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Editors
Nikoletta Fotaki, PhD, is Reader in Pharmaceutics, Department of Pharmacy and Pharmacology, University of Bath, UK. Her research interests are focused on the prediction of drug absorption through the oral and non-oral route; prediction of drug absorption in special populations (paediatrics; disease states), biorelevant dissolution methods, formulation development, and physiologically based pharmacokinetic modeling.
Sandra Klein, PhD, is Professor of Pharmaceutical Technology, Department of Pharmacy, University Greifswald, Germany. Her research is focused on developing bio-predictive in vitro models and oral dosage forms for special patient groups, particularly the paediatric and geriatric population; the design of predictive and accelerated test methods for lozenges, vaginal delivery systems and depot parenterals, and in establishing formulation strategies for enhancing the bioavailability of poorly soluble drugs.
List of Contributors xvii
Series Preface xix
Preface xxi
Part I Oral Dosage Forms 1
1 Lipid-Based Oral Formulations 3 Murat Kilic, Aikaterini Avzoti, Jennifer Dressman, and Christos Reppas
1.1 Introduction 3
1.2 Levels of Release Testing for Lipid-Based Dosