thoroughly in a laboratory scale wet mixer (Shiv

Pharma Engineers, India). Wet massing of the blend was performed for 10 min using purified

water. Wet mass was passed through mesh number 10 and dried at 60 ± 5 oC for 3 hrs (when

moisture content became less than 2.00% w/w). Dried mass was granulated through mesh

number 40, collected in a polythene bags and subjected to taste evaluation.


92

Table-2.3: Formulation of Taste Masked Itopride HCl Prepared by


Formulation ITP.HCl M.C.C. C.C. Sodium P.V.P. K-30 H.P.M.C. K4M

TIG-01 32.50 32.00 3.00 32.50 _

TIG-02 24.42 23.74 3.00 48.84 _

TIG-03 21.71 21.00 3.00 54.29 _

TIG-04 19.40 19.40 3.00 58.20 _

TIG-05 16.25 15.75 3.00 65.00 _

TIG-06 32.50 32.00 3.00 _ 32.50

TIG-07 24.42 23.74 3.00 _ 48.84

TIG-08 21.71 21.00 3.00 _ 54.29

TIG-09 19.40 19.40 3.00 _ 58.20

TIG-10 16.25 15.75 3.00 _ 65.00

Quantities are given as % w/w ITP HCl: Itopride HCl MCC: Micro Crystalline Cellulose C.C.Sodium: Cross Carmellose Sodium (Cross linked carboxy methyl cellulose sodium) PVP K-30: Polyvinyl Pyrollidone of K-30 Grade HPMC K4M: Hydroxypropyl Methyl Cellulose of K4M Grade


93

2.5.2.2 Taste Masking of Itopride HCl by Micro Encapsulation

Solvent evaporation technique was applied for microencapsulation of itopride HCl

[108]. Drug (Itopride HCl) and polymer were dissolved in acetone separately and mixed. Drug

polymer solution was poured drop wise into a beaker containing liquid paraffin (250 ml). The

mixture was stirred during the whole process at a higher speed. After complete addition of drug

polymer solution, stirring speed was reduced and continued till complete evaporation of acetone.

Micro capsules were hardened by addition of n-hexane to the system and continual stirring at

low speed for 30 min. Microcapsules were collected by decantation and filtration, washed with

n-hexane and dried at 40 ± 2 oC for 2 hrs. Preparation of microcapsules for taste masking of

itopride HCl is graphically presented in Fig-2.4.


94

Figure 2.4: Preparation of Microcapsules for Taste Masking of Itopride HCl


95

Table-2.4: Composition of Taste Masked Itopride HCl Prepared by Microencapsulation Technique

Formulation ITP HCl Eudragit E100 PVP-k90 PVP-k30 HPMC

TM-01 50.00 50.00 _ _ _

TM-02 33.33 66.67 _ _ _

TM-03 20.00 80.00 _ _ _

TM-04 50.00 _ 50.00 _ _

TM-05 33.33 _ 66.67 _ _

TM-06 20.00 _ 80.00 _ _

TM-07 33.33 _ _ 66.67 _

TM-08 20.00 _ _ 80.00 _

TM-09 14.29 _ _ 85.71 _

TM-10 50.00 _ _ _ 50.00

TM-11 33.33 _ _ _ 66.67

TM-12 20.00 _ _ _ 80.00

TM-13 20.00 _ 40.00 40.00 _

Quantities are given as %w/w ITP.HCl: Itopride HCl


96

2.5.2.3 Taste Masking of Itopride HCl by Solid Dispersion

Solid dispersions of itopride HCl were prepared by two methods i.e.

i. Solvent Method: Solvent method was applied for preparation of solid

dispersions using HPMC, PVP and PEGs

ii. Solvent Fusion Method:Solvent fusion method was used for preparation of solid

dispersions of PEGs and cetostearyl alcohol

In solvent method of solid dispersion preparation, [109] drug (Itopride HCl) and

polymer were dissolved in ethyl alcohol. Both the solutions were mixed with constant stirring

and solvent was evaporated on water bath. Solid dispersion was isolated, after complete

evaporation of solvent, pulverized and stored in air tight container for further use.

In solvent fusion method, polymer (PEG-4000, PEG-6000 and Cetostearyl alcohol) was

melted at 70 ± 3 oC and itopride HCl was dissolved in solvent (water or ethyl alcohol). Drug

solution was added to the molten polymer and stirred well. Solvent was removed by heating on

water bath; solid dispersion was pulverized and stored in air tight glass bottles.


97

Figure 2.5: Preparation of Solid Dispersion for Taste Masking of Itopride HCl by

Solvent Fusion Technique


98

Table-2.5: Composition of Taste Masked Itopride HCl Prepared by Solid


Formulation Code

ITP.HCl PEG-4000

PEG-6000

HPMC PVP-k30

PVP-k90

C.S.A

TIS-01 50.00 50.00 _ _ _ _ _

TIS-02 33.33 66.67 _ _ _ _ _

TIS-03 20.00 80.00 _ _ _ _ _

TIS-04 9.09 90.91 _ _ _ _ _

TIS-05 6.25 93.75 _ _ _ _ _

TIS-06 20.00 80.00 _ _ _ _ _

TIS-07 11.11 88.89 _ _ _ _ _

TIS-08 9.09 90.91 _ _ _ _ _

TIS-09 9.09 _ 90.91 _ _ _ _

TIS-10 7.69 _ 92.31 _ _ _ _

TIS-11 50.00 _ _ 50.00 _ _ _

TIS-12 50.00 _ _ 50.00 _ _ _

TIS-13 33.33 _ _ 66.67 _ _ _

TIS-14 25.00 _ _ 75.00 _ _ _

TIS-15 20.00 _ _ 80.00 _ _ _

TIS-16 9.09 _ _ 90.91 _ _ _

TIS-17 16.67 _ _ _ _ 83.33 _

TIS-18 9.09 _ _ _ _ 90.91 _

TIS-19 16.67 _ _ _ 83.33 _ _


99

TIS-20 9.09 _ _ _ 90.91 _ _

TIS-21 50.00 _ _ _ _ _ 50.00

TIS-22 33.33 _ _ _ _ _ 66.67

TIS-23 16.67 _ _ _ _ _ 83.33

TIS-24 9.09 _ _ _ _ _ 90.91

TIS-25 9.09 _ _ _ _ _ 90.91

TIS-26 8.33 _ _ _ _ _ 83.33

Quantities are given as %w/w CSA: Cetostearyl Alcohol ITP: Itopride HCl PEG: Poly Ethylene Glycol


100

2.5.3 Taste Evaluation of Taste Masked Itopride Hydrochloride

Taste of the taste masked itopride HCl was evaluated by the following two methods;

Spectrophotometric Methods

Panel Testing (Human Subjects)

2.5.3.1 Taste Evaluation by Spectrophotometric Method

Taste masked itopride HCl equivalent to per tablet quantity of itopride HCl was added

to a syringe (5 ml capacity) containing 3 ml of simulated slivary fluid (phosphate buffer pH

6.20).

The syringe was revolved end to end at a rate of 10 times per min for 3 min. The test

media was filtered through a filter paper of pore size of 0.50 micron and analyzed

spectrophotometrically for amount of drug released [71]. Absorbance was measured in triplicate

and results were presented as average ± S.D. Taste of the sample was estimated by the

comparison of absorbance of the solution with taste threshold of itopride HCl.

2.5.3.2 Taste Evaluation by Human Subjects (Panel Testing)

Taste was evaluated by a panel of 24 human volunteers (age range of 25 – 40 years)

trained about the characterization of different taste levels [110-111]. Each volunteer was given

taste masked itopride HCl equivalent to per tablet quantity of itopride HCl, and was asked to


101

retain it in oral cavity for 30 sec. After expectoration, taste level observed by the volunteer was

recorded according to the numerical scale ranging from 0 – 4 as under:

0: Tasteless

1: Bitter Sensation

2: Slightly Bitter

3: Bitter

4: Highly Bitter

After each determination oral cavity was rinsed with water and one hour was used as

washout time.


102

2.6 Preliminary Study

2.6.1 Determination of Per Tablet Quantity of Taste Making Agents in Orally

Disintegrating Tablets

Quantity of taste making agent per tablet of orally disintegrating tablets was determined

by preparation of placebo tablets with same excipients (intended to be used in formulation of

ODTs) containing sweetener (aspartame) and flavor (tutti frutti). Sweetener was used in different

concentrations (1.00%, 2.00%, 3.50% and 4.00% w/w) with constant concentration (0.50% w/w)

of flavor tutti frutti (Table-2.6). Placebo tablets were evaluated for taste by a panel of 24 healthy

male volunteers (age: 25 – 40 years) selected from Nowshera, Pakistan, through written consent

form. Single formulation was evaluated by complete panel and observations about taste and

mouth feel were recorded. All the volunteers were asked to rinse mouth with water after each

evaluation. One hour wash out time was included between taste evaluations of two formulations.

Taste of each combination was ranked as:

4 Strongly sweet 3 Sweet 2 Pleasant 1 Acceptable 0 Bitter tasting


103

Table-2.6: Formulation of Placebo Tablets for Determination of Quantity of

Taste Making Agents in Orally Disintegrating Tablets

Ingredients TP-01 TP-02 TP-03 TP-04 TP-05 TP-06

Micro Crystalline Cellulose 25.00 25.00 25.00 25.00 25.00 25.00

Tablettose-80 69.00 67.50 66.50 65.50 65.00 64.50

Flavor (Tutti frutti) 00.00 00.50 00.50 00.50 00.50 00.50

Aspartame 00.00 1.00 2.00 3.00 3.50 4.00

Colloidal Silicon Dioxide 1.00 1.00 1.00 1.00 1.00 1.00

Magnesium Stearate 1.50 1.50 1.50 1.50 1.50 1.50

Cross Carmellose Sodium 3.50 3.50 3.50 3.50 3.50 3.50

Quantities are given as % w/w

2.6.2 Determination of Per Tablet Quantity of Taste Making Agent in Effervescent

Tablets

Quantity of taste making agent in effervescent tablets was determined by taste

evaluation of different quantities of taste making agents. Placebo effervescent tablets [65] with

different levels of taste making combination were prepared using citric acid and sodium

bicarbonate as effervescent pair. Taste making combination consisted of flavor (tutti frutti) and a

sweetening agent (aspartame). Level of flavor was constant (0.50% w/w) and sweetener was

studied at five concentrations i.e. 1.00, 2.00, 3.00, 3.50 and 4.00% w/w of the tablet (Table-2.6).

One tablet from each combination was allowed to disperse in a glass of water (250 ml) at


104

ambient temperature. Taste of the dispersion was evaluated by a panel of 24 healthy male human

volunteers aged in the range of 25 – 40 years. One combination was tested at a time by the panel

and next was evaluated after a washout time of 01 hr. After taste evaluation each volunteer was

asked to rinse oral cavity with water. Observations of each volunteer were recorded on a scale

ranging from tasteless to strongly bitter as under;

4 Strongly sweet 3 Sweet 2 Pleasant 1 Acceptable 0 Bitter taste

Table-2.7: Composition of Placebo Tablets for Determination of Quantity of

Taste Making Agents in Effervescent Tablets

Ingredients TEE-01 TEE-02 TEE-03 TEE-04 TEE-05 TEE-06


Tablettose-80 53.00 51.50 50.50 49.50 48.50 47.50

Citric acid Anhydrous 10.00 10.00 10.00 10.00 10.00 10.00

Sodium Bicarbonate 10.00 10.00 10.00 10.00 10.00 10.00

Flavor (Tuti fruti) _ 00.50 00.50 00.50 00.50 00.50

Aspartame _ 1.00 2.00 3.00 4.00 5.00

Colloidal Silicon Dioxide 1.00 1.00 1.00 1.00 1.00 1.00


Cross Carmellose Sodium 2.50 2.50 2.50 2.50 2.50 2.50

Quantities are given as % w/w


105

2.6.3 Pulverization of Acid Moieties and Surface Passivation of Sodium

Bicarbonate

Prior to use both the acid moieties (citric acid and tartaric acid) intended to be used in

formulation of effervescent tablets were pulverized through a mesh number 40 using rotary

granulator (STC, China). After pulverization acidic moities were dried at 45 ± 5 oC for 1 hr to

remove any moisture adsorbed during pulverization. By pulverization crystalline structure of

acid moieties was converted into amorphous form facilitating uniform blending with rest of the

ingredients.

Surface passivation is defined as reducing active surface area available for reaction

with acid by converting some of the surface sodium bicarbonate to sodium carbonate.

Surface passivation was achieved by heating sodium bicarbonate at 120 ± 5 oC for 30

min. After heating for 30 min, sodium bicarbonate was cooled down to room temperature in

desiccators, sifted through mesh number 60 and stored in air tight container. This surface passive

sodium bicarbonate was used in formulation of effervescent tablets.

2.6.4 Selection of Acid to Base Ratio for Effervescence Reaction

Acid to base ratio of the effervescent pair was determined on the basis of stichometric

calculations of balanced acid and base neutralization reaction [65]. Effervescent reaction between

calculated amount of acid and base was carried out in purified water (200 ml, pH 7.00) at

ambient temperature. After completion of acid base reaction, pH of the solution was determined


106

to observe any remaining acid or base. Lower pH of the solution indicated presence of un-reacted

acid and vice versa for higher pH.

2.6.5 Determination of Per Tablet Quantity of Effervescent Pair

Quantity of effervescent pair (citric acid, tartaric acid/ sodium bicarbonate) in

effervescent tablets was determined by comparison of effervescence time of placebo tablets

containing different concentration of effervescent pair. Placebo effervescent tablets with three

different percentages (10%, 20% and 30%w/w) of effervescent pair were prepared and their

effervescence time was determined.

Acid/base pair constituted 10%, 20% and 30% of the total tablet weight and ratio of

acid to base in effervescence pair was 1:1 by weight. Compressed placebo tablets were subjected

to evaluation for effervescence time using purified water (200 ml) at ambient temperature.

Effervescence time was determined for 6 tablets, randomly selected from each combination and

their mean effervescence time was calculated.


107

2.7 Preparation of Powder Blend

Fast dispersible tablets of domperidone and itopride HCl were prepared by direct

compression. Excipients were selected for both types of fast dispersible tablets on the basis of

their SeDeM-ODT and SeDeM results. Preparation of powder blend involved mixing of all the

ingredients as per their respective formulations. All the ingredients were weighed accurately

using digital balance (Libror AEG-120, Schimadzu, Japan), according to their respective

formulations. Except magnesium stearate, all the ingredients were sifted through mesh # 20

(Endecott, England) and blended in laboratory scale double cone mixer for 10 min. Magnesium

stearate was sifted through mesh #60 and blended for further 5 min. In case of ODTs prepared

by sublimation technique, menthol was pulverized before blending.

Taste masked granules of were used in the preparation of fast dispersible tablets of

itopride HCl. Quantity of taste masked granules was calculated on the basis of drug content and

blended with rest of the excipients.

Powder blend for effervescent tablets was prepared by sifting all the material (except

magnesium stearate) through mesh # 20 and blended for 15 min. Magnesium stearate was

blended with rest of the ingredients after sifting through mesh # 60. Effervescent tablets are very

much sensitive to the atmospheric humidity. At elevated humidity components of effervescent

pair react with each other starting a self-propagating reaction resulting in complete deterioration

of the product. Therefore all the processing was carried under the controlled conditions of

humidity (relative humidity below 35 %).


108

Figure 2.6: Tablet Preparation by Direct Compression


109

2.8 Tablet Preparation

2.8.1 Preparation of Orally Disintegrating Tablets of Domperidone using Super

Disintegrants

Orally disintegrating tablets of domperidone were prepared by direct compression

method. Powder for each formulation was compressed into tablet using rotary compression

machine (ZP-21, STC, China). Oval shaped, shallow concave (10 mm) punches were used for

compression of orally disintegrating tablets of domperidone prepared using super disintegrants

(Table-2.8). Theoretical weight of tablet was 200 mg and at least 500 tablets were compressed

for each formulation.


110

Table-2.8: Formulation of Orally Disintegrating Tablets of Domperidone


Ingredients ODD-01 ODD-02 ODD-03 ODD-04

Domperidone 5.00 5.00 5.00 5.00

Micro Crystalline Cellulose 25.00 25.00 25.00 25.00

Magnesium Stearate 1.50 1.50 1.50 1.50

Flavor 4.00 4.00 4.00 4.00

Cross Carmellose Sodium 2.50 3.50 5.00 5.00

Starch Maize _ _ _ 5.00

PEG 4000 _ 1.50 1.50 _

Colloidal Silicon Dioxide 1.00 1.00 1.00 1.00

Manitol _ _ 10.00 _

Tablettose-80® 61.00 58.50 47.00 53.50

Quantities are given as %w/w Flavor: Flavoring Agent (tuti fruti flavor, 0.50%) and Sweetener (Aspartame, 3.50%)

2.8.2 Preparation of Orally Disintegrating Tablets of Domperidone by


Orally disintegrating tablets of domperidone prepared by sublimation technique (Table-

2.9) were compressed using 10 mm oval shallow concave punches.Compression weight was 200

mg/tablet and 500 tablets were compressed for each formulation.


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Table–2.9: Formulation of Orally Disintegrating Tablets of Domperidone Prepared by


Ingredients ODS-01 ODS-02 ODS-03 ODS-04 ODS-05 ODS-06 ODS-07 ODS-08 ODS-09

Domperidone 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00

Micro Crystalline Cellulose 25.00 25.00 25.00 25.00 25.00 25.00 25.00 25.00 25.00

Magnesium Stearate 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.5 1.50

Flavor 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00

Ammonium Bicarbonate _ _ _ _ _ 10.00 15.00 5.00 5.00

Menthol _ 10.00 15.00 5.00 5.00 _ _ _ _

Coloidal Silicon Dioxide 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00

Cross Carmellose Sodium _ _ _ _ 3.00 _ _ _ 3.00

Tablettose-80® 63.50 53.50 48.50 58.50 55.50 53.50 48.50 58.50 55.50

Quantities are given as %w/w Flavor: Flavoring Agent (tuti fruti flavor, 0.50%) and Sweetener (Aspartame, 3.50%) C.C.Sodium: Cross carmellose sodium (Cross linked carboxy methyl cellulose sodium)


112

2.8.3 Preparation of Effervescent Tablets of Domperidone

Effervescent tablets were relatively larger in size having higher compression weight.

Tablets were prepared by compressing lubricated powder blend using rotary compression

machine D3-A (Manesty, England) fitted with flat 13.00 mm round punches with bisection line

on one side. Effervescent tablets of domperidone had compression weight of 600 mg/tablet and

500 tablets were compressed for each formulation. Composition of effervescent tablets of

domperidone is presented in Table-2.10.


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Table-2.10: Formulations of Effervescent Tablets of Domperidone

Quantities are given as %w/w S. Bicarbonate: Sodium bicarbonate S. S. Glycolate: Sodium starch glycolate C.C. Sodium: Cross carmellose sodium (cross linked carboxy methyl cellulose sodium sodium) Mg. Stearate: Magnesium stearate M.C.C: Micro crystalline cellulose

Ingredients ED-01 ED-02 ED-03 ED-04 ED-05 ED-06 ED-07 ED-08 ED-09 ED-10 ED-11 ED-12

Domperidone 1.67 1.67 1.67 1.67 1.67 1.67 1.67 1.67 1.67 1.67 1.67 1.67

Citric acid 10.00 10.00 10.00 10.00 10.00 10.00 _ _ _ _ _ _

S.Bicarbonate 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00

Tartaric Acid _ _ _ _ _ _ 10.00 10.00 10.00 10.00 10.00 10.00

S. S. Glycolate _ _ _ 5.00 3.00 2.50 _ _ _ 5.00 3.00 2.50

C. C. Sodium _ 5.00 3.00 _ _ 2.50 _ 5.00 3.00 _ _ 2.50

Mg. Stearate 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50

Flavor 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00 3.00

M.C.Cellulose 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00

Tablettose-80 58.83 55.83 53.83 55.83 53.83 53.83 58.83 55.83 53.83 55.83 53.83 53.83


114

2.8.4 Preparation of Orally Disintegrating Tablets of Itopride HCl using Super

Disintegrants

Orally disintegrating tablets of itopride HCl were compressed using 10.00 mm round

shallow concave punch. Compression weight of the tablets was 350 mg and 500 tablets were

compressed for each formulation (Table-2.11). Taste masked itopride HCl prepared by

granulation technique was used in formulation of orally disintegrating tablets.

Table-2.11: Formulation of Orally Disintegrating Tablets of Itopride HCl


Ingredients ODI-01 ODI-02 ODI-03 ODI-04 ODI-05 ODI-06

Taste masked Itopride HCl 73.71 73.71 73.71 73.71 73.71 73.71


Flavor 4.00 4.00 4.00 4.00 4.00 4.00

Cross Carmellose Sodium _ 3.00 5.00 2.50 _ _

Sodium Starch Glycolate _ _ _ 2.50 3.00 5.00

Tablettose-80 14.58 11.58 9.58 9.58 11.58 9.58


Quantities are given as %w/w Flavor: Flavoring Agent (tuti fruti flavor, 0.50%) and Sweetener (Aspartame, 3.50%)


115

2.8.5 Preparation of Orally Disintegrating Tablets of Itopride HCl by Sublimation

Technique

Orally disintegrating tablets of itopride HCl prepared by sublimation technique were

compressed using 10.50 mm round, shallow concave punches (Table-2.12). Compression weight

of the tablets was 350 mg and 500 tablets were compressed for each formulation.


116

Table-2.12: Formulations of Orally Disintegrating Tablets of Itopride HCl Prepared by Sublimation

Technique

Ingredients OSI-01 OSI-02 OSI-03 OSI-04 OSI-05 OSI-06 OSI-07 OSI-08 OSI-09

Taste Masked ITP.HCl 73.71 73.71 73.71 73.71 73.71 73.71 73.71 73.71 73.71

Magnesium Stearate 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00

Flavor 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00

Ammonium Bicarbonate _ 5.00 10.00 15.00 5.00 _ _ _ _

Menthol _ _ _ _ _ 5.00 10.00 15.00 5.00

Tablettose-80 16.00 11.00 6.00 1.00 8.00 11.00 6.00 1.00 8.00

Micro Crystalline Cellulose 4.29 4.29 4.29 4.29 4.29 4.29 4.29 4.29 4.29

Cross Carmellose Sodium _ _ _ _ 3.00 _ _ _ 3.00

Quantities are given as %w/w ITP.HCl: Itopride HCl


117

2.8.6 Preparation of Effervescent Tablets of Itopride HCl

Effervescent tablets were compressed using rotary compression machine D3-A

(Manesty, England) fitted with flat 13.00 mm round punches with bisection line on one side.

Compression weight of the tablet was 600 mg/tablet and 500 tablets were compressed for each

formulation. Composition of effervescent tablets of itopride HCl is presented in Table-2.13.


118

Table-2.13: Formulations of Effervescent Tablets of Itopride HCl Ingredients EI-01 EI-02 EI-03 EI-04 EI-05 EI-06 EI-07 EI-08 EI-09 EI-10 EI-11 EI-12

Taste Masked ITP 43.00 43.00 43.00 43.00 43.00 43.00 43.00 43.00 43.00 43.00 43.00 43.00

Citric Acid 10.00 10.00 10.00 10.00 10.00 10.00 _ _ _ _ _ _

S. Bicarbonate 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00

Tartaric Acid _ _ _ _ _ _ 10.00 10.00 10.00 10.00 10.00 10.00

S.S. Glycolate _ _ _ 3.00 5.00 2.50 _ _ _ 3.00 5.00 2.50

C.C. Sodium _ 3.00 5.00 _ _ 2.50 _ 3.00 5.00 _ _ 2.50

M. Stearate 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50 1.50

M.C. Cellulose 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00

Tablettose-80 20.50 17.50 15.50 17.50 15.50 15.50 20.50 17.50 15.50 17.50 15.50 15.50

Quantities are given as %w/w M.C. Cellulose: Micro crystalline cellulose S.B.C: Sodium bicarbonate S.S.Glycolate: Sodium starch glycolate


119

2.9 In vitro Evaluation

In vitro evaluation of all the formulations, of fast dispersible tablets was divided into

pre compression evaluation and post compression evaluation.

2.9.1 Pre Compression Evaluation (Powder Blend Evaluation)

Prior to compression, powder blends were evaluated for their flow and compressibility.

Various parameters related to the flow and compressibility like bulk density, tapped density,

angle of repose, flow ability, compressibility index (Carr’s Index) and Hausner ratio were

determined for each formulation. All the parameters were determined according to the

procedures described in Section 1.4.2.1. All the determinations were made in triplicate and

results were presented as Mean ± Standard Deviation.


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2.9.2 Post Compression Evaluation

2.9.2.1 Physical Parameters of Tablets

Physical parameters of the tablets included weight variation, tablet thickness, wetting

time of tablet, mouth feel, loss on drying and drug content. They were determined individually

for each formulation.

Thickness of the Tablets

Thickness of the tablets was measured using digital hardness and thickness tester

(Pharma Test, Germany). Thickness was determined for 10 tablets randomly selected from each

formulation and their mean was taken (n = 10).

Weight Variation of Tablets

Weight variation test for compressed tablets was performed according to British

Pharmacopoeia [15]. Twenty tablets, randomly selected from each formulation, weighed using

digital balance (Schimadzu, Japan), average weight and weights on both extremes were

calculated. Weight variation was calculated from average weight and extreme weights.


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Wetting Time of Tablets

Wetting time of the tablet is an indicator of water penetration into the tablet core.

Smaller wetting time denotes quick water penetration into the tablet core and vice versa. Wetting

time of the tablets was measured using the reported method [112]. One tablet was placed on filter

paper soaked with water and the time for complete wetting of tablet was measured. Results were

obtained in triplicate for each formulation and results were presented as Mean ± S.D. (n = 3).

Mouth Feel of Tablets

Mouth feel was determined only for ODTs by panel method [113]. A penal consisting

of 24 healthy male volunteers with age range of 25 – 40 years were selected. Each volunteer was

asked to disintegrate one tablet in oral cavity and to record the mouth feeling according to the

following scale: Mouth feel of tablets was ranked as

++ =Very good

+ = Good

- = Not good

- G= Not good accompanied by grittiness


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Drug Content of Tablets

Drug content of both the drugs was determined using UV visible spectrophotometric

method of analysis, developed and validated for domperidone and itopride HCl. Twenty tablets

were randomly selected from each formulation and crushed to fine powder. Powder equivalent to

the 10 mg domperidone was transferred to a volumetric flask volumetric flask (100 ml)

containing methanol. Flask was shaken for 30 min to completely dissolve the drug using

mechanical flask shaker. Solution was filtered diluted to get a concentration of 10µg/ml.

Absorbance of the solution was measured at 284 nm using double beam spectrophotometer

(Shimadzu, Japan).

Itopride HCl was analyzed using the same method as described for Domperidone

except it was dissolved in water.

Standard solutions of the same concentration were prepared for domperidone and

itopride HCl using the same solvent and their absorbance was measured under same conditions.

Drug content was calculated using following equation;

%

100 ----------Eq-2.18

Where

A sample = Absorbance of sample solution

A standard = Absorbance of standard solution


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2.9.2.2 Mechanical Properties of Tablets

Crushing Strength of Tablets

Crushing strength of tablets was determined using digital hardness and thickness tester

(Pharma Test, Germany). Ten tablets were selected randomly from each formulation; their

crushing strength was measured and Mean crushing strength was calculated.

Tensile Strength of Tablets

Tensile strength of tablets was calculated from the mean crushing strength and mean

thickness (n = 10) of the tablets. Following equation [92] was used for calculation of tensile

strength;

T ------------- Eq-2.19

Where

T = Tensile strength of tablet (Kg/mm2)

F = Crushing strength of the tablet (Kg)

D = Diameter of the tablet (mm)

H = Tablet thickness (mm)

π = Constant of proportionality (3.143)


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Specific Crushing Strength of Tablets

Specific crushing strength of the tablet was calculated from mean values of their

crushing strength and thickness using the following equation;

τ ------------------ Eq-2.20

Where

τ = Specific hardness of tablet (Kg/mm2)

F = Crushing strength of the tablet (Kg)

T = Thickness of the tablet (mm)

D = Diameter of the tablet (mm)

Friability of Tablets

Friability of the tablets from each formulation was determined as per official

compendia, [114] using a single drum friabilator (Faisal Engineering, Pakistan). Tablets (6.5 g)

were randomly selected from each formulation and were de dusted. Tablets were loaded into the

drum of friabilator and rotated at 25 RPM for 4 min. After completion of revolutions, tablets

were unloaded, de dusted and reweighed. Friability of the tablets was calculated using following

equation;

F x100 ----------------- Eq-2.21

Where

F = Friability of the tablets (%)

Wb = Weight of tablets before rotation in friabilator (g)

Wa = Weight of tablets after rotation in friabilator (g)


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2.9.2.3 Disintegration Behavior of Tablets

Disintegration behavior of ODTs was determined from their disintegration time and

oral disintegration time. In case of effervescent tablets, effervescence time was used as

disintegration time of the tablet.

Disintegration Time

Disintegration time of the tablets was determined according to USP 32/NF 27, [100]

using USP tablet disintegration testing apparatus (Pharma Test, Germany). Distilled water held at

37 oC ± 2 oC was used as disintegration medium. Six tablets were selected randomly from each

formulation and disintegration time was determined. As ODTs had smaller disintegration time,

so it was determined individually for each tablet. Mean disintegration time was taken as

disintegration time of the tablet. Results were presented as Mean ± S.D.

Oral Disintegration Time

Oral disintegration time of ODTs was determined by a panel of six healthy male

volunteers with age range of 25 – 40 years. Before the test, each volunteer was asked to rinse his

mouth with water (200 ml). One tablet was placed on the tongue of the subject and stop watch

was started immediately. All the volunteers were instructed to cause tumbling action by moving

tablet gently against the upper part of oral cavity and avoided side to side tumbling or biting.


126

Time taken for complete disintegration of tablet was noted. Mean of six determinations was

taken as oral disintegration time [41].

Effervescence Time of Tablets

Effervescence time was determined as per European pharmacopoeia, 2005. One tablet

was dispersed in water (250 ml) at room temperature and noted time the time required for

completion of effervescence using digital stop watch (Sony, Japan). Effervescence time was

determined for six tablets, individually, from each formulation and their mean was taken as

effervescence time.

2.9.2.4 In vitro Drug Release (Dissolution Rate)

In-vitro drug release was studied only for orally disintegrating tablets. Dissolution rate

of domperidone was determined according to British pharmacopoeia using dissolution apparatus-

ІІ (paddle method) (Pharma Test, Germany). Dissolution rate was studied in 0.1 N Hydrochloric

acid (900 ml) held at 37 ± 2 oC. Speed of rotation of paddle was 50 RPM [15]. Sample (5 ml)

was withdrawn at regular time interval (0, 5 10, 15, 30, 45 and 60 min) and filtered. Amount of

drug released was determined by measuring UV absorbance the sample at 284 nm using double

beam U.V. spectrophotometer (Shimadzu, Japan). Absorbance of each sample was measured in

triplicate and results were presented as mean ± standard deviation. After each sampling, volume

of dissolution media was corrected with same quantity of the dissolution media held at the same

temperature.


127

In vitro drug release from orally disintegrating tablets of itopride HCl was studied using

USP dissolution apparatus-ІІ (paddle method). One tablet was added to the flask of dissolution

apparatus containing 900 ml of purified water (pH 7.00 ± 0.20) kept at 37 ± 2 oC as dissolution

medium. Speed of peddle was kept at 50 rpm. Sample (5 ml) was withdrawn at 0, 5, 15, 30, 45

and 60min. After each sampling, volume of dissolution media was corrected with same quantity

of dissolution media held at the same temperature. Absorbance of each sample was measured in

triplicate using double beam UV Visible spectrophotometer (Shimadzu, Japan) at 220 nm using

dissolution media as blank. Results were presented as Mean ± S.D. (n = 3).


128

2.9.3 Parametric Study

Fast dispersible tablets (ODTs and effervescent tablets) are susceptible to various

parameters like environmental humidity, compression force and tablet dimension. Effect of

theses parameters was studied on optimal formulations of ODTs and effervescent tablets..

2.9.3.1 Moisture Treatments of Orally Disintegrating Tablets

Effect of moisture treatment on ODTs was studied by subjecting tablets from optimal

formulation to elevated(85%) relative humidity in a climatic chamber for 24 hrs [48]. Tablets

samples were analyzed at 0, 2, 4, 8, 16 and 24 hrs for moisture content, mechanical properties

(crushing strength and friability), and disintegration time. Crushing strength of 10 tablets was

measured their mean and standard deviation were calculated (n = 10). Disintegration time was

determined for six tablets (n = 6) and moisture content was determined in triplicate (n = 3) at

each sampling point.

2.9.3.2 Compression Force Profile of Orally Disintegrating Tablets

Tablets from optimal formulation from ODTs of domperidone were used in

determination of compression force profile. Tablets from optimal formulation were compressed

at various levels of crushing strength by applying different compression force and effect of

compression force was evaluated on friability, disintegration time and oral disintegration time

[48].


129

Tablets (10.00 mm, oval shallow concave) were compressed at compression weight of

200 mg having crushing strength in the following three levels:

3 – 5 kg

6 – 8 kg

8 – 10 kg

2.9.3.3 Study of Effect of Different Parameters on Rate of Effervescence Reaction

Effervescence reaction of tablets is highly susceptible to various parameters of the

tablets like tablet dimension, tablet compressibility and presence of disintegrant. Effect of these

parameters on effervescence time of tablets was evaluated separately on effervescent tablets of

domperidone.

Effect of Tablet Dimension on Effervescence Time

Effect of tablet dimension (surface area of the tablet) on effervescence time was studied

by compressing effervescent domperidone tablets on smaller (10.00 mm oval, shallow concave)

punch and larger punch (13.00 mm round, flat surface). Effervescence time of the tablets was

determined according to European Pharmacopoeia [115]. Effect of tablets dimension was

evaluated by comparison of effervescence time of the two sized tablets. Crushing strength of

tablets compressed on smaller punch was kept in range so that its tensile strength and specific

crushing strength were similar to that of the larger sized tablets.


130

Effect of Disintegrants on Effervescence Time

Effect of disintegrants on effervescence time was evaluated on the basis of difference in

effervescence time of tablets with and without disintegrant at constant concentration of

effervescent material. Effervescent tablets were prepared with 20% w/w of effervescent pair

having crushing strength in the range of 7 – 10 kg. Disintegrants were included separately at two

concentrations (3% w/w and 5% w/w) and in combination (2.50 %w/w). Effervescence time was

determined for six tablets and their mean was taken.

Effect of Tablet Compressibility on Effervescence Time

Tablet porosity and water penetration are inversely related to compressibility of the

tablet. Effect of tablet compressibility on effervescence time was evaluated by comparison of

effervescence time of tablets compressed at different levels of crushing strength. Tablets from

optimal formulations of effervescent domperidone tablets were compressed at the following

three levels of crushing strength;

4 – 7 kg

7 – 12 kg

12 – 16 kg

Tablets were selected randomly from each level and their effervescence time was

determined individually according to European pharmacopoeia. Mean of six determinations (n =

6) was taken as effervescence time for tablets from each group.


131

2.9.4 In vivo Evaluation of Optimal Formulations of Fast Dispersible Tablets

In vivo evaluation included both pharmacokinetic evaluation and clinical evaluation.

Pharmacokinetic evaluation was carried out in albino rabbits while clinical evaluation in patients

receiving anti-cancer chemotherapy.

2.9.4.1 Pharmacokinetic Evaluation of Fast Dispersible Tablets

Pharmacokinetic evaluation of optimal formulations of fast dispersible tablets was

carried out in healthy albino rabbits.

Study Design for Pharmacokinetic Evaluation of Fast Dispersible Tablets

Pharmacokinetic evaluation of optimal formulations of fast dispersible tablets (ODTs

and Effervescent Tablets) was carried out in following different steps;

Animal handling

Drug administration and blood sampling

Determination of drug concentration in blood

Determination of pharmacokinetic parameters


132

Animal Handling

Pharmacokinetic evaluation of fast dispersible tablets (ODTs and effervescent tablets)

was carried out in healthy male albino rabbits weighing in the range of 1.50 – 2.50 kg. During all

these experiments current guidelines for the care of laboratory animals and ethical guidelines for

the investigation of experimental pain in conscious animals were followed strictly. Prior to

starting study all the animals were housed in separate cages under controlled environment (22 ±

5 oC, 50 ± 5% R.H and 12 hrs dark/light cycles). Prior to experiment rabbits were starved for 12

hrs and were allowed access to water only.

Drug Administration

Administration of Orally Disintegrating Tablets

Tablets were administered directly to the stomach of rabbit using gastric intubation tube

made of silicon. One tablet was set at the tip of the intubation tube and administered to the rabbit.

Administration of Effervescent Tablets

Effervescent tablets were dispersed in minimum amount of water (2.00 ml) and

administered to the stomach of the rabbit directly by gastric intubation tube.


133

Blood Sampling

Blood samples (1 ml) were collected from marginal marginal vien of the rabbit at 0, 5,

15, 30, 60, 120, 180, 240, 300 and 360 min after administration of tablets (ODTs and

Effervescent Tablets). Samples were collected using 3 ml disposable syringe in heparin tube. All

the blood samples were centrifuged at 4000 RPM for 10 min to separate plasma. Plasma samples

were isolated in separate ependorf tubes and stored till further analysis.

Analysis of Blood Samples

Concentration of each drug (Domperidone and Itopride HCl) in plasma samples,

collected at specified time intervals, was quantified by HPLC.

Determination of Pharmacokinetic Parameters

The plasma concentration of both the drugs (Domperidone and Itopride HCl) in rabbit’s

plasma samples was quantified at various time intervals following oral administration of fast

dispersible tablets. The data was fitted in the compartmental models to access different

pharmacokinetic parameters such as t max, Cmax, Half life (t ½) and Area under cure (AUC). The

pharmacokinetic data was assessed using Microsoft Excel 2007 and PK-Summit®, a

pharmacokinetics software.


134

2.9.4.2 Clinical Evaluation

Clinical evaluation of ODTs was carried out in patients receiving anti-cancer

chemotherapy. The study was approved by the ethical committee of the clinical setup (Anexture-

1) and all the patients were willing to participate. Optimal formulation of ODTs of domperidone

prepared using super disintegrants was selected for clinical evaluation. Each patient was given

orally disintegrating tablets of domperidone, conventional domperidone tablets (Motillium) and

drug free ODTs and their response was evaluated.

Patients Inclusion Criteria

Cancer patients receiving anti-cancer chemo therapy were included in the study. Total

60 patients (41 males and 19 females) were selected.

Patients Exclusion Criteria

Patients with any underlying disease causing nausea and vomiting like gastro

intestinal obstruction, active peptic ulcer and hyper calcemia were excluded from

the study.

Patients who have received medications with potential anti-emetic activity, during

24 hours prior to the study

Patients with impaired liver function

Patients taking alcohol/ snuff

Smokers


135

Drug Administration

Sixty patients receiving anti-cancer chemo therapy were randomly selected for

comparative evaluation of ODTs of domperidone and conventional domperidone tablets

(Motillium). Tablet Motillium manufactured by Johnsons and Johnsons, Pakistan, was selected

as standard conventional tablet for comparison with ODTs as it was the mostly prescribed

domperidone brand in Pakistan. Patients were divided into three groups (each of 20 patients) and

two day study was carried out in each group as per schedule presented in Table-2.14. Each

patient received three types of tablets for two days post chemotherapy cycle. Conventional

tablets were administered with a glass of water while ODTs were placed in mouth. Placebo ODT

was prepared using the same ingredients except active constituents. Drug free ODTs were

administered blindly to the patients and their response was evaluated under the same conditions.


136

Table-2.14: Schedule for Administration of Test Products to the Patients for

Anti Emetic Response Evaluation

Cycle Day Group-1 Group-2 Group-3

1st 1 ODTs Motillium Placebo ODTs

2 ODTs Motillium Placebo ODTs

2nd 1 Placebo ODTs ODTs Motillium

2 Placebo ODTs ODTs Motillium

3rd 1 Motillium Placebo ODTs ODTs

2 Motillium Placebo ODTs ODTs

Motillium: Conventional Domperidone Tablets ODTs: Orally Disintegrating Tablets of Domperidone Placebo ODTs: Drug Free Orally Disintegrating Tablets

The study was carried out as 3 sequences 3 periods study. In 1st sequence Group-1

received orally disintegrating tablets, Group-2 received Motillium and Group-3 received placebo

orally disintegrating tablets. Similarly in 2nd and 3rdperiods, regimen was changed for each group

so that each patient received ODTs, Motillium and placebo ODTs. Each patient was acting as

self-control as he was receiving all the three medications i.e. effect of the three medications was

evaluated in each patient. Rescue medication was allowed during the test period and it was

considered as treatment failure.


137

Table-2.15: Questionnaire to be completed by the Patient after Two Day

Study

1 Time taken for prevention of nausea/ vomiting (time of onset for action) Quick Slow

2 Difficulty felt during swallowing Yes No

3 Patient acceptance (Size, shape and taste of tablet)

4 Preference of the dosage form ODTs C. Tablet

5 Patient more compliant to which dosage form ODTs C. Tablet

6 Ease of administration ODTs C. Tablet

7 No of emetic episodes during study period

8 Severity of emetic episode

9 More nausea observed with ODTs C. Tablet

10 Rescue medication or other anti-emetic taken by the patient Yes No

ODTs: Orally disintegrating tablets C. Tablet: Conventional tablets (Motillium tablets 10 mg)

Patient’s Response Evaluation

Patients response was evaluated according the standard guideline of European

Medicines Agency [116]. Emesis included both vomiting and retching (nonproductive vomiting)

and were quantified by measuring number of emetic episodes [117-118]. Nausea was evaluated

separately as it is biologically different from emesis [119]. Episodes of nausea or vomiting were

evaluated for two days post-chemotherapy administration of ODTs, conventional tablets and

placebo ODTs by applying self-report method. Each patient was given diary cards (Table-2.16)

to record emesis and nausea episodes throughout the study period (two days). Day-1 was


138

considered to be started at the time of completion of chemo therapy infusion, ending for 24 hrs

interval and day-2 started after 24 hrs.

The patients were asked to record the following information on each day of the study

period;

Day and time of each emetic episode

Assessment of the worst experience of nausea (grade) on that day

Time of taking the study medication, and time of taking the rescue medication (if any)

Frequency, intensity and duration of nausea

After completion of the two-day study period, diary cards completed by all the patients

were reviewed on the number of emetic episodes, the intensity of nausea they experienced and

the use of any additional antiemetic drug they used.


139

Table-2.16: Daily Diary Card for Patient to Record Number of Emetic Episodes and Nausea

Time of medication administration

Number of emetic episode

Time of emetic episode

Number of nausea episode

Duration of nausea episode

Severity/Intensity of nausea Mild Moderate Severe

Two diary cards were given to each patient for two days of the study

Results of treatment were evaluated according to the standard guidelines [117, 120] as

follows;

Complete Emesis Control:

Absence of any episode of vomiting without any rescue medication and treatment

discontinuation

Major emesis control:

Up to two emetic episodes without any rescue medication and treatment discontinuation

were considered as major control of the emesis

Partial emesis control:

3 – 4 emetic episodes were considered to be partial emesis control


140

Treatment failure:

Five or more emetic episodes, or rescue medication, or treatment discontinuation were

considered as medication failure.

Quantification of nausea is relatively difficult and was quantified by its primary

characteristics as described by European Medicine Agency [116];

Frequency of Nausea: Each patient/attendant was asked to record number of episodes

of nausea each day in the given patient’s diary.

Intensity of Nausea: Intensity of nausea was determined by answering multi point

scale as mild, moderate and severe. A table of these three primary characteristics was provided in

the patient’s diary card (Table-2.16) and patients were asked to mark the episode accordingly.

Duration of Nausea: Each episodes of nausea having duration of one hour was

considered as single episode. When duration of the nausea exceeded one hour, each hour was

counted as supplementary episode [117].

Statistical Analysis

Statistical analysis was perormed using the software SPSS 10.00 system. The

significance level for all the statistical analysis was α = 0.05.

CHAPTER-3 RESULTS AND DISCUSSION

141

3. Results and Discussion

3.1 Drug Excipients Compatibility

Excipients are pharmacologically inert and perform a variety of functions in a dosage

form like lubrication, binding action and disintegration etc. These are chemical substances and

may interact with each other and API. In order to get a stable dosage form, excipients compatible

with each other and API should be selected. Drug excipients compatibility study was carried out

separately for Domperidone and Itopride HCl to find out chances of such interactions.

Compatibility of each drug was studied with;

Excipients used in the formulation of orally disintegrating tablets prepared by super

disintegrant technique

Excipients in the formulation of orally disintegrating tablets prepared by sublimation

technique

Excipients used in formulation of effervescent tablets

Excipients used for taste masking of itopride HCl (For itopride HCl only)

Binary mixture approach was applied for sample preparation using one gram of each

excipients and drug. After subjecting to stress conditions, each sample was evaluated for;

Drug content

Evaluation of FTIR spectra

Physical consistency


142

Drug content determination was applicable only to the samples containing drug.

Samples containing only excipients were used for excipient-excipient interaction and were

evaluated for physical consistency and FTIR spectra.

3.1.1 Drug Excipients Compatibility of Domperidone

3.1.1.1 Domperidone Content

Decrease in drug content, after subjecting to stress conditions, is determinant of drug

degradation as a result of incompatibility [121]. Moisture and heat are two factors that play main

role in drug excipients interactions and act as catalyst to initiate physical and chemical changes.

Most of the excipients are hygroscopic and absorb atmospheric moisture and tspeeds up

degradation of API. The stability of the drug(s) in combination with the excipients under the

stress storage conditions indicates the compatibility of the ingredients of the formulation.

The results of drug excipients compatibility in the present studies are shown in Table-

3.1. At each sampling point drug content was determined in triplicate and presented as Mean ±

S.D. (n = 3). Initial drug contents in mixtures was in the range of 99.20 – 99.90% and after 90

days of storage under stress conditions, the API content was in the range of 99.15 – 100.25%,

indicating that domperidone remained unaffected under tress conditions (40 oC and 75% R.H.).


143

Table-3.1: Results of Compatibility Study of Domperidone Analysis

Time Characteristic

Sample-

D1

Sample-

D2

Sample-

D3

Sample-

D4

Sample-

D5

Sample-

D6

Sample-

D7

Sample-

D8

Sample-

D9

Day-01

Drug Content *99.91 ± 0.27 _ 99.81 ± 0.29 99.59 ± 0.31 _ 99.62 ± 0.44 99.72 ± 0.51 _ 99.62 ± 0.22

I. R. Spectra † Complies Complies Complies Complies Complies Complies Complies Complies Complies

Physical Consistency Complies Complies Complies Complies Complies Complies Complies Complies Complies

Day-30

Drug Content 99.78 ± 0.32 _ 99.49 ± 0.22 99.73 ± 0.17 _ 99.69 ± 0.29 99.58 ± 0.48 _ 99.37 ± 0.26

I. R. Spectra Complies Complies Complies Complies Complies Complies Complies Complies Complies


Day-60

Drug Content 99.81 ± 0.44 _ 99.64 ± 0.41 99.52 ± 0.36 _ 99.31 ± 0.18 99.40 ± 0.53 _ 99.67 ± 0.19



Day-90

Drug Content 99.63 ± 0.59 _ 99.87 ± 0.37 99.42 ± 0.32 _ 99.37 ± 0.22 99.52 ± 0.43 _ 99.55 ± 0.29



*Mean ± Standard Deviation (n = 3) † The term complies means that IR spectrum is similar with the standard spectrum (Day-1 spectrum)


144

3.1.1.2 Evaluation of Infra Red Spectra

FTIR spectra were used to study the chemical incompatibility of the drugs and

excipients. The alteration in the functional group in the degradation products may have different

IR spectrum. The changes in the IR spectrum of the drugs and excipients were not observed

before and after the storage of the samples (mixtures) under the stress condition for 90 days (see

Fig-3.1).

Figure 3.1: FTIR Spectra of Domperidone and All the Excipients Used in Formulation of ODTs and Effervescent Tablets of Domperidone, Before Subjecting to Stress Conditions


145

3.1.1.3 Physical Consistency of Samples

Samples stored under the stress conditions did not showed in any changes in the

physical properties. Changes were not observed in the consistency and colour of the samples.

Moisture content of the samples was increased (2.61 ± 0.39 %, n = 3) with passage of

time that may be due to moisture absorbance by excipients at elevated humidity. Colloidal

silicon dioxide and micro crystalline cellulose absorb moisture when exposed to an environment

of elevated humidity for longer time [122].

3.1.2 Study of Itopride HCl Excipients Compatibility

3.1.2.1 Itopride HCl Content

The change in the percent content of itopride HCl was negligible and statistically not

significant when store for 90 days under the accelerated stability test conditions. Results of the

compatibility studies of the Itropride HCl with various excipients for used in formulation of Fast

Dispersible Tablets (FDT) and itopride HCl are shown in Table-3.2 and Table-3.3, respectively

indicating absence of degradation reaction.


146

Table-3.2: Result of Compatibility Study of ITP with Excipients Used in Formulation of Fast Dispersible

Tablets (ODTs and Effervescent Tablet)

Sampling Time Characteristic Sample-I1 Sample-I2 Sample-I3 Sample-I4 Sample -I5 Sample-I6

Day-1

Drug Content 99.27 ± 0.81 98.38 ± 0.42 99.24 ± 0.59 99.15 ± 0.64 99.43 ± 0.21 99.49 ± 0.35

I. R. Spectra Complies Complies Complies Complies Complies Complies

Physical Consistency Complies Complies Complies Complies Complies Complies

Day-30

Drug Content 98.58 ± 0.32 99.71 ± 0.60 99.63 ± 0.29 99.38 ± 0.56 98.62 ± 0.44 99.12 ± 0.73



Day-60

Drug Content 99.13 ± 0.19 99.43 ± 0.57 98.07 ± 0.31 99.62 ± 0.28 99.79 ± 0.57 98.61 ± 0.42



Day-90

Drug Content 99.36 ± 0.48 99.22 ± 0.39 99.17 ± 0.81 98.93 ± 0.26 99.43 ± 0.18 99.37 ± 0.49



Results are presented as Mean ± S.D. (n = 3)


147

Table-3.3: Results of Compatibility Study of Itopride HCl with Excipients Used for Taste Masking

Sampling Time

Characteristics Granulation Technique Micro Encapsulation Solid Dispersion

Sample-I7 Sample-I8 Sample-I9 Sample-I10 Sample-I11

Day-01

Drug Content 98.64 ± 0.52 98.22 ± 0.49 99.32 ± 0.63 99.65 ± 0.40 98.67 ± 0.55

I. R. Spectra Complies Complies Complies Complies Complies

Physical Consistency Complies Complies Complies Complies Complies

Day-30

Drug Content 99.50 ± 0.37 98.61 ± 0.70 98.83 ± 0.29 98.25 ± 0.43 99.36 ± 0.89



Day-60

Drug Content 99.63 ± 0.24 99.12 ± 0.81 99.67 ± 0.89 98.80 ± 0.69 99.48 ± 0.32



Day-90

Drug Content 98.77 ± 0.20 99.30 ± 0.53 99.26 ± 0.31 98.77 ± 0.38 99.17 ± 0.92





148

3.1.2.2 Evaluation of Infra Red Spectra

FTIR spectra of all samples were same after storage for 90 days under the stress

conditions compared with the fresh samples indicating the stability of the drugs with the

excipients designed for the formulation of the fast dispersible tablets.

Figure 3.2: FTIR Spectra of Itopride HCl and Excipients Used in Formulation of

Fast Dispersible Tablets (ODTs and Effervescent Tablets), Before Subjecting to Stress

Conditions


149

Figure 3.3: FTIR Spectra of Itopride HCl and Excipients Used for Taste Masking of Itopride

HCl Before Subjecting to Stress Conditions

3.1.2.3 Physical Consistency of the Samples

Samples stored under the stress conditions did not showed in any changes in the

physical properties. Changes were not observed in the consistency and colour of the samples.

On the basis of stability of both the drugs (Domperidone and Itopride HCl), alone and

with excipients, it was concluded that they were compatible with all the excipients included in

the study. Fast dispersible tablets (Effervescent Tablets and ODTs) of both drugs can be

formulated using these excipients without any risk of stability.


150

3.2 Characterization of Drug and Excipients According to SeDeM-ODT

Experts System

SeDeM-ODT expert system is pre formulation tool used for determination of suitability

of the powder for preparation of ODTs by direct compression. It predicts appropriateness of the

powder for direct compression and bucco-dispersibility simultaneously [89]. The Index of Good

Compressibility (IGC) and Index of Good Compressibility and Bucco-dispersibility (IGCB) were

calculated for each powder. IGC indicates good aptitude to be compressed while IGCB indicates

good aptitude for compression and dispersibility. As effervescent tablets are dispersed in water,

powder was evaluated for its suitability for direct compression only based on IGC value.

Both of the drugs (Domperidone and Itopride HCl) and excipients planned to be used in

formulation of fast dispersible tablets (except effervescent excipients) were characterized

according to SeDeM-ODT experts system [89-90, 101].

3.2.1 Characterization of APIs as per SeDeM-ODT Experts System

Domperidone and Itopride HCl (before and after taste masking) were characterized as

SeDeM-ODT experts system.

3.2.1.1 Characterization of Domperidone as per SeDeM-ODT Experts System

Suitability of domperidone (DMP) for preparation of ODTs by direct compression was

evaluated by determining 15 parameters as per SeDeM-ODT experts system. The data (Table-


151

3.4) indicates that domperidone is not a suitable candidate for direct compression as “r” values of

most of the parameters are below the acceptable limit (5 – 10). IGCB value of domperidone

(3.94) was very low and all the factors, except lubricity/dosage (7.50) and lubricity/stability

(7.24) had incidence value below acceptable limit (≥5).

The “r” value of the dimension factor i.e. 2.80 indicates the improper flow of the

powder that will results in tablets with range of weight variation. Domperidone is hygroscopic in

nature but not to the extent to require environment of controlled humidity for processing. Only

6.39 ± 0.09 % (n = 3) weight gain was observed during determination of hygroscopicity.

Disgregability factor predicts disintegration behavior of the powder compacts and

included three parameters i.e., disintegration time with disk, disintegration time without disk and

effervescence time. Domperidone powder was compressed under maximum compression force

and all the three parameters were determined according to the official monographs.

Disintegration time of the tablet (Domperidone powder compressed under maximum pressure)

with disk was 1.10 min and without disk was 1.40 min with corresponding “r” values of 6.33 and

5.33, respectively (Table-3.4). During effervescence test, domperidone tablets broke into large

pieces and did not dispersed completely. Core of the pieces was hard enough indicating failure of

tablet effervescence with in specified time resulting in 0.00 “r” value (Table-3.4). Disgregability

factor had “r” value (3.89) out of the acceptable range (5 – 10) and needed to be improved.

Excipient with good wet ability and wicking properties may be used to improve the rapid water

penetration and in turn better dispersion of the tablets.

Domperidone has low shaded area (Fig-3.4) indicating that most of the factors needed

to be improved in order to get orally disintegrating tablets by direct compression.


152

Table-3.4: The “r” Values of APIs Calculated as per SeDeM-ODT Experts System

Incidence Factor Parameter DMP ITP.HCl TM. ITP.HCl Acceptable Limit

Dimension Bulk Density 2.26 3.46 5.20

5 – 10 [89]

Tapped Density 3.36 5.08 7.10

Compressibility

Inter particle Porosity 0.00 7.71 4.29

Carr' Index 6.55 6.38 5.35

Cohesion Index 3.30 3.65 7.55

Flow ability/ Powder flow

Hausner Ratio 7.56 7.66 8.18

Angle of Repose 2.00 1.60 6.60

Powder flow 0.00 0.00 7.00

Lubricity/

Stability

Loss on Drying 7.66 5.87 7.62

Hygroscopicity 6.81 8.14 7.69

Lubricity/Dosage Particles < 50 9.80 9.73 9.52

Homogeneity Index 5.20 4.65 4.05

Disgregability

Effervescence Time 0.00 5.80 2.40

Disintegration Time with Disk

6.33 7.33 5.67

Disintegration Time without Disk

5.33 6.33 3.00


153

3.2.1.2 Characterization of Itopride HCl as per SeDeM-ODT Experts System

Prior to formulation additional step was added to mask the bitter taste of Itopride HCl.

Both Itopride HCl powder and taste masked granules of itopride HCl (selected for formulation of

fast dispersible tablets) were subjected to characterization as per SeDeM-ODT experts system.

The analysis of the data showed dimension factor (4.27) and flow ability/powder flow

factor (2.09) of itopride HCl powder need to be improved (see Table-3.5). Two parameters, bulk

density and tapped density, are included in dimension factors. Bulk density of itopride HCl is

0.35 with corresponding “r” value of 3.46 which is below the acceptable limits (5 – 10).

Incidence value (Mean of “r” values of the parameters included in the factor) of dimension factor

(4.27) is also below the limit (≥ 5).

Flowability/Powder flow factor of itopride HCl (2.09) was also below the limit. Three

parameters, Hausner ratio, angle of repose and powder flow are included in the factor. Only

Hausner ratio has “r” value (7.66) within the acceptable range (Table-3.4). Itopride HCl powder

was unable to flow due to its low bulk density. Angle of repose (1.60) and powder flow (0.00)

had “r” values below the acceptable limit (5 – 10). IGCB value of itopride HCl powder (5.04) is

within the acceptable limits (Table-3.6). By improving flow, itopride HCl powder can be

successfully used in preparation of fast dispersible tablets by direct compression.


154

Table-3.5: Mean Incidence Factor of APIs Calculated on the Basis of

SeDeM-ODT Experts System

Incidence Factor DMP ITP.HCl T.M. ITP.HCl Acceptable Range

Dimension 2.81 4.27 6.15

5 – 10 [89]

Compressibility 3.28 5.91 5.73

Flow ability / Powder flow 3.19 2.09 7.26

Lubricity / Stability 7.24 7.01 7.66

Lubricity / Dosage 7.50 7.19 6.79

Disgregability 3.89 6.49 3.69

DMP: Domperidone ITP.HCl: Itopride HCl T.M.ITP.HCl: Taste Masked Itopride HCl

3.2.1.3 Characterization of Taste Masked Itopride HCl as per SeDeM-ODT Experts

System

Taste masking of itopride HCl was carried out micro encapsulation [108], solid

dispersion [110] and granulation technique. Taste masked itopride HCl prepared by granulation

technique was selected for formulation of fast dispersible tablets and characterized as per

SeDeM-ODT experts system. Taste masking resulted in improved flow and compressibility of

the granules. Two factors dimension factor and flow ability/Powder flow factor of itopride HCl

powder were below the limit. Taste masking of itopride HCl powder by granulation with

polymeric excipients (HPMC and PVP) improved both the factors (Table-3.5). Incidence value

of the dimension factor of itopride HCl powder was 4.27 and after taste masking increased to


155

6.15. Similarly incidence value of flow ability/ powder flow factor increased to 7.26 which were

within the acceptable limits (≥ 5).

Taste masking of itopride HCl powder by hydrophilic polymer decreased incidence

value of disgregability factor (3.69) below the acceptable limit (≥ 5). Two parameters of the

disgregability factor, disintegration time without disk (3.00) and effervescence time (2.40) had

“r” values below the limit while disintegration time with disk (5.67) had “r” value within the

limit. Decrease in disgregability factor was due to increase in cohesion index by taste masking of

itopride HCl powder. Higher cohesion index resulted in strong compacts of taste masked itopride

HCl having higher disintegration time and effervescence time. IGCB value of taste masked

itopride HCl powder (5.91) and larger shaded area (Fig-3.4) indicate its suitability for

preparation of fast dispersible tablets by direct compression. In order to get ODTs by direct

compression disgregability factor of taste masked itopride will be improved by inclusion of super

disintegrants.

Table-3.6: Various Indices for APIs Calculated on the Basis of

SeDeM/SeDeM-ODT Experts System

Ingredient SeDeM Experts System SeDeM-ODT Experts

System Acceptable

Limit

I.P. I.P.P. I.G.C. I.P I.P.P. I.G.C.B.

5 – 10 [89-90]

Domperidone 0.50 4.54 4.32 0.40 4.06 3.94

Itopride HCl Powder 0.58 5.33 5.07 0.67 5.56 5.40

T. M. Itopride HCl 0.83 6.68 6.36 0.73 6.08 5.91

T.M. Itopride HCl; Taste Masked Itopride HCl


156

Figure 3.4: SeDeM-ODT and SeDeM Diagrams of Domperidone, Itopride HCl and Taste

Masked Itopride HCl

Shaded area shows parametric values with 5 as minimum acceptable limit

3.2.2 Characterization of Excipients as per SeDeM-ODT Experts System

Excipients used for the formulation of fast dispersible tablets (Effervescent Tablets and

ODTs) of both drugs (Domperidone and Itopride HCl) were evaluated according to the SeDeM-

ODT Expert System. These excipients includes Micro crystalline cellulose, Tablettose-80, cross

carmellose sodium, sodium starch glycolate, starch maize, citric acid, tartaric acid and sodium

bicarbonate.


157

3.2.2.1 Characterization of Diluents

Micro crystalline cellulose (MCC) and Tablettose-80 were planned to be used in

formulation of fast dispersible tablets as diluents. MCC is modified cellulose commonly used as

diluents in formulation of oral solid dosage forms (tablet/capsule) [122]. Data presented in

Table-3.8 demonstrate that MCC (Dimension factor = 4.55) requires improvement in dimension

factor, only. MCC has low bulk density resulting in “r” value (3.85) below the limit. SeDeM-

ODT diagram of MCC shows good compressibility, rheological properties and disgregability

(Fig-3.5). IGCB value of MCC (5.91) is within the acceptable range (5 – 10) making it a good

candidate for preparation of fast dispersible tablets (ODTs and Effervescent Tablets).

Tablettose-80, the smart excipients, is agglomerated form of lactose with improved

flow and commonly used as diluents in tablet. Talettose-80 requires improvement in

compressibility factor (Table-3.8). Incidence value of compressibility factor (4.70) is below the

limit (≥ 5) due to lower “r” values of inter particle porosity (3.16) and Carr’s Index (4.46). Rest

of the factors of Tablettose-80 has incidence values within the acceptable range. IGCB value of

Tablettose-80 (6.61) indicates its suitability for preparation of fast dispersible tablets.

The mixture of MCC and Tablettose-80 will show all the parameters of the SeDeM-

ODT experts system within the acceptable range as shown in the Fig-3.5. Lower incidence value

of dimension factor of MCC (4.70) will be compensated by higher incidence value of Tablettose-

80 (7.24) and MCC will compensate the lower incidence value of compressibility factor of

Tablettose-80.


158

Figure 3.5: SeDeM-ODT and SeDeM Diagrams of the Diluents (Micro Crystalline Cellulose

and Tablettose-80) Used in formulation of Fast Dispersible Tablets (ODTs and Effervescent

Tablets)

3.2.2.2 Characterization of Disintegrants

Disintegrants are usually used in smaller quantity in formulation and have no

significant effect on properties of the powder blend [89]. Two super disintegrants (cross linked

carboxy methyl cellulose sodium and sodium starch glycolate) and starch maize were studied for

any possible contribution when used in larger quantities. Cross linked carboxy methyl cellulose

sodium (CCNa) is modified cellulose while sodium starch glycolate (Primojel) is a modified

starch, rapidly absorb water and disintegrate the dosage form [123].


159

Table-3.7: The “r” Values of Excipients Calculated as per SeDeM-ODT Experts System

Parameter Diluents Disintegrants Effervescent Excipients

M.C.C. Tablettose C.C.Na S.S.G. Starch C.Acid T.Acid SBC

Bulk Density 3.85 6.10 5.89 8.36 6.21 7.52 9.21 6.80

Tapped Density 5.26 7.38 7.58 9.20 7.38 9.17 10.00 10.00

Inter Particle Porosity 5.80 4.33 3.16 1.13 2.13 1.99 0.87 3.92

Carr' Index 5.36 3.47 4.46 2.29 3.17 3.60 1.92 6.40

Cohesion Index 5.65 6.30 7.15 4.30 3.55 5.70 6.60 4.45

HausnerRatio 8.20 8.95 8.55 9.35 9.05 8.90 9.45 7.65

Angle of Repose 4.20 5.60 2.04 1.60 3.60 5.80 5.20 3.80

Powder Flow 6.00 7.00 6.50 6.50 3.00 6.50 6.00 4.00

Loss on Drying 5.93 9.52 5.70 5.17 6.11 6.28 5.70 7.84

Hygroscopicity 8.29 9.06 8.64 7.92 8.76 8.61 8.40 8.60

Particles < 50 8.41 9.93 8.36 9.26 9.76 9.90 9.86 9.72

Homogeneity Index 6.42 6.30 7.80 7.40 5.92 5.30 5.00 5.60

Effervescence Time 5.50 5.80 5.20 4.80 4.20 N.A N.A N.A

D. Time with Disk 6.50 6.67 6.33 5.99 6.33 N.A N.A N.A

D. Time without Disk 5.99 5.67 6.00 4.99 5.33 N.A N.A N.A

N.A: Not Applicable


160

All the disintegrants are deficient in compressibility factor. CCNa, SSG and Starch

have incidence value of 4.92, 2.57 and 2.95, respectively, which are below the acceptable limit

(5 – 10). Lower incidence values of compressibility factor indicate that all the disintegrants need

improvement in compressibility factor.

The data analysis using SeDeM-ODT system indicated the suitability of the CCNa

(IGCB = 6.04) as disintegrating agent in the in preparation of ODTs by direct compression

method. Most of the parameters were within the acceptable range of 5 – 10. Similarly SSG

(IGCB = 5.71) is also suitable for use in preparation of ODTs by direct compression. Although

compressibility factor of SSG (incidence value = 2.57) is below the limit but will get

compensated by the other excipients having higher incidence value of compressibility factor like

MCC.


161

Table-3.8: Mean Incidence Factors of Excipients Calculated on the Basis SeDeM-ODT Experts System

Incidence Factor Diluents Disintegrants Effervescent Excipients

M.C.C. Tablettose-80 C.C.Na S.S.G Starch C. Acid T. Acid S.B.C.

Dimension 4.55 7.24 6.74 8.78 6.80 8.34 9.61 8.40

Compressibility 5.60 4.70 4.92 2.57 2.95 3.76 3.13 4.92

Flowability/ Powder Flow

6.13 7.18 5.70 5.82 5.22 7.07 6.88 5.15

Lubricity / Stability 7.11 9.28 7.17 6.54 7.44 7.44 7.05 8.22

Lubricity / Dosage 7.42 8.12 8.08 8.33 7.84 7.64 7.43 7.66

Disgregability 6.00 6.47 5.84 5.26 5.29 _ _ _

C.C.Na: Cross CarmelloseSodium (Cross Linked CarboxyMethyl Cellulose Sodium) S.S.G: Sodium Starch Glycolate M.C.C.: Micro Crystalline Cellulose C. Acid: Citric Acid T. Acid: Tartaric Acid S.B.C.: Sodium Bicarbonate

Starch maize is deficient in flow and compressibility (incidence value = 2.95) (Table-

3.8). Incidence value of compressibility factor (2.95) was below the limit (≥ 5) and all the

included parameters had “r” values below acceptable limit (5 – 10). Rests of the factors of starch

maize were within the acceptable limits having IGCB (5.47) value within the acceptable range.

SeDeM-ODT diagram and IGCB value of starch (5.47) indicated its suitability for

direct compression but its flow and compressibility should be improved by other excipients with

better rheological properties.


162

Figure 3.6: SeDeM-ODT and SeDeM Diagrams of Disintegrants Used in Formulation of Fast

Dispersible Tablets (ODTs and Effervescent Tablets)

3.2.2.3 Characterization of Effervescent Excipients

Effervescent excipients intended to be used in formulation of effervescent tablets

consisted of citric acid, tartaric acid and sodium bicarbonate. Effervescent excipients were to be

used in formulation of effervescent tablets and were characterized as per SeDeM experts system

to find out their suitability for direct compression only. Citric acid and tartaric acid is crystalline

solid [124] and were pulverized through mesh number 40 before characterization.

SeDeM analysis of citric acid shows that it requires improvement in compressibility

factor. Mean incidence value of compressibility factor (3.76) was below the acceptable limit (≥5)


163

indicating its poor compressibility. Both the parameters (inter particle porosity and Carr’s index)

included in the factor had “r’ values below the limit (Table-3.7). Index of Good Compressibility

(IGC) value of citric (6.29) was within the acceptable range proving its suitability for direct

compression.

Tartaric acid had SeDeM profile similar to citric acid, (Fig-3.7) and compressibility

factor needs to be improvedwhile rests of the factors were within the acceptable range. IGC

value of tartaric acid (6.20) was within the acceptable range indicating its suitability for direct

compression.

Table-3.9: Various Indices for Excipients as per SeDeM-ODT Expert System

Ingredient SeDeM-ODT Experts System SeDeM Experts System

I.P I.P.P. I.G.C.B. I.P. I.P.P. I.G.C.


Tablettose-80 0.87 6.81 6.61 0.83 7.00 6.66

C.C. Sodium 0.80 6.22 6.04 0.75 6.32 6.02

Sodium Starch Glycolate 0.67 5.88 5.71 0.67 6.04 5.75

Starch 0.60 5.63 5.47 _ _ _

Citric Acid* _ _ _ 0.83 6.61 6.29

Tartaric Acid* _ _ _ 0.83 6.16 6.20

Sodium Bicarbonate* _ _ _ 0.67 6.56 6.25

I.P: Parameter Index I.P.P: Parameter Profile Index I.G.C.B: Index of Good Compressibility and Buccodispersibility *: Excipients included in Effervescent Tablets only


164

Sodium bicarbonate was the only base used in combination with citric acid and tartaric

acids in formulation of effervescent tablets. Sodium bicarbonate has poor rheological properties

and compressibility (Table-3.8). Only compressibility factor of sodium bicarbonate had

incidence value below the acceptable range (≥ 5) and needs improvement. Flow of sodium

bicarbonate was poor as angle of repose and powder flow had “r” values below the limit (Fig-

3.7). Flow will get improved with addition of standard quantity of lubricants and diluents in final

formulations. IGC value of sodium bicarbonate (6.25) is within the acceptable range indicating

its suitability for direct compression.

Figure 3.7: SeDeM Diagrams of Effervescent Excipients Used in Formulation of Effervescent

Tablet of Pro Kinetic Agents


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3.3 Development and Validation of U.V. Visible Spectrophotometric Method

of Analysis for Domperidone

U.V. visible spectrophotometric methods of analysis for domperidone in

pharmaceutical dosage form and raw material was developed and validated. The suitable wave-

length and solvent for the extraction was selected and method was successfully applied for the

analysis of domperidone in pharmaceutical dosage form.

3.3.1 Preparation of Solutions

3.3.1.1 Preparation of Stock solution

Stock solution of domperidone (100µg/ml) was prepared using analytical grade

methanol as solvent

3.3.1.2 Preparation of Dilutions

Dilutions of stock solution were prepared using purified water on daily basis.

3.3.2 Selection of Wave length of Maximum Absorbance (λmax)

The solution of domperidone (10µg/ml) was scanned in the range of 200 – 400 nm

using methanol as blank. The maximum absorbance of domperidone in methanol was observed

284 nm (Fig-3.8) and this wave length was selected for the in-vitro analysis drug.


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Figure 3.8: UV Absorbance of Domperidone Solution in Methanol (10µg/ml)

A: UV Absorbance

3.3.3 Validation of UV Visible Spectrophotometric Method of Analysis of Domperidone

UV Visible spectrophotometric method of analysis of domperidone (DMP) was

validated according to FDA/ICH [102] guide lines. Various validation parameters are shown in

Table-3.10.


167

3.3.3.1 Linearity

The linearity of the method was evaluated from the calibration curves of standard

solutions, constructed at seven concentration levels in the range of 0.10 – 100 µg/ml. The

instrumental response was linear in the given range. The regression equation and correlation co-

efficient are given in Table-3.10.

Table-3.10: Validation Parameters of UV Visible Spectrophotmetric Method of Analysis of Domperidone

Parameter Results

Linearity

Calibration Range 0.10 – 100 µg/ml

λ max 284 nm

Regression Equation 0.039 x + 0.051

Correlation Co-efficient (R2) 0.998

Accuracy (% Recovery) Mean ± S.D; %RSD

Sample without Excipients 99.30 ± 0.12; 0.12

Sample with Excipients 99.26 ± 0.25; 0.25

Stability (Amount Recovered) Mean ± SD; %RSD

Day-1 (n = 3) 9.91 ± 0.04; 0.40

Day-2 (n = 3) 9.87 ± 0.03; 0.30

Day-3 (n = 3) 9.53 ± 0.02; 0.21


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3.3.3.2 Stability of Solution

Stability studies were conducted at room temperature (25 oC), and at freezer

temperature (−20 oC) for 72 hrs. The results obtained have shown that domperidone solution in

methanol is stable at freezer temperature and room temperature.

3.3.3.3 Specificity and Selectivity

The specificity of the developed method was determined by percent recovery of

standard solution (20µg/ml) with and without excipients [102, 104]. Presence of excipients has

no effect on percent recovery as shown in Table-3.10.

3.3.3.4 Precision of the Method

The precision of the method was evaluated through analysis repeatability, and intra-

day, inter-day studies. Solution of domperidone (10µg/ml) was used for precision study and

average amount recovered (n = 3) was calculated as shown in Table-3.11. The intra-day and

inter day co-efficient of variation (% RSD) was in the ranges of 0.25 – 0.45 and 0.17 – 0.45,

respectively.


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Table-3.11: Intra Day and Inter Day studies of UV Visible Spectrophotmetric Method of Analysis of Domperidone

Sample Time Concentration Conc. Recovered (µg/ml) %RSD

0 h

10 µg/ml

9.84 ± 0.04 0.41

6 h 9.79 ± 0.02 0.20

12 h 9.82 ± 0.04 0.41

18 h 9.91 ± 0.04 0.40

24 h 9.76 ± 0.04 0.41

2nd Day 9.87 ± 0.03 0.30

3rd Day 9.53 ± 0.02 0.21

Results are presenetd as Mean ± S.D. R.S.D: Relative Standard Deviation


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3.4 Development and Validation of U.V. Visible Spectrophotometric

Method of Analysis for Itopride HCl

U.V. visible spectrophotometric method of analysis for itopride HCl was developed and

validated according to standard guidelines. The suitable wave-length and solvent was selected

and method was successfully applied for the analysis of domperidone in pharmaceutical dosage

form.

3.4.1 Preparation of Solutions


Stock solution of itopride HCl (100µg/ml) was prepared using purified water as

solvent.

3.4.1.2 Preparation of Dilutions

Dilutions of stock solution were prepared using purified water as solvent on daily basis.

3.4.2 Selection of Wave Length of Maximum Absorbance (λmax)

The solution of itopride HCl (10µg/ml) was scanned in the range of 200 – 400 nm using

purified water as blank. The maximum absorbance of itopride HCl in water was observed 220

nm (Fig-3.9) and this wave length was selected for the in-vitro analysis drug.


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Figure 3.9: UV Scan of Itopride HCl Solution in Water (10µg/ml) A: UV Absorbance of the Solution

3.4.3 Validation of UV Visible Spectrophotometric Method of Analysis of ItoprideHCl

UV Visible spectrophotometric method of analysis of itopride HCl was validated

according to FDA/ICH guide lines [125]. Various validation parameters are shown in Table-

3.12.

3.4.3.1 Linearity of the Method

The linearity of the method was evaluated from the calibration curves of standard

solutions, constructed at seven concentration levels in the range of 0.10 – 100 µg/ml. The


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instrumental response was linear in the given range. The regression equation and correlation co-

efficient are given in Table-3.12.

Table-3.12: Validation Parameters of UV Visible Spectrophotometric Method of Analysis of Itopride HCl

Parameter Results

Linearity

Calibration Range 0.1 – 100 µg/ml

λ max 220 nm

Regression Equation 0.068 x + 0.0168

Correlation Co-efficient (R2) 0.999

Accuracy (% Recovery) Mean ± S.D; %RSD

Sample without Excipients 99.41 ± 0.30; 0.30

Sample with Excipients 99.19 ± 0.13; 0.13

Stability (Amount Recovered) Mean ± SD; %RSD

Day-1 (n = 3) 9.92 ± 0.16; 1.61

Day-2 (n = 3) 9.91 ± 0.23; 2.32

Day-3 (n = 3) 9.88 ± 0.28; 2.83


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3.4.3.2 Stability of Solution

Stability studies were conducted at room temperature (25 oC), and at freezer

temperature (−20 oC) for 72 hrs. The results obtained have shown that itopride HCl solution in

water is stable at freezer temperature and room temperature for three days.

3.4.3.3 Specificity and Selectivity

The specificity of the developed method was determined by percent recovery of

standard solution (10µg/ml) with and without excipients [102, 104]. Presence of excipients has

no effect on percent recovery as shown in Table-3.12.

3.4.3.4 Precision

The precision of the method was evaluated through analysis repeatability, and intra-

day, inter-day studies. Solution of domperidone (10µg/ml) was used for precision study and

average amount recovered (n = 3) was calculated as shown in Table-3.13. The intra-day and

inter day co-efficient of variation (% RSD) was in the ranges of 0.25 – 0.45% and 0.17 – 0.45%,

respectively.


174

Table-3.13: Intra Day and Inter Day studies of UV Visible Spectrophotmetric Method of Analysis of Itopride HCl

Sample Time Concentration Conc. Recovered (µg/ml) %RSD

0 h

10 µg/ml

9.92 ± 0.13 1.31

6 h 9.93 ± 0.12 1.21

12 h 9.94 ± 0.16 1.61

18 h 9.91 ± 0.35 3.53

24 h 9.92 ± 0.16 1.61

2nd Day 9.91 ± 0.23 2.32

3rd Day 9.88 ± 0.28 2.83

Results are presenetd as Mean ± S.D. % R.S.D: % Relative Standard Deviation


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3.5 Development and Validation of HPLC-UV Method for Simultaneous Analysis

of Domperidone and Itopride HCl

RP-HPLC-UV method for simultaneous determination of the Itopride HCl and

domperidone was developed and validated according to FDA/ICH guidelines [103, 126].

Tenofavir was used as internal standard.

3.5.1 Solution Preparation

Stock solutions (1 mg/ml) of domperidone and Tenofavir, used as internal standard,

were prepared in methanol. Itopride HCl solution was prepared in HPLC grade water.

3.5.2 Extraction Solvent Selection

Methanol, acetonitrile and mobile phase (Water: ACN, 65:35) were evaluated for

extraction of anlytes from plasma. The drug recovery (% w/w) was better in the mobile phase

compared with the other solvents; the results are shown in Table-3.14.


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Table-3.14: Percent Recovery of Domperidone and Itopride HCl from Human

Plasma with Different Extraction Solvents

Extraction Solvent Domperidone (% Amount Recovered)

Itopride HCl (% Amount Recovered)

Mobile Phase 90.23 ± 1.80 86.51 ± 2.60

Acetonitrile 82.11 ± 2.91 81.37 ± 2.42

Methanol 65.39 ± 2.50 43.08 ± 2.11

Results are presented as Mean ± Standard Deviation

Mobile Phase: Water: ACN in ratio of 65:35 (v/v)

3.5.3 Optimization of Experimental Conditions

Different experimental parameters were optimized in the specified ranges to choose the

optimum mobile phase, stationary phase, detector’s wavelength, mobile phase flow rate, column

oven temperature and pH.

3.5.3.1 Selection of Stationary Phase

Hypersil BDS C8 Column (150 mm x 4.6 mm, 5µm) was used for separation of

domperidone and itopride HCl. Other columns like Discovery HS C18 column (150 mm × 4.6

mm, 5 µm), Symmetry C8 column (150 mm × 3.9 mm, 5 µm) and Symmetry C8 (250 mm × 4.6

mm, 5 µm) were also tried for analysis of domperidone and itopride HCl. Best resolution was

achieved with Hypersil BDS C8 column and was used for further analysis.


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Table-3.15: Various Parameters of HPLC Column used for Analysis of


Parameter Hypersil BDS C-8

Column length 150 mm

Internal diameter 4.6 mm

Particle size 5 µm

DMP ITP.HCl

Retention factor, k 0.19 0.40

Separation factor, α 2.16

Tailing factor, T 1.02 0.82

Resolution, Rs 17.76 21.14

3.5.3.2 Selection of Mobile Phase

Combination of organic solvents (methanol and acetonitrile) and purified water were

investigated in different ratios as mobile phase. Optimum retention time, peak area and

resolution were obtained with water and acetonitrile (65:35, v/v) as shown in Table-3.16.


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Table-3.16: Separation of Domperidone and Itopride HCl using Various

Solvents in Different Ratios as a Mobile phase

Mobile Phase Domperidone Itopride HCl

Rt PA Rt PA

Water : Methanol (75 : 25) 13.10 24312 5.14 13196

Water : Methanol : ACN (50 :25 :25) 8.44 26543 6.29 18702

Water : ACN (65 :35) 11.39 32670 8.37 24514

Rt: Retention Time (min) PA: Peak Area

The retention times of the studied compounds decreased with increasing the ratio of

acetonitrile (ACN) in the mobile phase. The overall analysis time decreased significantly with

increasing the ACN content (Fig-3.10).

Figure 3.10: Effect of Acetonitrile Ratio in Mobile Phase on Elution of Different Analytes.

A = Having 40% ACN, B = Having 35% ACN, C = Having 30% ACN. Peaks: 1) Internal Standard; 2) Itopride HCl; 3) Domperidone


179

3.5.3.3 Selection of Mobile Phase Flow Rate

Retention time, peak shape and peak area are significantly affected by flow rate of the

mobile phase. The flow of mobile phase was studied in the range of 1 – 2 ml/min to achieve

better resolution and response of the instrument. Increase in flow rate of the mobile phase

reduced the retention time of all the compounds and improved peak resolutions but significantly

reduced the sensitivity, particularly of the itopride HCl. Best results were obtained when mobile

phase was pumped at the 1.50 ml/min.

Figure 3.11: Effect of Mobile Phase Flow Rate on Elution of Different Analytes. A = At 1.5ml/min; B = At 1.8 ml/min, C = At 2ml/min.

Peaks: 1 = Internal Standard (Tenofavir), 2 = Itopride HCl; 3 = Domperidone.The chromatograms were obtained at column oven temperature of 40 oC using mobile phase Water:

ACN in the ratio of (65:35, v/v).


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3.5.3.4 Selection of Column Oven Temperature

The effect of column oven temperature in the range of 30 – 50 oC was investigated for

better resolution of the analytes. At higher temperature, resolution and sensitivity of the analytes

increased. However, the difference of resolution and sensitivity was not significant between 40

oC and 50 °C. Moreover, the higher temperature the stability of the column is adversely effected

[22] so 40 oC was selected as column oven temperature.

Figure 3.12: Effect of Column Oven Temperature on Elution of Domperidone and Itopride HCl A = at 50 oC, B = at 45 oC, C = at 30 oC, D = at 40 oC and E = at 35oC.

Peaks: 1: Internal Standard (Tenofavir), 2: Itopride HCl 3: Domperidone. The chromatograms were obtained using mobile phase water: acetonitrile (65:35, v/v) at flow rate of 1.5 ml/min.


181

3.5.3.5 Selection of pH of Mobile Phase

Acetonitrile: water (65:35) was used as a mobile phase. The pH of the aqueous phase

was varied in the range of 2 – 5. Better sensitivity and resolution were obtained at pH 3.0 among

different tested pH of mobile phase. Sensitivity, resolution and retention time of domperidone

were significantly affected by varying pH as shown in Fig-3.13. On the basis of better resolution

and sensitivity, pH 3.0 was selected as pH of the mobile phase.

Figure 3.13: Effect of pH of Mobile Phase on Elution of Different Analytes. Peaks: 1= Internal Standard (Tinofavir), 2 = Itopride HCl, 3 = Domperidone. The

chromatograms were obtained at column oven temperature of 40 oC using mobile phase Water: ACN in the ratio of (65:35, v/v), and flow rate of 1.5 ml/min.


182

3.5.3.6 Selection of Detector Wavelength

The samples were scanned in the range of 205 and 284 nm for domperidone and

itopride HCl solutions in the mobile phase. The optimum response for both of the analytes was

observed on 210 nm. Sensitivity of the analytes changed by varying detector wave length and

better response was observed at 210 nm, chromatograms are shown in Fig-3.14.

Figure-3.14: Effect of Detector Wave Length on Elution of Domperidone and Itopride HCl.

A = At 205 nm, B = At 210 nm, C = At 220 nm and D = At 215 nm. Peaks: 1: Internal Standard (Tenofavir), 2: Itopride HCl, 3: Domperidone. The chromatograms were obtained using water: ACN (65:35, v/v) pH 3.0 as mobile phase at flow rate of 1.5 ml/min


183

3.5.3.7 Selection of Internal Standard

Various compounds like ciprofloxacin, neproxin sodium, tenofavir and clopidogril were

investigated as internal standard. Tenofavir was selected as internal standard due to better

sensitivity, recovery and shorter retention time.

Figure-3.15: Representative Chromatograms of Standard Solutions and Spiked Plasma Samples of Internal Standard, Domperidone and Itopride HCl.

Peaks: 1 = Internal Standard (Tenofavir), 2 = Itopride HCl, 3 = Domperidone

3.5.4 Validation of the HPLC-UV Method of Analysis

The HPLC-UV method for the analysis for domperidone and itopride HCl was

validated according to the ICH guidelines [102]. Validation parameters of HPLC-UV method are

shown in Table-3.17.


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Table-3.17: Validation Parameters of HPLC-UV Method of Analysis of


Parameter Analytes

Domperidone Itopride HCl

Linearity 20 – 100 20 – 100

Calibration Range (ng/ml)

Standard solution

Regression Equation Y = 0.013x + 0.017 Y = 0.007x + 0.006

Correlation Coefficient (R2) 0.998 0.999

Spiked Plasma

Regression Equation Y = 0.011x + 0.021 Y = 0.005x + 0.001

Correlation Coefficient (R2) 0.997 0.996

Accuracy (% Recovery) Mean ± S.D; %RSD Mean ± SD; %RSD

Spiked Sample (1.00µg/ml) (n = 5) 91.26 ± 0.42; 0.46 89.82 ± 0.78; 0.87



Precision Mean ± SD; %RSD Mean ± SD; %RSD

Injection Repeatability

Spiked Sample (0.25 µg/ml) (n = 5) 11.39 ± 0.13; 1.14a 8.37 ± 0.06; 0.72a

Spiked Sample (0.25 µg/ml) (n = 5) 32670 ± 76.10; 0.23b 24514 ± 66.20; 0.27b

Analysis Repeatability

Spiked Sample (0.5 µg/ml) (n = 5) 0.42 ± 0.02; 4.76c 0.40 ± 0.01; 2.50c

Sensitivity

Limit of Detection (ng/ml) 5 12

Lower Limit of Quantification (ng/ml) 10 15

a: Retention Time of the Analyte (min) b; Peak area of the Analyte

c; Amount of the Analyte Recovered


185

3.5.4.1 Linearity of The Method

Linearity of the method was determined using calibration curve of the standards in the

range of 20 – 100 ng/ml spiked in mobile phase and human plasma. Calibration curves were

constructed at seven concentration levels in the range of 20 – 100 ng/ml separately for standard

mixture and spiked plasma. The instrument response was linear in the range of 20 – 100 ng/ml,

results are shown in Table-3.17.

Figure-3.16: RP-HPLC Chromatograms of Standard Solutions of Itopride HCl and

Domperidone and Internal Standard (Tenofavir). Chromatograms were obtained using BDS C-8 column, using water: ACN (65: 35, v/v), pH 3.0 as mobile at flow rate of 1.5 ml/min.


186

Calibration curves of standard mixtures and spiked plasma samples of domperidone and

itopride HCl are shown in Fig-3.17.

Figure-3.17: Calibration Curve of Domperidone and Itopride HCl Standard Solutions and Spiked Plasma Samples. “A” Represents Calibration Curve of Standard Solution and “B”

Represents Calibration Curve of Spiked Plasma Samples for Each Analyte.

3.5.4.2 Accuracy of the Method

Percent recovery of the method was used for determination of accuracy of the proposed

method. Percent recovery was determined at three concentration levels (1.00µg/ml, 0.50µg/ml

and 0.25µg/ml) of both analytes.

3.5.4.3 Precision of the Method

Precision of the method was evaluated through injection repeatability, analysis

repeatability, intra-day and inter-day studies as shown in Table-3.18. The intra-day co-efficient


187

of variation (% RSD) was in the ranges of 1.54 – 3.19 % and 2.76 – 3.74 % for domperidone and

itopride HCl, respectively. Similarly, their respective values for inter-day studies were in the

range of 1.67 – 4.16 % and 3.97 – 4.76 % for domperidone and itopride HCl, respectively.

Table-3.18: Inter day and Intra Day Studies Spiked Concentration

(µg/ml) Concentration Recovered (µg/ml)

Intra-Day (Mean ± SD) % RSD Inter Day (Mean ± SD) % RSD Domperidone 0.25 0.50 1.00

0.21 ± 0.01 0.41 ± 0.02 0.91 ±0.04

4.76 4.88 4.40

0.21 ± 0.01 0.42 ± 0.02 0.90 ± 0.02

4.76 4.76 2.22

Itopride HCl 0.25 0.50 1.00

0.20 ± 0.01 0.40 ± 0.01 0.83 ± 0.03

5.00 2.50 3.61

0.20 ± 0.01 0.40 ± 0.01 0.85 ± 0.03

5.00 2.50 3.53

3.5.4.4 Stability of Solutions

Stability of the sample solutions was investigated at room temperature (23 – 26 oC), 4

oC and -20 oC. Domperidone and Tenofavir (internal standard) were stable while Itopride HCl

degraded to 78.93% significantly (p > 0.05) when stored for seven days at room temperature.

However, when stored at -20 °C all of the analytes in samples were stable during the study

period.


188

3.5.4.5 Sensitivity of the Method

Lower limit of detection (LLOD) of domperidone and itopride HCl were 5ng/ml and

12ng/ml, respectively. Similarly lower limit of quantification for domperidone was 10ng/ml and

15ng/ml for itopride HCl. The results are shown in Table-3.17. The sensitivity of the method

was good for accurate quantification of the domperidone and itopride HCl in biological samples.

Figure3.18: Chromatograms Representing LOD and LLOQ Values of Domperidone and Itopride HCl


189

3.6 Preliminary Study

3.6.1 Determination of Quantity of Taste Making Agents per Tablet in ODTs

The taste of itopride HCl is bitter that is not tolerable when disintegrated or dissolved in

oral cavity. Therefore, it is necessary to mask the taste of the APIs and use the excipients with

acceptable taste in the formulating the ODTs. ODTs disintegrate in oral cavity making an open

contact of all the ingredients of the formulation with taste buds. Therefore ODTs should have

pleasant taste with smooth mouth feel. Apart from the taste, the grittiness, mainly due to the

excipients, give bad mouth feeling [43]. In formulating the ODTs it is necessary to resolve these

problems to improve the patient compliance.

The taste of ODTs of domperidone was improved by the addition of, sweetener

(Aspartame) and flavoring agent (Tutti frutti flavor) into the formulation.

The amount of the sweetener and flavoring agent was first optimized in placebo tablets.

The taste was evaluated by the 24 healthy human volunteers having normal taste response;

results are shown in Tabl-3.19.


190

Table-3.19: Volunteers Response about Taste of Placebo ODTs Containing

Different Quantities of Taste Making Agents (Sweetener and Flavoring Agent)

Formulation Code

Quantity of Taste Making Agents

(Sweetener + Flavor)

Number of Volunteers Rated Tablets as

0 1 2 3 4

TP-01 (0.00 + 0.00) %w/w - 24 - - -

TP-02 (1.00 + 0.50) %w/w - 21 3 - -

TP-03 (2.00 + 0.50) %w/w - - 6 18 -

TP-04 (3.00 + 0.50) %w/w - - 12 9 3

TP-05 (3.50 + 0.50) %w/w - - - - 24

TP-06` (4.00 + 0.5) %w/w - - 18 - 6

0: Bitter tasting 1: Acceptable 2: Pleasant 3: Sweet 4: Strongly sweet

The data of the volunteer response of the formulation TP-05 (containing 3.50%

aspartame and 0.50% flavor tutti frutti) was best and used in the formulations of ODTs of both

drugs (Domperidone and Itopride HCl).

Tutti frutti is an artificially created flavouring agent simulating the combined flavour of

many different fruits [127].

The first step in formulating the ODTs of itopride HCl was the masking of the bitter

taste. Taste masked granules of itopride HCl were used in formulation of ODTs of itopride HCl.


191

To better taste of ODTs, 4% w/w of taste making agents {Aspartame (3.50% w/w) and tutti frutti

(0.50% w/w)} was included in all the formulations.

3.6.2 Determination of Quantity of Taste Making Agent per Tablet in Effervescent

Tablets

The aspartame and tutti frutti was used as sweetener and flavoring agent, respectively

in the effervescent tablets formulations. The palatability of the taste un-masked and masked

effervescent tablets, evaluated in healthy human volunteers, results are depicted in Table-3.20.

On the basis of the volunteer’s response, taste making agents were included into the

formulation at the level of 3.5 %w/w (3.00 %w/w aspartame and 0.50 %w/w flavor tutti frutti).

The formulations containing aspartame 4.00 and 5.00 %w/w were having strong taste that was

not acceptable. The taste of the placebo tablets containing 3.00 %w/w aspartame and 0.50 %w/w

tutti frutti was selected by the volunteers; the results are shown in Table-3.20. Amount of taste

making agents in TEF-04 {Aspartame (3.00% w/w) and tutti frutti (0.50% w/w)} was selected

for inclusion into all formulations of effervescent tablets.


192

Table-3.20: Volunteers Response about Taste of Placebo Effervescent Tablets

Containing Different Quantities of Taste Making Agents

Formulation

Code

Quantity of Taste Making Agents

(Sweetener + Flavor)

Number of Volunteers Rated Placebo Tablets as

0 1 2 3 4

TEF-01 (0.00 + 0.00) %w/w – 24 – – –

TEF-02 (1.00 + 0.50) %w/w – 9 12 3 –

TEF-03 (2.00 + 0.5) %w/w – – 21 3 –

TEF-04 (3.00 + 0.5) %w/w – – 3 21 –

TEF-05 (4.00 + 0.50) %w/w – – – 9 15

TEF-06 (5.00 + 0.50) %w/w – – – – 24

0: Bitter Tasting 1: Acceptable 2: Pleasant 3: Sweet 4: Strongly Sweet

3.6.3 Selection of Acid to Base Ratio of Effervescent Tablets

The ratio of acid and base for effervescence reaction in the formulations of effervescent

tablets was calculated on molar basis of stichometric equation. The required amount of citric acid

and sodium bicarbonate was added to water and after completion of reaction; the pH of the

solution was (4.30 ± 0.08) acidic indicating the presence of un-reacted acid that also improved

the taste of the formulation.


193

The replacement of citric acid with tartaric acid showed higher pH of the solution (5.17

± 0.11) showing the dominancy of the base. Moreover, tartaric acid is more hygroscopic

compared the citric acid [128].

On the basis of pH of the dispersion the citric acid and sodium bicarbonate in the ratio

of 1:1 (on weight basis) were used in the formulations. The quantity of the acid was high (2%)

than that required for complete neutralization of base.

3.6.4 Determination of Quantity of Effervescent Pair per Tablet

The relationship between the effervescence time and quantity of effervescent pair was

evaluated in placebo effervescent tablets containing 10, 20 and 30 %w/w of the effervescent

excipients. The effervescence time for 30%, 20% and 10% (w/w) was 135.33 ± 4.50 (n = 6), 70.5

± 4.59 (n = 6) and 56.83 ± 3.06 (n = 6), respectively. The rapid effervescence was observed

using 30 %w/w effervescent pair. However 20% w/w of the effervescent pair was used due to:

Sodium bicarbonate shows poor compressibility and rheological properties, as

proven from its SeDeM diagram. Using sodium bicarbonate in higher

concentration may affect the final product adversely.

Difference between disintegration time using 20 %w/w and 30 %w/w effervescent pair was not

significant.


194

3.7 Taste Masking of Itopride HCl

3.7.1 Determination of Taste Threshold of Itopride HCl

The taste of the various concentrations of itopride HCl solutions (in water) was

evaluated by the panel of 24 healthy male human volunteers. The taste of itopride HCl solution

of (200 and 150 µg/ml) was bitter, the 100 µg/ml solution was palatable but with bitter sensation

during swallowing. However itopride HCl solution (80µg/ml) was palatable without any bitter

taste, the data is shown in Table-3.21. According to the data, the itopride HCl solution (80µg/ml)

was selected as taste threshold for itopride HCl.

The UV absorbance of the different concentrations of itopride HCl solutions was

correlated with the taste response. The absorbance lower than 2.86, the absorbance of 80µg/ml,

indicate the drug release from the formulation is below the taste threshold level of itopride HCl.

Table-3.21: Taste Response and UV Absorbance of Various Solutions of

Itopride HCl Prepared in Water

Concentration (µg/ml) 10 20 40 60 80 100 150 200

Mean Absorbance (n = 3)

0.54 0.92 1.67 2.34 2.86 3.04 4.90 6.01

Standard Deviation 0.06 0.02 0.08 0.05 0.05 0.02 0.02 0.03

Taste Response (n = 24)

Taste less

Taste less

Taste less

Taste less

Taste less

Bitter Sensation

Bitter Taste

Bitter Taste

Mean Abs: Mean UV absorbance of itopride HCl solution in water measured at 220 nm


195

3.7.2 Taste Masking of Itopride HCl by Granulation Technique

The granulation technique was developed to control the release of drug below the taste

threshold level in the oral cavity.

Hydroxyl propyl methyl cellulose (HPMC) and polyvinyl pyrolidone (P.V.P.) were

used in different concentrations to prepare the granules of itoride HCl for the taste masking. The

Micro crystalline cellulose and cross linked carboxymethyl cellulose sodium (CCNa) were used

as diluents and an internal disintegrant, respectively. The use of CCNa may improve the

dissolution rate of itopride HCl from compressed tablets which was expected to be retarded by

high polymer concentration.

Hydrophilic polymers retard drug release by formation of gel layer around the drug

particles. During this process, individual polymer chains absorb water resulting in the increase in

chain length (expands) and convert into a new solvated state that form gel layer [130]. Gel

formation is regarded as rate limiting step for controlled drug release from polymer [111, 130].

The polymer that forms a highly viscous gel rapidly will retard drug release efficiently compared

with the polymers that form a non-viscous gel layer. The volume occupied by gel layer depends

upon the molecular weight of the polymer. Higher molecular weight of the polymer, thick gel

layer will form around the drug particles and will retard the drug release more effectively.

HPMC is a hydrophilic gel forming polymer which is highly safe, cost effective and

have been applied for a wide range of pharmaceutical applications. It is available in different

grade (based on molecular weight and viscosity building properties) with different hydration rate

and gel forming rate [131]. HPMC k4M was used for taste masking of itopride HCl by

granulation technique.


196

PVP is a synthetic polymer consisting of linear 1-vinyl-2-pyrrolidinone groups. The

differing degree of polymerization results in polymers of various molecular weights. It is

nontoxic, physiologically compatible, stable, hygroscopic and soluble in a number of solvents

including water [132].

Various itopride HCl to polymer ratios (1:1, 1:2, 1:2.5, 1:3 and 1:4) of both polymers

were studied for taste masking. At lower drug polymers ratio the taste masking was not achieved

(Table-3.22 and Table-3.23). Using higher polymer ratios, the release of drug retarded below

the taste threshold level showing masking of the bitter taste of itopride HCl. The formulation

TIG-05 containing PVP-K30 in 1:4 (drug to polymer ratio, w/w) exhibited complete taste

masking without any bitter feel. UV absorbance of the unit dose (quantity equivalent to dose of

itopride HCl) of TIG-05 was 1.48 ± 0.04 (n = 3) indicating very low amount of drug released in

3 ml of test medium. The drug release was high and bitter taste was observed in rest of the

formulations and was not selected for further studies.

In case of HPMC-K4M, taste masking was achieved at concentrations lower than PVP.

Complete taste masking and better drug release was achieved at 1:3 (drug to polymer ratio, TIG-

09) that was also confirmed by the healthy human volunteers.


197

Table-3.22: Spectrophotometric Taste Evaluation of Taste masked Itopride HCl prepared by Granulation

Technique

Formulation Code TIG-01 TIG-02 TIG-03 TIG-04 TIG-05 TIG-06 TIG-07 TIG-08 TIG-09 TIG-10

Mean Absorbance 3.92 3.85 3.34 3.02 1.48 3.88 3.56 2.98 1.32 0.97

Standard Deviation 0.08 0.10 0.06 0.07 0.04 0.14 0.03 0.03 0.02 0.01

Taste Response Strongly Bitter

Strongly Bitter

Bitter Bitter

SensationTasteless

Strongly Bitter

Strongly Bitter

Bitter Sensation

Tasteless Tasteless

Data is rounded off to 2 digits after decimal point


198

The formulations TIG-09 and TIG-10 (contained HPMC in 1:3 and 1:4 drug to polymer

ratio), respectively were rated as completely tasteless by all volunteers. UV absorbance of both

of the formulations was also below the taste-threshold limits.

Table-3.23: Volunteers Response about Taste Masked Itopride HCl Prepared

by Granulation Technique

Formulations Drug to

Polymer Ratio

Number of Volunteers Rating the Formulation as

0 1 2 3 4

TIG-01 1:1 w/w - - - - 24

TIG-02 1:2 w/w - - - - 24

TIG-03 1:2.5 w/w - - 3 18 3

TIG-04 1:3 w/w 9 15 - - -

TIG-05 1:4 w/w 21 3 - - -

TIG-06 1:1 w/w - - - - 24

TIG-07 1:2 w/w - - - 15 9

TIG-08 1:2.5 w/w - 15 9 - -

TIG-09 1:3 w/w 24 - - - -

TIG-10 1:4 w/w 24 - - - -

0: Tasteless 1: Bitter Sensation 2: Slightly Bitter 3: Bitter 4: Strongly Bitter


199

Taste masking by granulation technique depends on granulation time (kneading time)

and amount of fluid used in the granulation. Formulation TIG-08 was rated as slightly bitter

when fluid volume used was 120 ml and granulated for 3 min. When the same formulation was

processed with increased water quantity (135 ml) and longer kneading time (5 min) during

granulation process, it was rated as tasteless.

On the basis of taste masking results, TIG-09 was selected for formulation of fast

dispersible tablets (ODTs and Effervescent Tablet) of itopride HCl due to completely masked

taste and simple preparation technique (water based wet granulation technique) and low drug to

polymer ratio (1:3).

3.7.3 Taste Masking of Itopride HCl by Solid Dispersion Technique

Solid dispersion is efficient method for taste masking [133]. Solid dispersions of

itopride HCl were prepared using poly ethylene glycol (PEG), cetostearyl alcohol, hydroxy

propyl methyl cellulose (HPMC) and poly vinyl pyrolidone (PVP).

3.7.3.1 Solid Dispersions of Itopride HCl Prepared with Poly Ethylene Glycol

Polyethylene glycol (PEG) is available in different grades depending upon the

molecular weights. PEG of lower molecular weight is being liquid while that of higher molecular

weights are solid having melting point 60 – 70 °C [134]. PEG has been extensively used in


200

controlled drug release dosage form. The retard in the drug release depends upon molecular

weight of PEG and increases with increase in molecular weight [135].

Solid dispersions using PEG were prepared by following two methods:

i. Solvent Method

ii. Solvent/Fusion Method

Taste masking was not observed using low proportion of PEG-4000 compared with

drug (1:10) However, formulation TIS-05 (containing drug-polymer 1:15) completely masked

the taste when evaluated by the volunteers (n = 24) and also confirmed by measuring the

absorbance at 220 nm, results are shown in Table-3.24 and Table-3.25.

The use of PEG of higher molecular weight at lower concentration was effective

compared with the lower molecular weight PEG. The use of PEG-6000 at the drug polymer ratio

of 1:10 effectively masked the taste compared with the PEG-4000 that masked the taste at drug

polymer ratio of 1:15.

The effect of ethanol and water used as a solvent for solid dispersion was not observed

on the taste masking of itopride HCl.


201

Table-3.24: Spectrophotometric Evaluation of Taste Masked Itopride HCl Prepared by Solid Dispersion

Technique

Solid Dispersion of Itopride HCl Prepared Using Poly Ethylene Glycol

Formulation TIS-01 TIS-02 TIS-03 TIS-04 TIS-05 TIS-06 TIS-07 TIS-08 TIS-09 TIS-10

Mean Absorbance

3.42 3.37 3.28 3.05 2.54 3.31 3.2 3.02 2.77 2.59

Standard Deviation

0.02 0.01 0.01 0.06 0.08 0.01 0.09 0.08 0.09 0.01

Taste Response

Strongly Bitter

Strongly Bitter

Strongly Bitter

Bitter Sensation

Tasteless Strongly

Bitter Bitter

Sensation Tasteless Tasteless Tasteless

Solid Dispersion of Itopride HCl Prepared Using HPMC and PVP

Formulation TIS-11 TIS-12 TIS-13 TIS-14 TIS-15 TIS-16 TIS-17 TIS-18 TIS-19 TIS-20

Mean Absorbance

3.5 3.5 3.29 3.13 2.79 2 2.58 2.14 3.2 2.43

Standard Deviation

0.08 0.05 0.08 0.08 0.01 0.03 0.02 0.07 0.01 0.06

Taste Response

Strongly Bitter

Strongly Bitter

Strongly Bitter

Bitter Sensation

Tasteless Tasteless Tasteless TastelessBitter

Sensation Tasteless

Solid Dispersion of Itopride HCl Prepared Using Cetostearyl Alcohol

Formulation TIS-21 TIS-22 TIS-23 TIS-24 TIS-25 TIS-26

Mean Absorbance 3.35 3.17 3.03 2.65 2.69 2.77

Standard Deviation 0.08 0.06 0.04 0.06 0.04 0.11

Taste Response Strongly Bitter Strongly Bitter Bitter Taste Tasteless Tasteless Tasteless


202

3.7.3.2 Preparation of Solid Dispersions of Itopride HCl Using Cetostearyl Alcohol

Cetostearyl alcohol is a mixture of solid aliphatic alcohols consisting mainly of stearyl

alcohol (50 – 70 %) and cetyl alcohol (20 – 35 %). The 90% of cetostearyl alcohol is comprised

of combined stearyl alcohol and cetyl alcohol and rest of the 10% is mainly comprised of

myristyl alcohol [136].

Cetostearyl alcohol is hydrophobic in nature, effectively retard the release of the drug

and in turn mask the taste of the drugs. In present studies the taste of itopride HCl was masked at

the drug polymer ratio of 1:10 (TIS-25). Alt lower drug: polymer ratios, it failed to mask the

taste of itopride HCl (TIS-23).

The role of solvent used i.e. ethanol or water in the taste masking was not observed.

However, the use of alcohol as solvent resulted in dispersion with the regular shape and good

flowability.


203

Table-3.25: Volunteers Response for Taste Masked Itopride HCl Prepared by

Solid Dispersion Technique

Polymer Formulation /

Drug to Polymer Ratio (w/w)


0 1 2 3 4

PEG-4000

TIS-01 (1:1) _ _ _ _ 24

TIS-02 (1:2) _ _ _ _ 24

TIS-03 (1:4) _ _ _ _ 24

TIS-04 (1:10) _ 15 6 3 _

TIS-05 (1:15) 24 _ _ _ _

TIS-06 (1:4) _ _ _ 3 21

TIS-07 (1:8) _ 18 6 _ _

TIS-08 (1:10) 21 3 _ _ _

PEG-6000 TIS-09 (1:10) 24 _ _ _ _

TIS-10 (1:12) 24 _ _ _ _

H.P.M.C

TIS-11 (1:1) _ _ _ _ 24

TIS-12 (1:1) _ _ _ _ 24

TIS-13 (1:2) _ _ _ 3 21

TIS-14 (1:3) _ 12 9 3 _

TIS-15 (1:4) 15 9 _ _ _

TIS-16 (1:10) 24 _ _ _ _

PVP-K90 TIS-17 (1:5) 18 6 _ _ _

TIS-18 (1:10) 24 _ _ _ _


204

PVP-K30 TIS-19 (1:5) _ 15 3 6 _

TIS-20 (1:10) 21 3 _ _ _

Cetostearyl

Alcohol

TIS-21 (1:1) _ _ _ _ 24

TIS-22 (1:2) _ _ _ _ 24

TIS-23 (1:5) _ _ 15 6 3

TIS-24 (1:10) 21 3 _ _ _

TIS-25 (1:10) 24 _ _ _ _

TIS-26 (1:11) 18 6 _ _ _

0: Tasteless 1: Bitter Sensation 2: Slightly Bitter 3: Bitter 4: Highly Bitter

3.7.3.3 Solid Dispersions of Itopride HCl Prepared Using HPMC and PVP

Solid dispersions of itopride HCl using HPMC, PVP-90 and PVP-K30 were prepared

by solvent method at five drug to polymer ratios. The better taste masking was achieved with

lower drug polymer ratio of HPMC compared with PVP.

The formulation TIS-15, having drug: polymer ration of 1:4, effectively masked the

taste of itopride HCl. The UV absorbance of the solution of unit dose in 3 ml of test media

showed the drug release below the taste threshold level and was further confirmed by the healthy

human volunteers (n = 24), results are depicted in Table-3.24 and Table-3.25.


205

The PVP-K30 masked the taste of itopride HCl with drug: polymer ratio of 1:10 and

fail at the 1:5. While PVP-K90, being a higher molecular weight successfully masked the bitter

taste of itopride HCl when used with the drug: polymer ratio of 1:5 and was comparable with the

HPMC.

The UV absorbance at 220 nm for PVP-K30 was higher compared with the PVP-K90,

indicating the higher drug release from the low molecular weight polymer (Fig-3.19).

Figure-3.19: Comparison of UV Absorbance of Unit Dose of Solid Dispersions of PVP K-30 and PVP K-90 in 3 ml Test Media at 220 nm

Polymer concentration shows percent quantity of polymer in preparation of solid dispersion


206

3.7.4 Taste Masking of Itopride HCl by Microencapsulation Technique

Solvent evaporation technique was applied for preparation of micro capsules of itopride

HCl using three polymers (Eudragit, PVP k90 and HPMC). Eudragit is a hydrophobic polymer

while rests of the two polymers are hydrophilic in nature. All the polymers were used in five

different drug to polymer ratios. Taste of itopride HCl was completely masked using Eudragit at

1:2, drug to polymer ratio (TM-02), data shown in Table-3.26. Drug release from TM-02 was

low and most of the volunteers rated it tasteless (Table-3.27). UV absorbance of unit dose in 3

ml test medium was also within the range of taste masked.


207

Table-3.26: Spectrophotometric Evaluation of Taste Masked Itopride HCl Prepared by Micro-

Encapsulation Technique

Formulation TM-01 TM-02 TM-03 TM-04 TM-05 TM-06

Mean Absorbance 3.56 2.71 2.35 3.52 3.05 2.68


Taste Response Strongly Bitter Tasteless Tasteless Strongly Bitter Bitter Sensation Tasteless

Formulation TM-07 TM-08 TM-09 TM-10 TM-11 TM-12

Mean Absorbance 3.16 3.12 2.59 3.83 3.07 2.77


Taste Response Strongly Bitter Bitter Sensation Tasteless Strongly Bitter Slightly Bitter Tasteless


208

PVP-k30 masked taste in relatively higher concentration. Taste of itopride HCl was

masked at 1:6 drug to polymer ratio (TM-09) and bitter taste was observed at 1:4 (TM-08).

Molecular weight of PVP had significant effect on taste masking. When PVP-k90 was used in

1:4 (TM-06) taste was completely masked. UV absorbance of unit dose of TM-06 in 3 ml test

medium was lower compared with the same ratio of PVP-k30 indicating that PVP-k90 retarded

drug release to the level below the taste threshold. When both grades of PVP were used in

combination (1:1) taste was masked completely (TM-13). Although UV absorbance was higher

than that of PVP-k90 when used alone showing that rate of drug release was same when these

grades were used alone and there is no synergistic effect of the combination.

When HPMC was used in 1:2 (TM-11) slightly bitter taste was observed and complete

taste masking was achieved at 1:4 (TM-12). Taste response and UV absorbance of HPMC were

better than that of PVP at the same level.


209

Table-3.27: Volunteers Response about Taste Masked Micro-capsules of

Itopride HCl

Formulation

Code

Drug to Polymer

Ratio (w/w)


0 1 2 3 4

TM-01 1:1 _ _ _ 6 18

TM-02 1:2 9 15 _ _ _

TM-03 1:4 24 _ _ _ _

TM-04 1:1 _ _ _ _ 24

TM-05 1:2 _ _ 9 15 _

TM-06 1:4 21 3 _ _ _

TM-07 1:1 _ _ _ _ 24

TM-08 1:4

18 3 3 _

TM-09 1:6 24 _ _ _ _

TM-10 1:1 _ _ _ _ 24

TM-11 1:2 _ _ 18 3 3

TM-12 1:4 21 3 _ _ _


210

3.8 In-vitro Evaluation of the Fast Dispersible Tablets

3.8.1 Pre Compression Evaluation

The present work is based on the preparation of fast dispersible tablets (ODTs and

Effervescent Tablets) using direct compression. The ingredients of the formulations were

blended and the powder mixtures were evaluated for rheological characteristics like Hausner

ratio, Carr’s index, flow ability and angle of repose.

Flowability and angle of repose are direct indicators to determine the flow of the

powder however they are highly sensitive to experimental errors, like slight variations in

adjusting the height of the funnel, give major variation in the results. Therefore, the Hausner

ratio and Carr’s index of the powder were also studied to counter the check the results of the

other tests.

3.8.1.1 Pre Compression Evaluation of ODTs of Domperidone Prepared using Super

Disintegrant

Flow characteristics of domperidone were poor but effectively masked by excipients

having good rheological properties (MCC and Tablettose-80). Micro crystalline cellulose and

tabletose-80 were the two diluents constituting more than 70% w/w of all the formulations. The

analysis of the excipients data using SeDeM-ODT shows that IGCB values for both MCC and

Tablettose-80 is above 5 and are suitable for direct compression of domperidone in small dose

(10 mg/tablet).


211

Bulk volume, bulk density, tapped volume and tapped density of all the formulation

were similar as the same excipients were used in all formulations. The flow properties of all of

the blend formulation were within the acceptable range [94]. The results are depicted in Table-

3.28.

Flowability and angle of repose of ODD-02 was best of all the formulations, the Carr

index and Hausner ratio were 10.37 and 1.12, respectively [94].The replacement of Tablettose-80

(10%) with mannitol reduced the flow properties of the formulation (ODD-03) that may be due

to the granular structure of Tablettose-80 compared with the mannitol. The flow properties of the

formulation ODD-02 was also in the acceptable range.


212

Table-3.28: Physical properties of Pre Compressed Formulations of ODTs of

Domperidone Prepared using Super Disintegrants

Characteristics (Unit) ODD-01 ODD-02 ODD-03 ODD-04

Bulk Volume (ml) 50.00 ± 0.40 50.00 ± 0.20 50.00 ± 0.20 50.00 ± 0.60

Tapped Volume (ml) 46.40 ± 0.40 44.80 ± 0.80 45.20 ± 0.60 44.60 ± 0.40

Bulk Density (g/ml) 0.70 ± 0.06 0.70 ± 0.04 0.70 ± 0.06 0.70 ± 0.08

Tapped Density (g/ml) 0.75 ± 0.04 0.78 ± 0.04 0.77 ± 0.06 0.78 ± 0.03

Hausner Ratio* 1.08 1.12 1.11 1.12

Carr´s Index* 7.16 10.37 9.56 10.83

Flowability (sec) 16.09 ± 2.17 14.18 ± 2.33 14.27 ± 2.10 18.13 ± 2.09

Angle of Repose (o) 26.80 ± 1.80 24.91 ± 2.20 25.37 ± 1.40 29.16 ± 1.20

Results are presented as Mean ± Standard Deviation (n = 3) *: Calculated on the basis of Mean Bulk Density and Mean Tapped Density

3.8.1.2 Pre Compression Evaluation of ODTs of Domperidone Prepared by


Powder blends for ODTs of domperidone prepared by sublimation technique exhibited

better flow characteristics (Table-3.29). The angle of repose for all formulations was below 25o

and their flowability was also good. Flow of the powder was further evaluated by Hausner ratio

and Carr’s index that were in the range of 1.08 – 1.12 and 7.65 – 10.37, respectively, indicating

good flow properties of powder.


213

Table-3.29: Physical Properties of Pre Compressed Formulations of ODTs of Domperidone Prepared by


Formulation Bulk

Volume (ml)

Tapped Volume (ml)

Bulk Density (g/ml)

Tapped Density (g/ml)

*Hausner

Ratio

*Carr's

Index

Angle of

Repose (o) Flowability

(Sec)

ODS-01 50.00 ± 0.13 45.80 ± 0.40 0.73 ± 0.08 0.76 ± 0.03 1.09 8.38 18.97 ± 2.00 14.29 ± 2.65

ODS-02 50.00 ± 0.19 46.20 ± 0.60 0.70 ± 0.02 0.76 ± 0.05 1.08 7.65 21.65 ± 2.24 15.34 ± 2.71

ODS-03 50.00 ± 0.17 45.20 ± 0.80 0.73 ± 0.08 0.77 ± 0.05 1.11 9.56 19.43 ± 2.50 14.00 ± 2.16

ODS-04 50.00 ± 0.28 45.80 ± 0.40 0.73 ± 0.03 0.76 ± 0.03 1.09 8.38 18.75 ± 2.00 14.44 ± 2.48

ODS-05 50.00 ± 0.21 44.80 ± 0.20 0.75 ± 0.06 0.78 ± 0.06 1.12 10.37 21.55 ± 2.53 13.00 ± 2.59

ODS-06 50.00 ± 0.29 45.40 ± 0.40 0.72 ± 0.09 0.77 ± 0.03 1.10 9.21 18.40 ± 2.25 16.08 ± 2.39

ODS-07 50.00 ± 0.22 45.60 ± 0.40 0.70 ± 0.04 0.77 ± 0.07 1.10 8.85 23.82 ± 1.69 15.00 ± 3.01

ODS-08 50.00 ± 0.18 46.20 ± 0.60 0.71 ± 0.08 0.76 ± 0.02 1.08 7.65 20.70 ± 2.10 15.33 ± 2.67

ODS-09 50.00 ± 0.26 45.20 ± 0.60 0.74 ± 0.06 0.77 ± 0.08 1.11 9.56 18.91 ± 1.39 14.26 ± 2.31

Results presented as Mean ± Standard Deviation (n = 3) *Hausner Ratio and Carr’s Index were calculated from Mean Bulk Density and Mean Tapped Density


214

3.8.1.3 Pre Compression Evaluation of Effervescent Formulations of Domperidone

The SeDeM profiles of all of the excipients, except sodium bicarbonate, used in

formulation of effervescent tablets of domperidone, showed efficient flow properties and on that

basis better rheological properties were expected. On the basis of SeDeM profile, both

Tablettose-80 and micro crystalline cellulose were used as diluents. The use of these diluents

also improved the poor flowability of the drug.

The angle of repose, Carr’s index and Hausner ratio for all of the formulations were

indicating the good flow properties of the powder (Table-3.30). The angle of repose for all of the

formulations was less than 31o while Hausner ratio and Carr’s Index were below 1.15 and 12.01,

respectively. The replacement of Tablettose-80 with disintegrants affects the flow properties of

the powder and small variations were observed.


215

Table-3.30: Physical Properties of Pre Compressed Formulations of Effervescent Tablets of

Domperidone

Formulation

Code

Bulk Volume

(ml)

Tapped

Volume (ml)

Bulk

Density (g/ml)

Tapped

Density (g/ml)

*Hausner

Ratio

*Carr's

Index

Angle of

Repose (o)

ED-01 30.00 ± 0.87 27.75 ± 0.46 0.83 ± 0.02 0.90 ± 0.05 1.08 8.16 23.80 ± 0.05

ED-02 30.00 ± 0.79 27.50 ± 0.53 0.83 ± 0.03 0.91 ± 0.03 1.09 9.21 26.41 ± 0.08

ED-03 30.00 ± 1.03 27.25 ± 0.42 0.83 ± 0.02 0.92 ± 0.07 1.11 11.06 28.96 ± 0.07

ED-04 30.00 ± 1.09 27.45 ± 0.69 0.83 ± 0.04 0.91 ± 0.05 1.10 9.48 27.12 ± 0.13

ED-05 30.00 ± 0.76 27.15 ± 0.72 0.83 ± 0.08 0.92 ± 0.03 1.08 10.78 29.46 ± 0.10

ED-06 30.00 ± 0.57 27.05 ± 0.53 0.83 ± 0.06 0.92 ± 0.02 1.11 11.08 28.59 ± 0.20

ED-07 30.00 ± 0.88 27.80 ± 0.49 0.83 ± 0.04 0.90 ± 0.03 1.08 7.92 21.94 ± 0.18

ED-08 30.00 ± 0.60 27.15 ± 0.77 0.83 ± 0.08 0.92 ± 0.01 1.11 10.56 28.73 ± 0.20

ED-09 30.00 ± 0.80 26.80 ± 0.45 0.84 ± 0.05 0.93 ± 0.02 1.11 11.34 29.81 ± 0.20

ED-10 30.00 ± 0.78 27.20 ± 0.84 0.84 ± 0.04 0.92 ± 0.06 1.10 10.41 28.77 ± 0.14

ED-11 30.00 ± 0.53 27.60 ± 0.63 0.84 ± 0.07 0.91 ± 0.01 1.09 8.732 23.63 ± 0.17

ED-12 30.00 ± 0.82 26.80 ± 0.49 0.83 ± 0.08 0.93 ± 0.04 1.10 12.01 30.21 ± 0.33

Results presented as average ± standard deviation (n = 3) *Hausner ratio and Carr’ index were calculated from average bulk density and average tapped density of each formulation


216

3.8.1.4 Pre Compression Evaluation of ODTs Formulations of Itopride HCl Prepared

using Super Disintegrants

The Taste masked itopride HCl granules were prepared by wet granulation method. The

flow properties of the taste masked granules were good as per SeDeM-ODT analysis.

Taste masked itopride HCl granules were mixed with rest of the excipients and

compressed. Flow characteristics for all the formulations were in the acceptable range. Bulk

density and tapped density for all the formulations was in the range of 0.61 – 0.69 g/ml and 0.71

– 0.75 g/ml, respectively (Table-3.31).

All of the formulations of ODTs of itopride HCl prepared using super disintegrant

showed the flow properties in the acceptable range. Flowability of the various powder mixes was

in the range of showing good flow properties of the powder.

Hausner ratio was in the range of 1.12 – 1.15 while Carr’s index was in the range of

10.86 – 13.16 (Table-3.31). All these values indicated good flow characteristics of the powder

blend [94].


217

Table-3.31: Physical Properties of Pre Compressed Formulations of ODTs of

Itopride HCl Prepared using Super Disintegrant

Characteristics ODI-01 ODI-02 ODI-03 ODI-04 ODI-05 ODI-06

Bulk Volume (ml)

50.00 ± 0.04 50.00 ± 0.09 50.00 ± 0.04 50.00 ± 0.08 50.00 ± 0.08 50.00 ± 0.06

Tapped Volume (ml)

43.43 ± 0.03 43.81 ± 0.08 43.5 ± 0.03 44.13 ± 0.04 43.40 ± 0.03 44.61 ± 0.05

Bulk Density (g/ml)

0.64 ± 0.03 0.66 ± 0.01 0.63 ± 0.07 0.63 ± 0.04 0.65 ± 0.02 0.67 ± 0.04


0.74 ± 0.04 0.73 ± 0.04 0.74 ± 0.03 0.73 ± 0.07 0.74 ± 0.04 0.72 ± 0.06

Hausner Ratio* 1.15 1.14 1.15 1.13 1.15 1.12

Carr´s Index* 13.16 12.45 13.04 11.85 13.16 10.86

Flowability (Sec)

8.33 ± 2.08 12.00 ± 2.65 9.33 ± 1.56 8.33 ± 1.56 10.00 ± 2.65 8.00 ± 2.65

Angle of Repose (o)

21.3 ± 3.73 24.52 ± 2.50 23.4 ± 2.73 22.19 ± 0.85 22.8 ± 3.22 20.64 ± 2.91

Results are presented as Mean ± Standard Deviation (n = 3)

*: Calculated on the basis of Mean Bulk Density and Mean Tapped Density

3.8.1.5 Pre Compression Evaluation of ODTs of Itopride HCl Prepared by


Taste masked granules of itopride HCl prepared by wet granulation technique were

used in formulation of ODTs by sublimation techniques.

Bulk density and tapped density for all the formulations was in the range of 0.61 – 0.69

g/ml and 0.71 – 0.73 g/ml, respectively, results are shown in Table-3.32.


218

Angle of repose and flowability indicated better flow characteristics for all

formulations. Highest angle of repose was observed to be 21.43 ± 1.7 (n = 3) for OSI-08 which

was indicating good flow [137]. The Carr’s index and Hausner ratio were in the range of 9.35 –

12.45 % and 1.10 – 1.14, respectively indicating good flow properties of the granules.


219

Table-3.32: Physical Properties of Pre Compressed Formulations of ODTs of Itopride HCl Prepared by


Formulation

Bulk Volume

(ml)

Tapped Volume

(ml)

Bulk Density (g/ml)


*Hausner Ratio

*Carr's Index

Angle of Repose (o)

Flowability (Sec)

OSI-01 50.00 ± 0.27 44.30 ± 0.20 00.64 ± 0.09 0.72 ± 0.04 1.13 11.36 19.46 ± 1.13 9.00 ± 3.00

OSI-02 50.00 ± 0.13 44.80 ± 0.60 00.63 ± 0.04 0.71 ± 0.09 1.12 10.36 20.18 ± 1.72 10.00 ± 3.23

OSI-03 50.00 ± 0.21 44.20 ± 0.20 00.69 ± 0.07 0.72 ± 0.07 1.13 11.60 20.26 ± 1.39 8.00 ± 2.76

OSI-04 50.00 ± 0.08 45.30 ± 0.50 00.63 ± 0.04 0.71 ± 0.04 1.10 9.35 19.58 ± 2.29 8.00 ± 2.00

OSI-05 50.00 ± 0.17 44.70 ± 0.30 00.65 ± 0.03 0.72 ± 0.08 1.12 10.61 21.10 ± 1.81 11.00 ± 3.03

OSI-06 50.00 ± 0.09 45.10 ± 0.20 00.68 ± 0.07 0.71 ± 0.03 1.11 9.86 20.60 ± 1.63 10.00 ± 2.07

OSI-07 50.00 ± 0.10 43.80 ± 0.60 00.66 ± 0.06 0.73 ± 0.03 1.14 12.45 20.52 ± 0.93 10.00 ± 2.51

OSI-08 50.00 ± 0.29 44.60 ± 0.20 00.61 ± 0.09 0.72 ± 0.05 1.12 10.86 21.43 ± 1.70 8.00 ± 2.33

OSI-09 50.00 ± 0.37 44.50 ± 0.40 00.67 ± 0.05 0.72 ± 0.05 1.12 10.99 19.73 ± 1.59 9.00 ± 3.01



220

3.5.1.1 Pre Compression Evaluation of Effervescent Formulations of Itopride

HCl

The SeDeM profile of the taste masked itopride HCl granules, prepared by wet

granulation process, and other excipients except sodium bicarbonate showed good flow

properties. The addition of the lubricant enhanced the flow properties of the powder mix. The

Table-3.33 shows the rheological properties for all of the formulations were in the good

acceptable range.


221

Table-3.33: Physical Properties of Pre Compressed Formulations of Effervescent Tablets of Itopride HCl

Formulation Code

Bulk Volume (ml)

Tapped Volume

(ml)

Bulk Density (g/ml)


*Hausner Ratio

*Carr's Index

Angle of Repose (o)

Flowability (Sec)

EI-01 50.00 ± 0.06 44.13 ± 0.03 0.66 ± 0.02 0.75 ± 0.04 1.13 11.76 20.63 ± 0.29 9.63 ± 1.73

EI-02 50.00 ± 0.09 43.87 ± 0.08 0.63 ± 0.07 0.75 ± 0.07 1.14 12.35 20.19 ± 0.48 8.07 ± 2.09

EI-03 50.00 ± 0.05 43.73 ± 0.06 0.67 ± 0.05 0.76 ± 0.09 1.14 12.58 22.00 ± 0.39 11.33 ± 2.16

EI-04 50.00 ± 0.08 44.26 ± 0.10 0.65 ± 0.09 0.75 ± 0.05 1.13 11.65 20.40 ± 0.61 10.29 ± 1.81

EI-05 50.00 ± 0.05 43.50 ± 0.08 0.65 ± 0.04 0.76 ± 0.04 1.15 13.04 22.58 ± 0.18 10.00 ± 2.02

EI-06 50.00 ± 0.08 43.73 ± 0.12 0.66 ± 0.08 0.76 ± 0.05 1.14 12.58 24.43 ± 0.26 11.31 ± 2.07

EI-07 50.00 ± 0.03 42.84 ± 0.12 0.68 ± 0.03 0.77 ± 0.08 1.17 14.40 23.51 ± 0.38 10.41 ± 2.18

EI-08 50.00 ± 0.08 42.67 ± 0.06 0.64 ± 0.07 0.78 ± 0.03 1.17 14.84 22.84 ± 0.51 9.23 ± 1.93

EI-09 50.00 ± 0.10 43.22 ± 0.04 0.63 ± 0.05 0.76 ± 0.05 1.16 13.61 20.27 ± 0.39 10.09 ± 2.31

EI-10 50.00 ± 0.07 42.80 ± 0.12 0.65 ± 0.06 0.77 ± 0.06 1.17 14.40 24.37 ± 0.31 10.45 ± 1.79

EI-11 50.00 ± 0.09 42.53 ± 0.08 0.63 ± 0.06 0.78 ± 0.10 1.18 14.95 21.94 ± 0.21 8.25 ± 1.92

EI-12 50.00 ± 0.03 42.61 ± 0.13 0.67 ± 0.04 0.78 ± 0.07 1.17 14.84 22.64 ± 0.35 10.07 ± 2.05



222

3.8.2 Tablet Evaluation

Tablets evaluation was categorized into following tests:

Physical characteristics (weight variation, tablet thickness, wetting time, drug

content and moisture content)

Mechanical strength of tablets (crushing strength, tensile strength, specific crushing

strength and friability)

Disintegration behavior (disintegration time, oral disintegration time and

effervescence time)

In-vitro drug release rate

In-vivo evaluation (Pharmacokinetic evaluation in healthy rabbits and

pharmacodynemic evaluation in cancer patients)

3.8.2.1 Tablets Evaluation of ODTs of Domperidone Prepared using Super

Disintegrants

Physical Characteristics of ODTs of Domperidone Prepared using Super Disintegrants

The theoretical weight of the orally disintegrating tablets of domperidone was 200 mg.

The ODTs of domperidone prepared using super disintegrants was in the range of 2.3 – 2.7%.

These values were within the official limits [15].


223

Tablets from all the formulations were smooth and shiny without any sticking. Using

poly ethylene glycol 4000 (PEG-4000) as lubricant (ODD-03), produced tablets dull (in

appearance) indicating its poor lubrication compared with magnesium stearate used as lubricant

in the same concentration. Surface of the tablets containing starch maize (ODD-04) was more

smooth and shiny compared with rest of the formulations.

Moisture content determined for ODTs, prepared using super disintegrant, and was

below 2.5 % for all formulations (Table-3.34). The optimum moisture contents are important for

good mechanical strength and friability of the tablets and in present studies no edging and

capping was observed in all formulations.

Wetting time of ODTs of domperidone prepared using super disintegrants was in the

range of 35 – 70 sec.wetting time reduced by increasing the contents of super disintegrant and by

reduction the compression force.

Drug contents of all the formulations were within the 98 – 102 % which was within the

official limits. Uniform drug content confirmed proper mixing of the drug with excipients.


224

Table-3.34: Physical Parameters of ODTs of Domperidone Prepared using

Super Disintegrants

Formulation Code ODD-01 ODD-02 ODD-03 ODD-04

Weight Variation (%) ± 2.50 ± 2.30 ± 2.70 ± 2.30

Tablet Thickness (mm) 3.74 ± 0.24 3.66 ± 0.17 3.70 ± 0.11 3.55 ± 0.32

Moisture Content (%) 2.29 ± 0.49 2.11 ± 0.73 2.43 ± 0.58 2.40 ± 0.42

Drug Content (%) 98.39 ± 0.29 98.16 ± 0.47 101.93 ± 0.26 99.51 ± 0.38

Wetting Time (Sec) 47.00 ± 4.69 38.00 ± 3.91 39.00 ± 4.23 63.00 ± 4.06

Results are presented as Mean ± S.D.

Mechanical Strength of ODTs of Domperidone Prepared using Super Disintegrants

Crushing strength of ODTs of domperidone prepared using super disintegrants was in

the range of 3.00 – 7.50 kg. The low crushing strength was observed for ODD-03, where

Tablettose-80, was partially replaced with manitol.

Friability of the tablets from all the formulations was within the permissible range (<

1%) [114] and edging and capping were not observed with any formulation. When Crushing

strength of ODD-03 was increased up to 4.60 kg ± 0.52, some edging was observed during

friability testing. Friability was best for ODD-04 (0.15 %). In ODD-04 starch provided extra

compactness leading to reduced friability of the tablets.


225

Table-3.35: Mechanical Strength of ODTs of Domperidone Prepared using Super Disintegrant

Formulation †Crushing Strength

(Kg) Friability

(%) Tensile Strength*

(kg/mm2 ) Specific Crushing

Strength*(kg/mm2 )

ODD-01 5.72 ± 0.38 0.18 0.35 0.15

ODD-02 6.51 ± 0.59 0.18 0.39 0.17

ODD-03 3.97 ± 0.72 0.31 0.24 0.10

ODD-04 6.83 ± 0.47 0.15 0.41 0.18

†: Results are presented as Mean ± Standard Deviation (n = 10) *: Calculated on the basis of mean crushing strength and mean thickness of tablets

Disintegration Behavior of ODTs of Domperidone Prepared using Super Disintegrants

The disintegration time for all the formulations containing super disintegrants was less

than 1 min. Formulation ODD-04 (containing sodium carboxy methyl cellulose and maiz starch)

showed the longest disintegration time (53 ± 3.2 sec) while the shortest disintegration time was

observed for ODD-02 (21 ± 4.28 sec).

Oral disintegration time was determined by a panel of 12 healthy male volunteers,

results are shown in Fig-3.20. The fastest disintegration time observed for formulation ODD-02

(27 sec ± 4.63) and longest time was for ODD-04 (73 sec ± 4.28).

Good correlation was observed between oral disintegration time of the tablet in-vitro

disintegration time, results were depicted in Fig-3.20.


226

Figure 3.20: Disintegration Time and Oral Disintegration Time of ODTs of Domperidone

Prepared Using Super Disintegrants. D. Time: In-vitro Disintegration Time, O. D. Time: Oral Disintegration Time

In-vitro Drug Release from ODTs of Domperidone Prepared using Super Disintegrants

In-vitro drug release from ODTs of domperidone was studied according to British

Pharmacopoeia, using 900 ml of 0.1N HCl as dissolution media held at 37 ± 2 oC.Drug release

from ODTs of domperidone prepared using super disintegrants, increased with concentration of

the super disintegrant (cross carmellose sodium) and lowest drug release was observed with

lowest concentration (2.50%) (ODD-01).

Different burst drug release was observed during initial 15 minutes (Q15min) for various

formulations containing different concentrations of disintegrants. Highest Q15min (83.08 ± 2.16


227

%) and maximum drug release (93.65 ± 2.10 %) were observed for ODD-03, containing cross

carmellose sodium (5 %w/w) as disintegrant.

In rest of the formulations drug release was lower than ODD-03 both in terms of their

burst release (Q15min) and maximum release (Q 60min).

Figure 3.21: In-vitro Drug Release from ODTs of Domperidone Prepared using Super

Disintegrants Drug release was studied using 0.1N HCl (900 ml) as dissolution media held at 37 ± 2 oC


228

3.8.2.2 Post Compression Evaluation of ODTs of Domperidone Prepared by


Sublimation of Sublimating Agents from ODTs of Domperidone Prepared by Sublimation

Technique

Ammonium bicarbonate and menthol were used as sublimating agents in the

formulations of ODTs DMP. The sublimating agents were removed under the high temperature

(50 ± 2 oC), weight of the tablets was determined and presented as percent weight loss.

Maximum weight loss of formulation ODS-01 (without sublimating agent) was 3.87%

after 3 hrs of exposure at 50 ± 2 oC. That may be due to evaporation of intrinsic moisture present

in the tablets. That may be the cause of low crushing strength and breaking of the tablets during

friability test.

Figure-3.22: Sublimation Rate from ODTs of Domperidone Prepared by Sublimation Technique, Containing Different Concentrations of Menthol

ODS-01 is without any sublimating agent and was used as control


229

Rate of sublimation was higher for the formulations containing menthol compared with

the ammonium bicarbonate as shown in Fig-3.22. The ODS-03, containing 15% w/w menthol

showed the complete sublimation (13.81%) in 3 h at 50 ± 2 oC that may be sufficient average

time to remove methanol contents from the formulations. Formulation containing 10% and 5%

menthol showed an average weight loss of 9.76% w/w (n = 10) and 5.91% (n = 10), respectively.

Average weight loss of ammonium bicarbonate at 50 ± 2 oC was about half of the

concentration of subliming agent (Fig-3.23), therefore to improve the process, the temperature

was increased to 60 ± 2 oC for further 2 hrs. The data showed that higher temperature (60 ± 2 oC)

for longer time was required for sublimation of ammonium bicarbonate from tablets.

Figure-3.23: Sublimation Rate from ODTs of Domperidone Prepared by Sublimation Technique Containing Different Concentrations of Ammonium Bicarbonate


230

Drug content of all the formulations was determined after sublimation of sublimating

agents. Drug content of all the formulations was in the range of 99 – 103.5% showing that

domperidone did not degraded by exposure to high temperature (60 ± 2 oC) for sublimation of

sublimating agents.


231

Table-3.36: Comparison of Tablet Weight of ODTs of Domperidone before and after Sublimation of

Sublimating Agents

Formulation Sublimating

Agent

Amount of SublimatingAgent (%)

Mean Tablet Weight (mg) % Loss (w/w)

Drug Content Before Sublimation

After Sublimation

ODS-02

Menthol

10 198.43 ± 0.09 179.06 ± 0.48 9.76 ± 0.10 99.30 ± 2.01

ODS-03 15 197.37 ± 0.37 177.48 ± 0.29 10.08 ± 0.06 102.89 ± 1.33

ODS-04 5 202.45 ± 0.19 190.48 ± 0.60 5.91 ± 0.09 97.50 ± 1.67

ODS-05 5 204.70 ± 0.12 191.38 ± 0.48 6.51 ± 0.11 99.03 ± 2.16

ODS-06

Ammonium

Bicarbonate

10 203.43 ± 0.20 189.31 ± 0.41 6.94 ± 0.06 99.76 ± 2.11

ODS-07 15 201.30 ± 0.31 184.81 ± 0.59 8.19 ± 0.13 103.20 ± 2.09

ODS-08 5 203.29 ± 0.35 196.43 ± 0.44 3.38 ± 0.08 102.39 ± 2.91

ODS-09 5 203.73 ± 0.22 194.18 ± 0.61 4.69 ± 0.09 99.67 ± 2.05

Results are presented as Mean ± S.D. ODS-01 was not included in the table as it contained no sublimating agent Drug Content: Drug content of the tablet after sublimation of volatile ingredients


232

Physical Characteristics of ODTs of Domperidone Prepared by Sublimation Technique

The theoretical weight of the orally disintegrating tablets of domperidone prepared by

sublimation technique was 200 mg. The weight variation in ODTs of domperidone prepared by

sublimation technique was in the range of 2.30 – 3.70 %. These values were within the official

limits [15].

Thickness of the tablets was not significantly different results are shown in Table-3.37.

That may be due to the same weight of the tablets and using the same facilities for compression.

The mean dimension of the tablets was such thatit can be easily use by the patient. The surface of

the ODTs, prepared by sublimation technique, was slightly rough compared to the tablets

prepared using super disintegrants.

The wetting time of the ODTs domperidone prepared by sublimation technique was 50

– 133 sec before sublimation of sublimating agents and reduced to 16 – 53 sec after sublimation.

That may be due to formation of micro channels in the tablets after sublimation of sublimating

agents which facilitated distribution of fluid. Wetting time of final ODTs prepared by

sublimation was very low compared with the ODTs prepared using super disintegrants.

Drug contents of all the formulations were within the 94 – 104 % which was within the

official limits.


233

Table-3.37: Physical Parameters of ODTs of Domperidone Prepared by


Formulations Drug Content (%)

Thickness (mm)

Wetting Time (sec)

Weight Variation (%)

ODS-01 96.53 ± 2.63 3.46 ± 0.24 41.29 ± 2.53 ± 2.70

ODS-02 97.60 ± 1.91 3.43 ± 0.18 31.75 ± 4.07 ± 2.30

ODS-03 101.21 ± 2.33 3.43 ± 0.14 19.33 ± 2.79 ± 3.10

ODS-04 96.73 ± 2.15 3.59 ± 0.20 23.00 ± 3.21 ± 2.60

ODS-05 99.24 ± 2.33 3.64 ± 0.09 29.67 ± 2.63 ± 3.50

ODS-06 95.80 ± 3.10 3.07 ± 0.14 42.00 ± 2.71 ± 2.50

ODS-07 99.43 ± 1.60 3.47 ± 0.11 26.33 ± 4.03 ± 3.60

ODS-08 98.64 ± 3.40 3.43 ± 0.13 49.33 ± 3.96 ± 2.80

ODS-09 97.89 ± 1.73 3.49 ± 0.21 31.00 ± 3.48 ± 3.10


Mechanical Strength of ODTs of Domperidone Prepared by Sublimation Technique

Mechanical strength of tablets from all formulations of ODTs of domperidone prepared

by sublimation technique was evaluated before and after sublimation of sublimating agents

(menthol and ammonium bicarbonate). Before sublimation of sublimating agents, tablets had

high mechanical strength. Mean crushing strength of the tablets was in the range of 5 – 11kg (n =

10). Friability for all the formulations was below 0.25% i.e. within the permissible limits [114]

indicating good mechanical characteristics of the tablets.


234

Table-3.38: Mechanical Properties of ODTs of Domperidone Prepared by

Sublimation Technique, Before and After Sublimation of Sublimating Agents

Status Formulation †Crushing Strength

(Kg) Friability

(%) *Tensile Strength

(kg/mm2 ) *Specific Crushing Strength (kg/mm2 )

Bef

ore

Su

bli

mat

ion

ODS-01 6.08 ± 0.45 0.30 0.11 0.17

ODS-02 5.77 ± 0.32 0.35 0.11 0.16

ODS-03 5.68 ± 0.32 0.15 0.11 0.16

ODS-04 5.87 ± 0.40 0.30 0.10 0.16

ODS-05 5.83 ± 0.30 0.30 0.10 0.15

0DS-06 5.53 ± 0.30 0.30 0.13 0.17

ODS-07 6.62 ± 0.25 0.45 0.12 0.18

ODS-08 8.99 ± 0.94 0.15 0.17 0.25

ODS-09 6.24 ± 0.52 0.15 0.11 0.17

Aft

er S

ub

lim

atio

n

ODS-01 4.88 ± 0.21 Failed 0.11 0.13

ODS-02 3.57 ± 0.27 Failed 0.11 0.09

ODS-03 4.32 ± 0.24 0.39 0.11 0.12

ODS-04 4.87 ± 0.33 0.45 0.10 0.13

ODS-05 4.27 ± 0.34 0.60 0.10 0.11

ODS-06 4.65 ± 0.31 0.51 0.13 0.12

ODS-07 5.35 ± 0.44 0.73 0.12 0.14

ODS-08 6.59 ± 0.87 0.62 0.17 0.18

ODS-09 5.60 ± 0.23 0.38 0.11 0.15

†: Results are presented as Mean ± Standard Deviation (n = 10) *: Calculated on the basis of mean crushing strength and mean tablet thickness


235

Following sublimation the crushing strength of tablets of ODS-01 (controlled batch)

was reduced to 4.88 kg ± 0.21 from 6.08 kg ± 0.45 and also failed the friability test.

Increase in porosity resulted in lower crushing strength of the tablet. The crushing

strength depends on the number of contact points between the particles and inter particle binding

forces [138]. Fragmentation of the brittle powder during compression develop large number of

contact points resulting in tablets with high mechanical strength [139]. Sublimation of volatile

ingredients from tablets lead to alteration in porosity of tablets, reducing number of contact

points between the particles and resulted in reduced mechanical strength. Low porosity will bring

particles in close contact with each other forming solid bridges that increased the mechanical

strength.

Results of percent weight loss showed complete sublimation of methanol and the

resultant tablets had maximum porosity that formed the dosage form with low mechanical

properties. Crushing strength of the tablets was in the range of 3.5 – 4.5 kg. However, Friability

of the tablets was within the official limits [114] and no capping or lamination was observed in

any formulation except ODS-02.

Crushing strength of the tablets containing ammonium bicarbonate was higher after

sublimation compared with the tablets containing menthol. The crushing strength was not

significantly different between the tablets dried at 50 °C for one hour compared with the un-

treated tablets. Highest weight loss was observed (6.25%) in tablets containing ammonium

bicarbonate (15% w/w). The drying at 60 oC for three hours reduced the crushing strength to 4.50

– 6.60 kg. The friability was also better than the formulation based on methanol.


236

The better mechanical properties of the tablets containing ammonium carbonate

compare with the formulations prepared using methanol may be due to the rapid and complete

sublimation of menthol that increased tablet porosity to a large extent compared with ammonium

bicarbonate. Comparison of crushing strength of tablets containing different sublimating agents

is shown in Fig-3.24.

Figure-3.24: Comparison of Crushing Strength of ODTs of Domperidone after Sublimation of Menthol and Ammonium Bicarbonate

Disintegration Behavior of ODTs of Domperidone Prepared by Sublimation Technique

The disintegration time of the ODTs before sublimation of the methanol or ammonium

carbonate, was high compared with the tablets processed to remove the sublimating agents.

Disintegration time of the tablet depends on the hydrophilicity, swelling ability; inter particle

forces of attraction of ingredients, crushing strength and porosity of the tablets [28]. The


237

relationship between the porosity and fluid penetration can be evaluated using following

equation:

----------------- Eq-3.1

Where

l = Penetration length at time t

r = Average radius of capillary

u = Contact angle between the liquid and the powder surface

= Viscosity of the liquid

= Surface tension of the liquid

Water penetration into the core of the tablet is directly related to level of porosity, and

radius of the pores. Penetration of the water into the core of tablet breaks the inter particles bonds

and results in the disintegration of the tablets [140].

The disintegration time of formulation ODS-01 (without sublimating agent) was

decreased after heating that may be due to decrease in the crushing strength of the tablets. The

disintegration time of the tablets after the sublimation process was less than 40 sec. The

disintegration time was less for tablets containing methanol compared with the ammonium

bicarbonate. The ODS-08, containing 15.0% ammonium bicarbonate, was disintegrated in 34 ±

4sec. The shortest oral disintegration time (25 ± 3.51 sec) was observed for formulation ODS-05,

results are shown in Table-3.39.


238

Table-3.39: Disintegration Time and Oral Disintegration Time of ODTs of

Domperidone Prepared by Sublimation Technique

Formulation

Disintegration Time (sec) Oral Disintegration Time (sec)

Before Sublimation

After Sublimation

Before Sublimation

After Sublimation

ODS-01 52 ± 2.65 36 ± 4.51 87 ± 4.18 58 ± 2.52

ODS-02 58 ± 4.51 17 ± 4.13 91 ± 4.73 30 ± 4.18

ODS-03 43 ± 4.00 13 ± 2.09 67 ± 4.73 27 ± 4.24

ODS-04 57 ± 4.03 15 ± 3.51 83 ± 4.58 35 ± 3.37

ODS-05 47 ± 4.56 16 ± 3.61 70 ± 2.52 25 ± 3.51

ODS-06 47 ± 4.00 26 ± 4.55 81 ± 4.73 51 ± 4.09

ODS-07 62 ± 3.57 15 ± 1.16 92 ± 4.11 32 ± 3.51

ODS-08 96 ± 4.02 34 ± 4.11 112 ± 4.03 54 ± 3.87

ODS-09 52 ± 4.51 12 ± 1.53 88 ± 3.51 34 ± 3.36


The mean disintegration time (54 ± 3.87 sec ) of the formulation containing 5% w/w

ammonium bicarbonate was significantly high (p > 0.05) compared with the formulation

containing methanol as sublimating agents (Table-3.39). The results show that menthol is more

efficient in sublimation and porosity enhancing compared with the ammonium bicarbonate. The

rapid sublimation of methanol may develop micro-channels leads to rapid disintegration.


239

Figure 3.25: Comparison of In-vitro Disintegration Time and Oral Disintegration Time of ODTs

of Domperidone Prepared by Sublimation Technique

Complete and rapid removal of sublimating agents with smaller particles left behind

tablets with a large network of micro channels that facilitate penetration of fluid and fast

disintegration of dosage form. Particles of ammonium bicarbonate were fine compared with the

menthol but removal from the tablets was slow and incomplete that led to the less porous tablets

compared with the menthol.


240

Figure 3.26: Comparison of Disintegration Time of ODTs of Domperidone Containing

Different Concentrations of Sublimating Agents. 5+3: Combination of Sublimating Agent and Disintgerant (5% + 3%)

In-vitro Drug Release From Orally Disintegrating Tablets of Domperidone Prepared by


Drug release from ODTs of domperidone prepared by sublimation technique was

studied using 0.1N HCl (900 ml) as dissolution media. ODS-01 was without any sublimating

agent and used as control. Drug release from ODS-01 was slow and 46.26 ± 2.38% of drug

released during initial 15 min (Fig-3.27). Addition of sublimating agents increased drug release

and 76.29 ± 2.01 % drug release, during initial 15 min, was observed with 15% menthol (ODS-

03). Maximum drug release from ODTs of domperidone prepared by sublimation technique

containing menthol as sublimating agent was above 90%.


241

Figure 3.27: In-vitro Drug Release from ODTs of Domperidone Prepared by Sublimation Technique using Menthol as Sublimating Agent

Drug release from ODTs of domperidone containing ammonium bicarbonate as

sublimating agent was slower compared ODTs containing menthol as shown in Fig-3.28. Drug

release during initial 15 min was 66.53 ± 2.62 % from ODS-07 containing 15% ammonium

bicarbonate. Inclusion of super disintegrant improved drug release significantly and 71.91 ±

2.69% drug releae during initial 15 min was observed with ODTs-09 containing

superdisintegrant (5 %w/w) in combination with ammonium bicarbonate.


242

Figure3.28: In-vitro Drug Release from ODTs of Domperidone Prepared by Sublimation Technique using Ammonium Bicarbonate as Sublimating Agent


243

3.8.2.3 Evaluation of Effervescent Tablets of Domperidone

Physical Characteristics of Effervescent Tablets of Domperidone

The surface of effervescent domperidone tablets was smooth and shiny without any

sticking and picking. The sifting through mesh (250 µm) and subsequent drying at 60 oC for 60

min may have improved the lubricating properties of magnesium stearate [6].

Weight variation for all of the formulation was with the permissible limits i.e.± 5%

[15]. The highest weight variation was observed for formulation ED-12 (± 3.40%) which was

also in acceptable range. Thickness of the tablets was also in the narrow range (3.50 – 3.80 mm)

indicating the good flow properties of granules and efficiency of the lubricant.

Drug contents of all the formulations were within the permissible range of 97 – 102 %

[15] indicating uniform mixing of drug and excipients (Table-3.40).

Moisture content of all the formulations was within the range of 1.3 – 1.8 % w/w which

was not high enough to initiate any premature effervescence [62].


244

Table-3.40: Physical Characteristics of Effervescent Tablets of Domperidone

Formulation Moisture

Content (%)

Drug content

(%)

Thickness

(mm)

Wetting

Time (sec)

Weight

Variation (%)

ED-01 1.79 ± 0.20 97.35 ± 0.93 3.65 ± 0.29 181 ± 2.97 ± 2.13

ED-02 1.57 ± 0.50 101.19 ± 0.37 3.72 ± 0.33 170 ± 3.01 ± 2.94

ED-03 1.49 ± 0.43 99.72 ± 1.03 3.75 ± 0.17 166 ± 3.96 ± 3.20

ED-04 1.36 ± 0.08 100.53 ± 0.87 3.70 ± 0.23 160 ± 3.13 ± 2.51

ED-05 1.42 ± 0.07 98.11 ± 0.96 3.65 ± 0.38 146 ± 2.07 ± 3.20

ED-06 1.77 ± 0.09 97.26 ± 0.80 3.60 ± 0.31 150 ± 3.98 ± 3.67

ED-07 1.83 ± 0.06 99.67 ± 1.06 3.61 ± 0.26 192 ± 3.14 ± 2.49

ED-08 1.61 ± 0.10 98.42 ± 1.10 3.60 ± 0.21 176 ± 2.63 ± 2.60

ED-09 1.73 ± 0.09 97.90 ± 0.78 3.60 ± 0.30 184 ± 3.04 ± 2.80

ED-10 1.47 ± 0.21 99.32 ± 0.99 3.60 ± 0.19 168 ± 2.31 ± 2.51

ED-11 1.30 ± 0.26 101.76 ± 0.89 3.55 ± 0.27 150 ± 2.07 ± 1.93

ED-12 1.83 ± 0.10 98.79 ± 1.17 3.58 ± 0.18 159 ± 3.11 ± 3.41


Mechanical Strength of Effervescent Tablets of Domperidone

Crushing strengths of effervescent tablets of domperidone was in the range of 6 – 10 kg

(Table-3.41). Formulation ED-09 containing 56.83% w/w of Tablettose-80 showed the highest

crushing strength (9.35 ± 1.38 kg), and lowest friability. Tablet from all the formulations were

hard enough to with stand handling during processing.


245

Tensile strength and specific crushing strength for all formulations were in the range of

0.08 – 0.13 kg/mm2 and 0.13 – 0.2 kg/mm2, respectively, indicative of the good mechanical

properties of the formulations (Table-3.41). The friability of the tablets was also in good

agreement with official compendium and no edging or lamination or breaking of the tablets was

observed.

Table-3.41: Mechanical Strength of Effervescent Domperidone Tablets

Formulation †Crushing Strength

(Kg)

Friability

(%)

*Tensile Strength

(kg/mm2)

*Specific Crushing

Strength (kg/mm2)

ED-01 9.20 ± 1.53 0.31 0.12 0.19

ED-02 8.61 ± 1.81 0.45 0.11 0.18

ED-03 6.68 ± 1.74 0.15 0.09 0.14

ED-04 7.06 ± 1.40 0.15 0.09 0.15

ED-05 6.54 ± 0.90 0.15 0.09 0.14

ED-06 8.64 ± 1.21 0.30 0.12 0.19

ED-07 9.15 ± 1.82 0.30 0.12 0.20

ED-08 8.93 ± 1.67 0.45 0.12 0.19

ED-09 9.35 ± 1.38 0.32 0.13 0.20

ED-10 8.42 ± 1.70 0.30 0.11 0.18

ED-11 7.13 ± 1.30 0.30 0.10 0.15

ED-12 7.25 ± 1.83 0.31 0.10 0.16

†: Results are presented as Mean ± S.D. (n = 10)

*: Calculated on the basis of mean crushing strength and mean thickness of the tablets


246

Disintegration Behavior of Effervescent Tablets of Domperidone

Effervescence time was determined individually for six tablets from each formulation

[115]. Effervescence time of the tablet containing only citric acid and sodium bicarbonate (ED-

01) was 87 ± 3.71 sec and reaction was very slow and gradual. Effervescence time for

formulation ED-07 containing tartaric acid and sodium bicarbonate, in the same concentration

was 75 ± 3.01 sec. That may be due to slow interaction between the citiric acid and sodium

bicarbonate compared with the tartaric acid and sodium bicarbonate. Addition of super

disintegrants had a significant effect on effervescence time with both types of effervescent pairs.

Smallest effervescence time was observed with ED-11 (29 ± 2.09 sec, n = 6) containing tartaric

acid and sodium bicarbonate in combination with 5% w/w super disintegrant (sodium starch

glycolate).

Effervescence reaction between tartaric acid and sodium bicarbonate was rapid in

comparison to the reaction between citric acid and sodium bicarbonate. Addition of disintegrants

with both acid base pairs enhanced effervescence reaction and lowest effervescent time was

observed in the presence of disintegrants. Disintegrants absorb water due to their strong wicking

action enhancing effervescence reaction.


247

Figure 3.29: Effervescence Time of Effervescent Tablet of Domperidone (10 mg)

Figure 3.30: Comparison of Effervescence Time with Different Effervescent Pairs and Varying Concentration of Disintegrant


248

3.8.2.4 Tablet Evaluation of ODTs of Itopride HCl Prepared using Super

Disintegrants

Physical Characteristics of ODTs of Itopride HCl Prepared using Super Disintegrants

The ODTs of itopride HCl were compressed using 10.50 mm round shallow concave

punches with bisection line on one side. Tablets of all the formulations were smooth and shiny.

The calculated weight of tablets was 350 mg and observed weight variation was within the

official limits (± 5 %) for all formulations. Thickness of the tablets of all the formulations was in

the rage of 3.50 – 3.80 mm.

Mean drug content of all formulations of ODTs of itopride HCl prepared using super

disintegrants was in the range of 98 – 102 %. Moisture content of the tablets was less than 2.50

%, results are shown in Table-3.42.

Wetting time of the ODTs prepared using super disintegrants was shorter compared

with the tablets prepared by sublimation technique. That may be due to use of larger quantity of

super disintegrants which may results in strong wicking action leading to reduced wetting.


249

Table-3.42: Physical Characteristics of ODTs of Itopride HCl Prepared using

Super Disintegrants


Content (%) Drug

Content (%) Thickness

(mm) Wetting

Time (sec) Weight

Variation (%)

ODI-01 1.69 ± 0.41 101.27 ± 0.53 3.76 ± 0.13 71 ± 3.43 ± 0.29

ODI-01 2.10 ± 0.27 98.59 ± 0.92 3.61 ± 0.09 57 ± 4.13 ± 2.47

ODI-03 1.56 ± 0.24 99.69 ± 0.86 3.64 ± 0.17 44 ± 3.00 ± 3.21

ODI-04 1.72 ± 0.29 99.13 ± 0.78 3.73 ± 0.22 49 ± 4.27 ± 3.54

ODI-05 1.79 ± 0.38 99.48 ± 1.35 3.78 ± 0.14 63 ± 2.71 ± 2.83

ODI-06 1.86 ± 0.53 98.27 ± 0.84 3.58 ± 0.11 41 ± 3.59 ± 2.75

Mechanical Strength of ODTs of Itopride HCl Prepared using Super Disintegrants

Orally disintegrating tablets of taste masked itopride HCl using super disintegrants

showed good mechanical properties. Crushing strength, tensile strength and specific crushing

strength were in the range of 9 – 12 kg, 0.16 – 0.2 kg/mm2 and 0.25 – 0.31 kg/mm2, respectively.

Friability of the formulations was within the limits [114] without any capping and edging.


250

Table-3.43: Mechanical Properties of ODTs of Itopride HCl Prepared using

Super Disintegrants

Formulation †Crushing

Strength (Kg) Friability

(%) *Tensile Strength

(kg/mm2) *Specific Crushing Strength (kg/mm2 )

ODI-01 10.54 ± 1.18 0.30 0.17 0.27

ODI-01 9.88 ± 0.92 0.31 0.17 0.26

ODI-03 10.32 ± 1.09 0.15 0.17 0.27

ODI-04 10.78 ± 1.21 0.45 0.18 0.28

ODI-05 10.17 ± 1.52 0.30 0.16 0.26

ODI-06 11.65 ± 1.01 0.45 0.20 0.31

†: Mean ± S.D.

*: Calculated on the basis of mean crushing strength and mean thickness of the tablet

Disintegration Behavior of ODTs of Itopride HCl Prepared using Super Disintegrants

The in-vitro and in-vivo disintegration time of the controlled batch (without super

disintegrant) was 129 ± 5.30 sec and 163 ± 4.70 sec, respectively, indicating strong inter particle

bonding. It was difficult for disintegration medium to penetrate the tablets with good mechanical

strength. Therefore super disintegrant was required in large quantity to produce a strong wicking

action, extreme expulsion and breaking of tablets. Three levels of super disintegrant

concentration (5%, 7.50% and 10% w/w) were selected. Taste masked granules of itopride HCl

also contained some internal disintegrant (Cross carmellose sodium) that may compensate

decrease in dissolution rate of the drug due to high polymer content.


251

Table-3.44: Disintegration Behavior of ODTs of Itopride HCl Prepared using

Super Disintegrants

Formulation D. Time (sec) O. D. Time (sec)

ODI-01 129.00 ± 3.31 163.29 ± 3.69

ODI-02 53.83 ± 4.08 81.00 ± 3.90

ODI-03 32.51 ± 2.11 48.00 ± 4.61

ODI-04 27.09 ± 2.93 36.39 ± 4.10

ODI-05 57.00 ± 3.37 84.13 ± 3.52

ODI-06 22.08 ± 2.70 31.00 ± 3.21

Results are presented as average ± S.D. (n = 6) D. Time; Disintegration time O. D. Time; Oral disintegration time

In-vitro Drug Release from ODTs of Itopride HCl prepared using Super Disintegrants

In-vitro drug release from ODTs of itopride HCl was studied using purified water (900

ml) as dissolution media kept at 37 ± 2 oC. Dissolution rate from ODTs of itopride HCl was

lower due to larger quantity of polymer used for taste masking. Drug release during initial 5 min

was very low that increased with the passage of time (Fig-3.31) that may be due to the retarding

properties of HPMC, used for the taste masking of itopride HCl however, more than 50% of the

drug was released in 30 min.


252

The drug release was slow in formulation ODI-01, containing higher concentration of

polymers and without disintegrants. Addition of super disintegrant into the formulations

increased the drug release. Maximum drug release during initial 30 min (79.31 ± 1.82%) was

observed with ODI-06, containing sodium starch glycolate (5% w/w) as disintegrant.

The maximum drug release from all the formulations, except ODI-01 (without any

disintegratnt), was above 90%.

Figure 3.31: In-vitro Drug Release from ODTs of Itopride HCl Prepared using super Disintegrants


253

3.8.2.5 Tablet Evaluation of ODTs of Itopride HCl Prepared by Sublimation

Technique

Sublimation of Sublimating Agents from ODTs of Itopride HCl

Rate of sublimation of sublimating agent from ODTs of itopride HCl was relatively

slower compared with ODTs of domperidone. Higher mechanical strength of tablets due to taste

masked granules of itopride HCl may be responsible for slow sublimation of sublimating agents

as they were strongly held between particles. The formulation OSI-01 (without sublimating

agent) was used as control, showed 3.17 ± 0.38% w/w weight loss when exposed at 60 ± 2 oC

for 3 hrs (Fig-3.32).

Figure 3.32: Sublimation Rate from ODTs of Itopride HCl Prepared by Sublimation Technique Containing Different Concentrations of Ammonium Bicarbonate


254

Rate of sublimation of menthol from ODTs of itopride HCl was higher compared with

ammonium bicarbonate. Generally the rate of sublimation of methanol from ODTs of itopride

HCl was slower compared with the ODTs of domperidone. The formulation containing 15%

menthol (OSI-08) showed only 12.75 ± 0.36 w/w loss when stored at 60 °C for 3 hrs.

Figure-3.33: Sublimation Rate from ODTs of Itopride HCl Prepared by Sublimation Technique Containing Different Concentrations of Menthol

Drug content for all the formulations was determined after sublimation of sublimating

agents and was in the range of 99 – 103 % (Table-3.45), indicating stability of the drug at high

temperature (60 ± 2 oC).


255

Table-3.45: Comparison of Tablet Weight of ODTs of Itopride HCl before and after Sublimation of

Sublimating Agents

Formulation Sublimating

Agent

Amount of Sublimating Agent (%)

Mean Tablet Weight (mg) % Loss (w/w)

Drug Content (%)

Before Sublimation

After Sublimation

OSI-02

Menthol

5 351.81 ± 0.13 339.66 ± 0.31 3.45 ± 0.35 101.21 ± 0.59

OSI-03 10 353.22 ± 0.27 324.96 ± 0.18 8.00 ± 0.27 102.91 ± 1.49

OSI-04 15 351.97 ± 0.09 315.91 ± 0.40 10.24 ± 0.41 101.87 ± 2.09

OSI-05 5 352.19 ± 0.11 338.11 ± 0.29 4.00 ± 0.25 100.56 ± 1.72

OSI-06

Ammonium

Bicarbonate

5 351.72 ± 0.10 337.87 ± 0.22 3.94 ± 0.23 101.01 ± 1.38

OSI-07 10 352.38 ± 0.18 320.67 ± 0.33 9.00 ± 0.16 99.17 ± 1.02

OSI-08 15 351.26 ± 0.24 306.47 ± 0.19 12.75 ± 0.36 99.79 ± 2.11

OSI-09 5 351.63 ± 0.18 339.48 ± 0.37 3.46 ± 0.13 99.01 ± 2.89

Results are presented as Mean ± S.D Drug Content: Drug content of the tablet after sublimation of volatile ingredients OSI-01 was not included in the table as it contained no sublimating agent


256

Physical Characteristics of ODTs of Itopride HCl Prepared by Sublimation Technique

The ODTs of itopride HCl prepared by sublimation technique were compressed using

10.50 mm round shallow concave punches with bisection line on one side. Tablets of all the

formulations were smooth and shiny. The calculated weight of tablets was 350 mg and observed

weight variation was within the official limits (± 5 %) for all formulations. Thickness of the

tablets of all the formulations was in the rage of 3.70 – 3.90 mm.

Mean drug content of all formulations were in the range of 97 – 102 % of the claimed

quantity. Wetting time of the tablets prepared using super disintegrants was shorter compared

with the tablets prepared by sublimation technique. That may be due to reduced porosity of the

tablets resulting from incomplete sublimation of sublimating agents.


257

Table-3.46: Physical Characteristics of ODTs of Itopride HCl Prepared using

Super Disintegrants

Formulation Drug

Content (%) Thickness

(mm) Wetting

Time (sec) Weight

Variation (%)

OSI-01 98.14 ± 1.59 3.81 ± 0.16 63 ± 3.22 ± 3.67

OSI-02 99.53 ± 0.78 3.74 ± 0.29 56 ± 4.53 ± 2.91

OSI-03 100.74 ± 1.03 3.71 ± 0.11 42 ± 3.81 ± 3.42

OSI-04 98.37 ± 0.73 3.86 ± 0.10 31 ± 3.08 ± 3.93

OSI-05 99.81 ± 1.29 3.90 ± 0.19 44 ± 3.45 ± 3.72

0SI-06 99.23 ± 0.67 3.82 ± 0.17 52 ± 4.29 ± 3.98

OSI-07 98.59 ± 0.74 3.78 ± 0.26 37 ± 3.35 ± 3.57

OSI-08 99.63 ± 1.39 3.81 ± 0.07 29 ± 4.06 ± 3.12

OSI-09 98.42 ± 1.17 3.89 ± 0.24 38 ± 3.58 ± 3.71


Mechanical Strength of ODTs of Itopride HCl Prepared by Sublimation Technique

The sublimation process reduced the mechanical strength of the ODTs of itopride HCl

(see Table-3.47); however, the impact was not compared with the similar DMP formulation.

The friability of the tablets also increased with decrease in the mechanical properties of the

dosage form but all value were in the acceptable limits [114].

Characterization of mechanical strength of the ODTs of itopride HCl prepared by

sublimation technique, indicated good mechanical strength of the tablets after sublimation of

volatile ingredients (Table-3.47).


258

Table-3.47: Mechanical Strength of ODTs of ItoprideHCl Prepared by


Status Formulation

†Crushing Strength

(Kg)

Friability (%)

*Tensile Strength (kg/mm2)

*Specific Crushing Strength (kg/mm2 )

Bef

ore

Su

bli

mat

ion

OSI-01 8.93 ± 0.92 0.16 0.14 0.22

OSI-02 8.14 ± 0.75 0.15 0.14 0.21

OSI-03 10.68 ± 1.03 0.30 0.18 0.27

OSI-04 9.43 ± 0.69 0.15 0.15 0.23

OSI-05 7.98 ± 0.57 0.45 0.12 0.20

OSI-06 8.37 ± 0.94 0.30 0.13 0.21

OSI-07 10.19 ± 1.08 0.45 0.16 0.26

OSI-08 8.52 ± 0.73 0.15 0.14 0.21

OSI-09 8.66 ±1.14 0.15 0.14 0.21

Aft

er S

ub

lim

atio

n

OSI-01 7.62 ± 0.82 0.75 0.12 0.19

OSI-02 6.47 ± 0.97 0.45 0.12 0.16

OSI-03 7.81 ± 0.58 0.45 0.13 0.20

OSI-04 6.37 ± 0.53 0.60 0.10 0.16

OSI-05 6.19 ± 0.61 0.30 0.10 0.15

OSI-06 6.98 ± 0.59 0.45 0.11 0.02

OSI-07 7.13 ± 0.83 0.60 0.11 0.18

OSI-08 6.40 ± 0.49 0.60 0.10 0.16

OSI-09 7.29 ± 0.85 0.30 0.11 0.18

*Mean ± Standard Deviation (n = 10)


259

Disintegration Behavior of ODTs of Itopride HCl Prepared by Sublimation Technique

The in-vitro and in-vivo disintegration time of the controlled batch (without super

disintegrant) was 129 ± 3.31 sec and 163 ± 3.69 sec, respectively, indicating strong inter particle

bonding. It was difficult for disintegration medium to penetrate the tablets with good mechanical

strength. Therefore super disintegrant was required in large quantity to produce a strong wicking

action, extreme expulsion and breaking of tablets. Three levels of super disintegrant

concentration (5.00 %, 7.50 % and 10.00 % w/w) were selected. Taste masked granules of

itopride HCl also contained some internal disintegrant (Cross carmellose sodium) that may

compensate decrease in dissolution rate of the drug due to high polymer content.

Table-3.48: Disintegration Behavior of ODTs of Itopride HCl Prepared by Sublimation Technique

Formulation Code D. Time O. D.Time

OSI-01 49 ± 1.83 79 ± 1.09

OSI-02 39 ± 2.41 51 ± 3.12

OSI-03 28 ± 3.23 40 ± 2.80

OSI-04 21 ± 3.00 31 ± 4.83

OSI-05 41 ± 2.81 46 ± 3.95

OSI-06 32 ± 3.60 49 ± 4.10

OSI-07 24 ± 2.90 36 ± 3.90

OSI-08 18 ± 2.11 31 ± 3.17

OSI-09 23 ± 2.50 38 ± 4.39

Results are presented as average ± S.D. (n = 6) D. Time; Disintegration time O. D. Time; Oral disintegration time


260

In-vitro Drug Release of ODTs of Itopride HCl Prepared by Sublimation Technique

In-vitro drug release from ODTs of itopride HCl prepared by sublimation technique

was studied using purified water (900 ml) as dissolution media. During initial 15min, 21.44 ±

2.17% drug was released by OSI-01, without any sublimating agent, used as controlled

formulation. The addition of sublimating agent increased the dissolution rate (See Fig-3.34).

Ammonium bicarbonate (15 %w/w) increased drug release to 80.76 ± 2.49% during initial 15

min (OSI-04). The addition of super disintegrants in combination with the sublimating agents

further enhanced the drug release.


Technique, using Ammonium Bicarbonate as Sublimating Agent


261

The use of menthol, as sublimating agent, showed higher drug release compared

formulation containing ammonium bicarbonate. Increasing the concentration of menthol from

5% to 15% increased the release of drug from 71.38 ± 2.39% to 85.33 ± 2.31% during initial 15

min, results are shown in Fig-3.35. Maximum drug release from all the formulations was above

90%.

Addition of super disintegrant to formulation containing 5% menthol increased Q 15min

to 79.29 ± 2.15% (OSI-09).

Figure 3.35: In-vitro Drug Release from ODTs of Itopride HCl Prepared by Sublimation Technique using Menthol as Sublimating Agent


262

3.8.2.6 Evaluation of Effervescent Tablets of Itopride HCl

Physical Characteristics of Effervescent Tablets of Itopride HCl

Physical characteristics of effervescent tablets of itopride HCl are shown in Table-3.49,

low weight variations (1.70 – 3.80 %) and thickness of the tablets in the range of 3.40 – 3.70

mm. Moisture contents of the tablets were below 2.50% was not enough to initiate any premature

effervescence. These results indicate the good flow characteristics of the powder.

Wetting time of effervescent itopride HCl tablets was longer compared with the

effervescent tablets of domperidone. This may be due to the lower porosity, as tensile strength

and specific crushing strength of effervescent tablets of itopride HCl are higher compared with

the domperidone effervescent tablets. Low porosity reduced imbibitions of water and increased

the wetting time, the longest wetting time was observed for EI-01 (143 ± 3sec) that was

formulated without any disintegrant. Wetting time of the tablet decreased to 82 ± 3 (ED-12) by

addition of disintegrants.

Drug contents of all the formulations were within the 98 – 102% which was within the

official limits.


263

Table-3.49: Physical Characteristics of Effervescent Tablets of Itopride HCl


Content (%) Drug Content

(%) Thickness

(mm) Wetting

Time (sec) Weight

Variation (%)

EI-01 1.97 ± 0.14 98.65 ± 1.03 3.57 ± 0.11 143 ± 2.96 ± 2.13

EI-02 2.26 ± 0.08 98.43 ± 0.69 3.52 ± 0.19 119 ± 5.00 ± 1.72

EI-03 1.99 ± 0.31 101.59 ± 0.74 3.61 ± 0.16 104 ± 2.17 ± 2.90

EI-04 2.31 ± 0.19 97.94 ± 1.21 3.54 ± 0.28 131 ± 3.04 ± 2.44

EI-05 1.98 ± 0.43 99.32 ± 0.79 3.48 ± 0.13 99 ± 3.00 ± 2.51

EI-06 2.37 ± 0.38 98.67 ± 1.09 3.56 ± 0.22 87 ± 4.19 ± 3.70

EI-07 1.93 ± 0.11 99.26 ± 1.13 3.52 ± 0.28 128 ± 3.27 ± 2.89

EI-08 2.11 ± 0.37 101.71 ± 0.29 3.61 ± 0.31 113 ± 4.01 ± 3.29

EI-09 2.16 ± 0.44 101.28 ± 0.37 3.55 ± 0.17 96 ± 2.33 ± 3.17

EI-10 2.35 ± 0.46 99.86 ± 1.26 3.43 ± 0.29 109 ± 2.00 ± 2.59

EI-11 2.10 ± 0.22 99.35 ± 0.81 3.48 ± 0.12 93 ± 4.13 ± 3.18

EI-12 2.17 ± 0.19 99.78 ± 0.32 3.63 ± 0.26 82 ± 3.00 ± 3.26

Results are presented as Mean ± Standard Deviation

Mechanical Strength of Effervescent Tablets of Itopride HCl

Effervescent tablets of itopride HCl were mechanically stronger than effervescent

domperidone tablets (Table-3.50). Crushing strength (12 – 14 kg), tensile strength (0.17 – 0.19

kg/mm2) and specific crushing strength (0.26 – 0.31 kg/mm2) of effervescent tablets of itopride


264

HCl were high compared with the domperidone effervescent tablets. The high mechanical

properties may be due to the formation uniform granules of taste masked itopride HCl. Taste

masked itopride HCl granules constituted main portion of all the formulations of effervescent

tablets of itopride HCl (43 % w/w).

Table-3.50: Mechanical Strength of Effervescent Tablets of Itopride HCl

Formulation Crushing Strength† (kg)

Friability (%)

*Tensile Strength(kg/mm2)

*Specific Crushing Strength (kg/mm2)

EI-01 13.64 ± 0.38 0.31 0.19 0.29

EI-02 12.39 ± 0.71 0.45 0.17 0.27

EI-03 12.70 ± 0.29 0.15 0.17 0.27

EI-04 13.25 ± 0.21 0.15 0.18 0.29

EI-05 13.17 ± 0.57 0.15 0.18 0.29

EI-06 12.54 ± 0.39 0.30 0.17 0.27

EI-07 12.31 ± 0.44 0.15 0.17 0.27

EI-08 12.19 ± 0.28 0.45 0.16 0.26

EI-09 12.48 ± 0.35 0.15 0.17 0.27

EI-10 13.20 ± 0.46 0.60 0.19 0.30

EI-11 13.81 ± 0.27 0.15 0.19 0.31

EI-12 12.58 ± 0.21 0.30 0.17 0.27

†: Results are presented as Mean ± Standard Deviation (n = 10) *: Calculated on the basis of mean crushing strength and mean thickness of the tablets


265

Disintegration Behavior of Effervescent Tablets of Itopride HCl

Effervescence time of effervescent tablets of itopride HCl was larger compared with

effervescent domperidone tablets that may be due to strong mechanical strength of the tablets.

Effervescence time of the tablet containing citric acid and sodium bicarbonate as effervescent

pair was 84 ± 2.07 sec. Different disintegrants, added in same concentration to the formulation,

showed different decrease in effervescent time. Effervescence time decreased to 59 ± 2.11 sec

and 51 ± 4.08 sec with addition of 5% cross carmellose sodium and sodium starch glycolate,

respectively.

Effervescence reaction between tartaric acid and sodium bicarbonate was faster

compared with reaction between citric acid and sodium bicarbonate. Effervescence time of EI-

07, containing tartaric acid and sodium bicarbonate, was 75 ± 3.61 sec which was smaller than

effervescence time with citric acid and sodium bicarbonate, alone (EI-01). Smallest

effervescence time (38 ± 4.06 sec) was observed using tartaric acid sodium bicarbonate as

effervescent pair and 5% sodium starch glycolate (EI-11).


266

Figure-3.36: Effervescence Time of Effervescent Tablets of Itopride HCl Containing Different

Combinations of Effervescent Pairs and Disintegrants


267

3.9 Selection of Optimal Formulations

The optimal formulations were selected on the basis of the ratio of disintegration time

to the crushing strength of the tablets [48]. Ratio of disintegration time to crushing strength of

the tablets was calculated for all the formulations on the basis of mean crushing strength and

mean disintegration time and formulations with the highest ratio were selected as optimal

formulations.

Table-3.51: Ratio of Disintegration Time to the Crushing Strength of ODTs of

Domperidone and Itopride HCl Prepared by Sublimation Technique

Formulations D.T/ C. Strength Formulation D.T/ C. Strength

ODS-01 0.14 OSI-01 0.16

ODS-02 0.21 OSI-02 0.17

ODS-03 0.33 OSI-03 0.28

ODS-04 0.32 OSI-04 0.30

ODS-05 0.27 OSI-05 0.15

ODS-06 0.18 OSI-06 0.22

ODS-07 0.35 OSI-07 0.30

ODS-08 0.19 OSI-08 0.36

ODS-09 0.47 OSI-09 0.32

DT: Disintegration Time of Tablets (sec) C. Strength: Crushing Strength (kg)

On the basis of the ratio of disintegration time to crushing strength of the tablet,

formulations ODS-09 was selected as optimal formulations of ODTs of domperidone prepared


268

by sublimation technique while OSI-08 was selected as optimal formulation of ODTs of itooride

HCl prepared by sublimation technique.

Highest ratio of disintegration time to crushing strength, for ODTs of domperidone

prepared using super disintegrants, was observed for ODD-02 (Table-3.52) and selected as

optimal formulation. ODI-06 was selected as optimal formulation of ODTs of itopride HCl

prepared using super disintegrants due to highest ratio (0.48) of disintegration time to crushing

strength.

Table-3.52: Ratio of Disintegration Time to Crushing Strength of ODTs

Prepared using Super Disintegrants

Formulation DT/C Strength Formulation DT/C Strength

ODD-01 0.14 ODI-01 0.08

ODD-02 0.31 ODI-02 0.18

ODD-03 0.14 ODI-03 0.32

ODD-04 0.13 ODI-04 0.40

ODI-05 0.18

ODI-06 0.48

Ratio of effervescence time to the crushing strength of the tablet was applied for

selection of optimal formulation of effervescent tablets. Highest ratio of effervescence time to

crushing strength of effervescent tablets of domperidone was observed for ED-11 (0.25) and

selected as optimal formulation. Similarly, EI-11 was selected as optimal formulation of


269

effervescent tablets of itopride HCl on the basis of highest ratio (0.36) of crushing strength to

effervescence time.

Table-3.53: Ratio of Effervescence Time to Crushing Strength of Effervescent

Tablets of Domperidone and Itopride HCl

Formulation DT/C Strength Formulations DT/C Strength

ED-01 0.12 EI-01 0.16

ED-02 0.16 EI-02 0.17

ED-03 0.09 EI-03 0.22

ED-04 0.11 EI-04 0.17

ED-05 0.20 EI-05 0.26

ED-06 0.16 EI-06 0.26

ED-07 0.18 EI-07 0.16

ED-08 0.20 EI-08 0.19

ED-09 0.12 EI-09 0.22

ED-10 0.17 EI-10 0.22

ED-11 0.25 EI-11 0.36

ED-12 0.18 EI-12 0.20


270

3.10 Parametric Study

The ODTs and effervescent tablets were subjected to different conditions to evaluate

the impact of different parameters. These include moisture treatment of ODTs at high relative

humidity, effect of various levels of compressibility on disintegration [46, 48, 62] time and effect

of surface area and disintegrants on effervescence time of the tablets.

3.10.1 Orally Disintegrating Tablets

3.10.1.1 Moisture Treatment of ODTs

ODTs are sensitive to elevated humidity due to their porous nature [56]. The

domperidone formulations ODD-02, ODS-05 and ODS-09 were stored under the 85% ± 5% R.H

for 24 hrs at 25 ± 2 oC. The moisture contents, mechanical strength and disintegration behavior

of the tablets were evaluated before and after subjecting to moisture treatment (results are shown

in Table-3.54).

The moisture content and crushing strength of ODD-02 was increased by 2.24% and 3

kg, respectively, while the friability remained unchanged however these values were within the

official limit [115]. In-vitro disintegration time was increased from 21 ± 4.80 to 32 ± 3.90 sec

Increase in disintegration time was due to increase in crushing strength of the tablets.

Super disintegrant (Cross carmellose sodium) is hygroscopic in nature and can absorb moisture

to a significant extent which negatively effects its disintegrating efficiency [48]. Hardness of the

tablets increases with moisture uptake and subsequently loosing it. At higher relative humidity


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Tablettose-80 absorbs moisture and forms liquid layer on particle surface due to dissolution and

form liquid bridges between adjacent particles by merging with each other. After losing moisture

solid bridges are formed between these particles increasing hardness of the tablets [141-142].

Wetting time of the tablet was reduced to 31 sec compared with the wetting time before

subjecting to moisture treatment due to increase in moisture content.

The moisture content in tablets containing menthol was increased by 3.11% and

formulation based on ammonium bicarbonate was 2.84% but the no significant changes were

observed in crushing strength (Table-3.54). Disintegration time and oral disintegration time of

the tablets were not reduced significantly.

Drug content of the tablets were determined before and after subjecting to moisture

treatment and remained un-affected (Table-3.54).


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Tabe-3.54: Effect of Moisture Treatment on Optimal formulations of ODTs of Domperidone

Characteristics (Unit) Before Moisture Treatment After Moisture Treatment

ODD-02 ODS-05 ODS-09 ODD-02 ODS-05 ODS-09

Crushing Strength (kg) 6.51 ± 0.59 4.27 ± 0.34 5.60 ± 0.23 9.31 ± 0.69 5.03 ± 0.38 6.17 ± 0.42

Friability (%) 0.18 0.60 0.38 0.15 0.58 0.30

Disintegration Time (sec) 21 ± 4.28 16 ± 3.61 12 ± 1.53 32 ± 3.90 19 ± 3.20 15 ± 2.10

Oral D. Time (sec) 27 ± 4.63 25 ± 3.51 34 ± 3.36 39 ± 5.32 31 ± 2.79 41 ± 2.61

Drug Content (%) 98.03 ± 1.39 99.41 ± 1.82 98.29 ± 2.07 96.17 ± 1.01 96.91 ± 1.62 97.85 ± 1.91

Results are presented as Mean ± S.D. Oral D. Time: Oral Disintegration Time (sec)


273

3.10.1.2 Compression Force Profile of ODTs

Compression force profile of ODTs was studied by compressing optimal formulation of

ODTs of domperidone prepared using super disintegrants under different compression force.

Crushing strength is indicator of compression force of the tablets and tablets compressed under

different compression force show different crushing strength [138, 143]. By increasing

compression force of the tablet, porosity is reduced and particles come in close contact with each

other and result in compact particle that increases the crushing strength [143]. Tablets were

compressed showing a range of crushing strength (Table-3.55) and various parameters like

disintegration time, oral disintegration time, wetting time and friability were determined.

The disintegration time, oral disintegration time and wetting time were increased with

the compression force (Table-3.55). That may be due high porosity of the tablets at low

compression force which allow rapid penetration of the liquid in to the tablets and activation of

super disintegrant.

Friability of the tablets reduced at higher level of compression force. At low

compression force tablets lack sufficient mechanical strength and are prone to edging and

breakage during friability testing. Using high compression force a compact mass with closely

packed particles is formed in the tablets that lead to less friable product.


274

Table-3.55: Effect of Crushing Strength on Tablet Disintegration Time and Friability

Parameter (Unit) Level-1 (3 – 5 kg) Level-2 (6 – 8 kg) Level-3 (8 – 10 kg)

Crushing Strength (kg) 4.65 ± 0.48 6.91 ± 0.62 9.28 ± 0.86

Weight of Tablet (mg) 200.76 ± 2.14† 201.17 ± 1.88† 200.42 ± 1.59†

Thickness of Tablets (mm) 4.28 ± 0.21 3.96 ± 0.10 3.63 ± 0.14

Disintegration Time (sec) 13 ± 3.71 21 ± 4.28 48 ± 3.62

Oral Disintegration Time (sec) 16 ± 3.29 27 ± 4.63 75 ± 4.01

Friability (%) 0.60 0.18 0.15

Wetting time (seconds) 18 ± 3.00 38 ± 3.91 127 ± 60


†: Weight Variation (%)

3.10.2 Effect of Various Parameters on Effervescence Reaction

3.10.2.1 Effect of Surface Area of the Tablet

Effect of tablet dimension (surface area of the tablet) on rate of effervescence reaction

was studied by compressing tablets in two different size punches (10.00 mm oval and 13.00 mm

round).

An important factor which can effect effervescent time is the hardness level of the

tablet. Hardness level of the tablet is highly dependent on tablet dimension and different sized

tablets will show different hardness level at same compression force [144]. This problem was


275

overcome by calculating the specific crushing strength and tensile strength of the tablet which

were independent of tablet dimension and were used to compare hardness level of two different

sized tablets. Two sized tablet were compressed at compression force that produced the tablets

with similar tensile strength and specific crushing strength and their effervescent time was

compared.


276

Table-3.56: Mechanical Properties of Large (13.00 mm) and Small (10.00 mm) Sized Effervescent Tablets

Formulation Larger Size (13mm) Effervescent Tablet Small Size (10mm) Effervescent Tablets

K T D T.S τ K T D τ T.S

ED-01 9.20 3.65 13.00 0.12 0.19 7.14 3.50 10.00 0.20 0.13

ED-02 8.61 3.72 13.00 0.11 0.18 6.67 3.45 10.00 0.19 0.12

ED-03 6.68 3.75 13.00 0.10 0.14 5.35 3.45 10.00 0.16 0.10

ED-04 7.06 3.70 13.00 0.10 0.15 5.78 3.60 10.00 0.16 0.10

ED-05 6.54 3.65 13.00 0.10 0.14 5.52 3.55 10.00 0.16 0.10

ED-06 8.64 3.60 13.00 0.12 0.18 6.99 3.50 10.00 0.20 0.13

ED-07 9.15 3.61 13.00 0.12 0.20 7.47 3.60 10.00 0.21 0.13

ED-08 8.93 3.60 13.00 0.12 0.20 7.58 3.50 10.00 0.22 0.14

ED-09 9.35 3.60 13.00 0.13 0.20 7.50 3.55 10.00 0.21 0.13

ED-10 8.42 3.60 13.00 0.11 0.18 6.65 3.46 10.00 0.19 0.12

ED-11 7.13 3.55 13.00 0.10 0.15 5.99 3.50 10.00 0.17 0.11

ED-12 7.25 3.58 13.00 0.10 0.16 5.90 3.48 10.00 0.17 0.11

K: Crushing Strength of Tablets (kg) T.S: Tensile Strength of Tablet (kg/mm2) T: Thickness of Tablet (mm) τ: Specific Crushing Strength of Tablet (kg/mm2) D: Diameter of the Tablet (mm)


277

Decrease in the tablet size caused a significant increase in effervescence time as shown

in the Fig-3.37. Crushing strength of the small sized tablet and large sized tablets was 5.00 –

7.50 kg and 6.50 – 9.35 kg, respectively. At this compression force both sized tablets had same

tensile strength and specific crushing strength (f2 = 99.50). Decrease in surface area available for

effervescence reaction resulted in a large increase in effervescence time of all the formulations,

irrespective of acid base pair and super disintegrants added to the formulation. Increase in

effervescence time was in the range of 192 – 307 %, as shown in the Table-3.57.

Figure-3.37: Comparison of Effervescence Time of Large Sized (13.00 mm) and Small Sized (10.00 mm) effervescent Tablets


278

Table-3.57: Effect of Tablet Size on Effervescence Time of the Effervescent

Tablets of Domperidone

Formulation Effervescence Time (sec) Percent Increase in

Effervescence Time Large Punch Small Punch

ED-01 78 ± 3.71 163 ± 4.12 208.97

ED-02 54 ± 3.42 126 ± 3.91 233.33

ED-03 71 ± 4.01 137 ± 3.78 192.95

ED-04 63 ± 3.59 142 ± 3.81 225.40

ED-05 32 ± 2.81 98 ± 4.07 306.25

ED-06 53 ± 3.19 112 ± 3.93 211.32

ED-07 52 ± 3.01 119 ± 2.99 228.85

ED-08 44 ± 2.38 97 ± 2.87 220.45

ED-09 75 ± 3.93 153 ± 3.81 204.00

ED-10 49 ± 2.70 112 ± 3.69 228.57

ED-11 29 ± 2.09 87 ± 4.10 300.00

ED-12 41 ± 3.16 102 ± 4.11 248.78



279

3.10.2.2 Effect of Disintegrants on Effervescence Time

The addition of 3% w/w, super disintegrant with acid/base pair, enhanced the

effervescence reaction. Disintegrants acted as wicking agent, increased water penetration into the

inner core of the tablets that exposed the acid/base pair to water and accelerated the

effervescence reaction. At higher concentration cross carmellose sodium (5% w/w) absorbed

water and formed a gel like material. Core of the tablet remained intact and inner portion of the

tablet slowly exposed to water and reduced the rate of effervescent reaction. The present study

showed that cross carmellose sodium is efficient at low concentration (3%, w/w) compared with

high percentage (5%, w/w).

SSG produced a concentration dependent decrease in disintegration time with both

CA/SBC and TA/SBC pairs. At lower concentrations (3% w/w) drop in disintegration time by

SSG was smaller than that caused by same concentration of cross carmellose sodium. But at

higher concentration (5% w/w), SSG was more effective, causing significant decrease in

effervescence time as compared to CCNa.

3.10.2.3 Effect of Tablet Compressibility on Effervescence Reaction

Crushing strength of the tablet is an indicator of tablet compressibility; higher crushing

strength denotes higher compressibility and vice versa [143]. Different level of crushing strength

shows different levels of tablet compressibility.

Effervescent time of the tablets varied with compressibility of the tablets and longer

effervescent time was observed at higher level of rushing strength. Effervescent time of the


280

tablets increased from 38 ± 4.00 sec to 52 ± 3.91 sec with increase of crushing strength from

5.68 ± 0.49 kg to 12.39 ± 0.85 kg. By increasing crushing strength of the tablet, water penetrates

into the tablet core layer by layer, overcoming hard tablet surface as a result effervescence pair

exposes slowly to the water and effervescence reaction occurs at a low rate. At lower crushing

strength water penetration to the tablet core is rapid due to high porosity, effervescence pair is

quickly exposed to water leading to fast effervescence reaction.

Table-3.58: Effect of Tablet Compressibility on Effervescence Time of

Optimal Formulation of Effervescent Tablets of Domperidone

Parameter (Unit) Level – 1 Level –2 Level –3

Crushing Strength (kg) 5.68 ± 0.49 9.21 ± 1.27 12.39 ± 0.85

Weight (mg) 607.52 ± 1.36† 603.86 ± 1.40† 604.37 ± 1.51†

Thickness (mm) 3.93 ± 0.07 3.70 ± 0.06 3.61 ± 0.06

Effervescence Time (sec) 38 ± 4.00 45 ± 3.58 52 ± 3.91

Results are presented as Mean ± S. D. †: Weight Variation (%) Level-1: 4 – 7 kg Level-2: 7 – 12 kg Level-3: 12 – 14 kg


281

3.11 In-vivo Evaluation

3.11.1 Pharmacokinetic Evaluation

Pharmacokinetics of the optimal formulations of ODTs and Effervescent tablets of both

drugs (Domperidone and Itopride HCl) were studied in rabbits (n = 6 /each group) using

Motillium and Dynetic tablets as a reference drugs for domperidone and itopride HCl,

respectively.

The pharmacokinetics parameters were calculated using non-compartmental model by

PK-summit® software.

3.11.1.1 Pharmacokinetic Evaluation of Fast Dispersible Tablets of Domperidone

Pharmacokinetics parameters were determined in healthy rabbits after administration of

ODTs, effervescent tablet and conventional tablets of domperidone (10 mg). Both types of fast

dispersible tablets (ODTs and Effervescent Tablets) resulted in higher Cmax in comparison with

the conventional tablets of domperidone (plain tablet). Highest Cmax was observed with ODTs of

domperidone which was 83.26 ± 5.88 ng/ml and was not significantly different from the Cmax of

the effervescent tablets. During formulation development acid component of the effervescent

pair was slightly higher (2% w/w) than required for neutralization of base component and

remained un-reacted that may reduce pH of the dispersion. This may have contributed to

relatively better absorption in comparison to conventional tablets taken with plain drinking

water.


282

Significant difference was observed in Tmax of the conventional tablet and fast

dispersible tablets. Tmax of ODTs, effervescent tablets and reference tablets was 30.39 ± 4.29, 30

± 5.37 and 60 ± 5.67, respectively. That may be due to the longer disintegration time and

dissolution of the conventional tablets.

The AUC for the effervescent tablets was high that may be due to rapid release of drug

from fast dispersible tablets compared with the conventional dosage form.

Table-3.59: Pharmacokinetics Parameters of Domperidone Determined in

Healthy Rabbits after Administration of Fast Dispersible Tablets and


Parameter Effervescent Tablets ODTs Conventional Tablets

C max (ng/ml) 77.33 ± 6.01 83.26 ± 5.88 70.11 ± 6.43

T max (min) 30.00 ± 5.37 30.39 ± 4.29 60.00 ± 5.67

AUC (0-t) (ng-min/ml) 14587.49 ± 6.33 14204.72 ± 6.41 13926.19 ± 5.73

MRT (min) 235.56 ± 166.92 247.27 ± 81.79 199.27 ± 68.75

Vd (ml/Kg) 60.50 ± 25.46 59.99 ± 27.65 43.72 ± 15.93

Cl (ml/Kg/min) 0.27 ± 0.89 0.27 ± 0.36 0.31 ± 0.16

Results are presented as Mean ± S.D (n = 6)


283

Figure-3.38: Plasma Concentration (ng/ml) of Domperidone at Various Time Intervals in Healthy Male Rabbits (n = 3) After Administration of ODTs, Effervescent Tablets and


3.11.1.2 Pharmacokinetic Evaluation of Fast Dispersible Tablets of Itopride HCl

The plasma drug concentration at various time intervals after oral administration of fast

dispersible tablets and conventional tablets of itopride HCl (50mg) is shown in Fig-3.39. Higher

Cmax was observed with both types of fast dispersible tablets of Itopride HCl in comparison to

conventional tablets. Highest Cmax was observed with effervescent tablets of itopride HCl

(304.33 ± 8.12 ng/ml). The pharmacokinetic parameters calculated using PK-Summit are given

in Table 3.60.


284

Table-3.60: Pharmacokinetics Parameters of Itopride HCl Determined in Healthy Rabbits after Administration of Fast Dispersible Tablets and

Conventional Tablets of Itopride HCl (50 mg) Parameter Effervescent Tablets ODTs Conventional Tablets

C max (ng/ml) 304.33 ± 8.12 288.90 ± 4.38 287.30 ± 6.09

T max (min) 60.00 ± 3.40 60.00 ± 3.92 90.00 ± 2.89

AUC 0-t 60982.00 ± 52.79 68332.11 ± 71.22 54920.10 ± 48.53

T1/2 46.51 43.60 50.66

Absorption Half-life 37.34 33.78 33.29

Vd (ml/Kg) 79072.00 ± 29034.33 75528.97 ± 26601.99 75571.43 ± 199245.63

MRT (min) 371.86 260.92 249.87

Cl (ml/Kg/min) 262.26 233.81 280.58


The Tmax of the ODTs of itopride HCl and effervescent itopride HCl was 60.00 ± 3.40

min and 60.00 ± 3.92 min, respectively, that was significantly shorter compared with the

conventional itopride HCl tablets (90.00 ± 2.89) min.

The disintegration time of the conventional tablets was 13.35 min and fast dispersible

tablets were dispersed in less than a minute that may be the reason for the rapid Tmax of the ODTs

compared with the conventional itopride HCl tablets (film coated).

Highest AUC was observed for orally disintegrating tablets of itopride HCl, as shown

in Fig-3.39. The AUC for study time for the ODTs itopride HCl was higher compared with the

effervescent tablets and reference drug and was lowest for the reference drug. That may be due


285

to the slow release of the drug from film coated tablets following the disintegration and

dissolution of the dosage form. The ODTs disintegrate and dissolve in the oral cavity that may

result in the higher AUC. The Tmax was significantly shorter for the ODTs and effervescent

tablets that may be due to the rapid absorption of the drug compared with the film coated

reference tablets.

The present studies showed that the newly designed ODTs and effervescent tablet are

better rapid release of drug and onset of action.

Figure-3.39: Plasma Concentration (ng/ml) of Itopride HCl at Various Time Intervals in Healthy

Male Rabbits (n = 3) After Administration of ODTs, Effervescent Tablets and Conventional Tablets of Itopride HCl (50 mg)


286

3.11.2 Clinical Evaluation of Orally Disintegrating Tablets of Domperidone

Clinical evaluation of ODTs of domperidone was carried out in patients on

chemotherapy in a private cancer treatment center at Peshawar. The study was approved by the

Ethical Committee of the treatment center and was carried out under the supervision of

experience physician using single blind method. Motillium (Johnsons and Johnsons, pvt. Ltd.

Pakistan) is the mostly prescribed brand of domperidone in Pakistan, was selected as

conventional tablets (as Reference Dosage Form) for comparison with ODTs of domperidone (10

mg). Drug free ODTs were included in the study to find out placebo effect with ODTs.

Optimal formulation of ODTs of domperidone prepared using super disintegrant

(ODD-02) was selected for the study because of its lowest disintegration time and highest

mechanical strength.

3.11.2.1 Patients Acceptance and Onset of Action

In the present study, clinical efficacy of the ODTs and the conventional tablets of

domperidone, in the same dose strength of 10 mg (Motillium, manufactured by Johnsons and

Johnsons, Pakistan) were compared. Comparison was made in terms of emesis control, time

required for onset of action, patient’s acceptance, patient preference and ease of administration.

Sixty patients receiving anti-cancer chemotherapy were selected following strict

inclusion and exclusion criteria (see section 2.9.4.2) and the study was carried out in a two day

post chemotherapy cycle as per study design given in Table-2.14. Each patient was administered


287

ODTs, conventional tablets and drug free ODTs (placebo ODTs) in cyclic way i.e. each patient

received ODTs, conventional tablets and placebo ODTs acting as control for himself.

Analysis of the data showed the better acceptance of ODTs (98.33%) compared with

the conventional tablets by the patients. That may be due to easy administration; pleasant taste

and mouth feel of ODTs. Most of the patients (98.33%) preferred to take ODTs compared with

the conventional tablets as patients complained that water intake enhanced emesis and nausea.

Better control of emesis was observed when tablets were administered without water

i.e. ODTs. One patient out of sixty favored the drug administration with water. Better taste and

mouth feel of ODTs also contributed to high acceptance of ODTs. The data indicates that ODTs

were easy to use and more acceptable compared with conventional tablets.

Quick onset of action was observed with ODTs compared with conventional tablets,

83.33% of the total patients ranked ODTs better in onset of action and 16.67% patients observed

no difference in onset of action between two types of tablets. Onset of action of oral tablets

depends on the series of event i.e. disintegration, dissolution and the absorption form the GIT

[41]. Drug release from the tablets is further enhanced with disintegration as individual granules

are exposed and availability of larger surface area for drug-liquid interaction. Official limit for

disintegration time of un-coated conventional tablets is 15 min i.e. it can take up to 15 min to

disintegrate and then dissolution and absorption. Domperidone is a BCS class II drug with low

water solubility and high permeability [145] and after release from tablet it rapidly absorbed into

the blood stream. That may be reason for the rapid onset of action with ODTs of domperidone in

comparison with conventional tablets.


288

3.11.2.2 Evaluation of Emesis Control

Initial 24 hours (1st day) following chemotherapy is considered as the period of severe

emesis with persistent nausea. As shown in the Fig-3.40, about 74.6% of the emetic episodes

were observed on day-1 of the chemotherapy and on that basis it was considered to be the worst

day of emesis.

Figure 3.40: Distribution of Emetic Episodes on Day-1 and Day-2 of Anti Cancer Chemotherapy

On day first following the chemotherapy showed significantly lower emetic episodes

with new formulation (39.27%) compared with the Motillium® (60.73%) and placebo ODTs.

Data indicate the ODTs are more efficient to control the emesis compared with the Motillium®

tablets. That may be due to the rapid bioavailability of the drug from ODTs compared with the

conventional tablets.


289

The administration of the ODTs of Domperidone and Mottilium® on day-2 of

chemotherapy also showed better control of emetic episodes of (43.75%) compared with the

Motillium® (56.25%).

Complete Emesis Control

Emesis control in patients receiving anti-cancer chemotherapy was divided into;

complete emesis control, major emesis control, partial emesis control and treatment failure. More

than four emetic episodes, and/or treatment discontinuation or taking rescue medication were

considered as treatment failure.

Complete emesis control (less than two emetic episodes) was observed in small number

of patients with both type of tablets. Complete emesis control using ODTs was observed only

11.67% patients, although it is low percentage but was significantly more effectivecompared

with the Mtillium® where it was shown only in 8.33% patients. The results are shown in Table-

3.61.


290

Table-3.61: Control of Emesis with ODTs, Conventional Tablets of

Domperidone (10 mg) and Placebo ODTs in patients Undergoing

Chemotherapy

Observations ODTs C. Tablet Placebo ODTs

Complete Emesis Control 7 (11.67%) 5 (8.33%) 2 (3.33%)

Major Emesis Control 43 (71.67%) 36 (60.00%) 5 (8.33%)

Partial Emesis Control 4 (6.67%) 10 (16.67%) 4 (6.67%)

Medication Failure 6 (10.00%) 9 (15.00%) 49 (81.67%)

Results are presented as number of patients out of 60 (percentage) ODTs: Orally Disintegrating Tablets of Domperidone C. Tablets: Conventional Tablets of Domperidone (Motillium) Placebo ODTs: Drug Free Orally Disintegrating Tablets

Major Emesis Control

Ratio of complete emesis was very low compared with the major emesis control and

about two emetic episodes were observed in majority of the patients. Major emesis control using

both ODTs and conventional tablets of domperidone was good. However, the control was

significantly better with ODTs formulation (71.67%) compared with the conventional dosage

form (60%) and placebo (8.33%), results are shown in Table-3.61.


291

Partial Emesis Control

Partial emesis was better controlled by conventional dosage form compared with the

ODTs of domperidone and placebo ODTs. Partial emesis control was observed in 16.67%

patients with conventional tablets of domperidone while in ODTs and placebo ODTs the

percentage was 6.67%.

Treatment Failure

All the patients were allowed to take rescue medication (Dexamethasone) during the

study if the emesis could not be controlled with product under studies and considered as failure

of the treatment. Rescue medication was mostly used by the patients prescribed with the placebo

(81.67%) compared with the OSTs (10.00%) and conventional domperidone tablets (15.00%),

results are depicted in Fig-3.41.

Oral domperidone is effective in control of emesis of different etiology. It is well

tolerated and has an excellent safety profile [145]. Improved patient preference of the ODTs and

better emesis control with domperidone resulted in enhanced therapeutic out comes. Formulation

of domperidone as orally disintegrating tablets was an ideal tool for control of emesis in patients

receiving anti-cancer chemotherapy. It overcame the problem of dysphagia and was successfully

used in pediatric and geriatric patients resulting in improved patient compliance.


292

Figure-3.41: Emesis Control with ODTs of Domperidone, Conventional Tablets of Domperidone and Placebo ODTs


293

3.11.2.3 Nausea Control

Nausea was recorded in 56.67% of the patients using ODTs of domperidone. The ratio

was lower compared with the Motillium® (73.33%). Most of the patients reported persistent

nausea throughout the day on first day of the chemotherapy.

Nausea control rate differed marginally between ODTs and conventional tablets of

domperidone. On day-1, 64.71% of the total nausea episodes were observed with ODTs while

with conventional tablets the ratio was 63.64%, as shown in Fig-3.42. On day-2 the ratios were

35.29% and 36.36% for ODTs and conventional tablets of domperidone, respectively.

Figure 3.42: Control of Nausea with ODTs and Motillium® (Conventional Tablets of Domperidone) on Day-1 and Day-2 Following Anti Cancer Chemotherapy


294

Severe nausea with extended duration was observed with conventional domperidone

tablets compared with the ODTs where it was less severe and of short duration.

Better taste of ODTs, pleasant mouth feel and lack of water intake may have

contributed to reduced severity of the nausea. As shown in the Fig-3.43, ODTs were more

effective in control of nausea as compared to conventional tablets of domperidone. Severe

nausea was observed by all the patients taking placebo ODTs.

Figure-3.43: Comparison of Control of Nausea with ODTs and Conventional Tablets of Domperidone


295

3.11.2.4 Conclusion of Clinical Trials

Data of the present study reveals that orally disintegrating tablets (ODTs) of

domperidone are effective in control of emesis compared with conventional tablets. Better

emesis control was achieved with ODTs even during worst conditions following chemotherapy.

ODTs of domperidone were acceptable to the majority of the patients compared with

conventional tablets. Moreover, ODTs showed better efficacy and onset of action in controlling

the emesis compared with the conventional tablets. The patient compliance was better due to

administration of drug without water. ODTs of domperidone disintegrated rapidly in the oral

cavity that ensured the rapid bioavailability of the drug (see Section 3.10.1) and may lead to

rapid onset of action.

CHAPTER-4 CONCLUSION

296

4. Conclusion

The present study was carried out to develop stable formulations of fast dispersible

tablets (Orally Disintegrating Tablets and Effervescent Tablets) of prokinetic drugs

(Domperidone and Itopride HCl) by direct compression. Domperidone and Itopride HCl are

compatible with all the excipients used in formulation of fast dispersible tablets. SeDeM-ODT

experts system is a useful tool for prediction of powder behavior and utilization in direct

compression.

Fast dispersible tablets having sufficient mechanical strength, can be successfully

prepared by direct compression using commonly available excipients. Super disintegrant and

sublimating agents can be used to achieve rapid disintegration of tablets. Super disintegrant

improved tablet disintegration due to strong wicking action while sublimating agents acted by

enhancing tablet porosity. Two excipients (cross linked carboxy methyl cellulose and sodium

starch glycolate) were evaluated for disintegration enhancing effect. Both of them exhibited

concentration dependent effect on disintegration time of the tablets. Effect of two volatile

materials (menthol and ammonium bicarbonate) on disintegration time and oral disintegration

time of the tablets was evaluated. Menthol exhibited relatively higher decrease in disintegration

time due complete and rapid sublimation from compressed tablets. Higher temperature for longer

time was required for complete sublimation of ammonium bicarbonate from compressed tablets

to get highly porous tablets.

Effervescent tablets with good mechanical strength can be prepared by direct

compression using hydrophilic excipients. Rapid effervescence was achieved with citric acid

compared to tartaric acid which was further enhanced by addition of super disintegrants in to the


297

formulations. Compressibility of the tablet had negligible effect on effervescence reaction of

tablets.

Masking of bitter taste of highly water soluble drugs can be successfully achieved using

hydrophyllic polymers in different ways. Micro encapsulation of drug particles with different

polymers showed varying degree of taste masking. Eudragit was found to mask the bitter taste at

lowest drug to polymer ratio. Similarly taste can be effectively masked by forming solid

dispersions with hydrophilic polymers and hydrophobic excipients like cetostearyl alcohol.

Granulation of itopride with hydrophilic polymers resulted in better taste masking. Granulation

with hydrophilic polymers is a simple and cost effective method. The resultant taste masked

granules have better flow and compressibility. Granulation technique can be successfully applied

for higher dose of highly water soluble drugs.

Optimal formulations of ODTs were selected on the basis of ratio of disintegration time

to crushing strength of the tablet. On that basis ODD-02 and ODS-09 were selected as optimal

formulation of ODTs of domperidone prepared using super disintegrants and by sublimation

technique, respectively.Similarly ODI-06 and OSI-08 were selected as optimal formulations of

ODTs of itopride HCl prepared using super disintegrant and by sublimation technique. Optimal

formulations of both drugs prepared using super disintegrants were used for pharmacokinetic

evaluation in healthy rabbits.

Optimal formulations of effervescent tablets were selected on the basis of the ratio of

effervescence time to the crushing strength and ED-11 and EI-11 were selected as optimal

formulations of effervescent tablets of domperidone and itopride HCl, respectively. Both the

formulations were used for pharmacokinetic evaluation in healthy rabbits.


298

Better pharmacokinetic profile of the drug was achieved with fast dispersible tablets.

Higher peak plasma concentration was achieved in relatively smaller time indicating better

absorption and better therapeutic outcome with fast dispersible tablets.

Fast dispersible tablets were found more effective in control of post chemotherapy

emesis compared with conventional tablets. ODTs showed better patients compliance due to ease

of administration, better taste and mouth feel. Rapid onset of action was achieved with fast

dispersible tablets as drug is made available for absorption quickly compared with conventional

tablets.

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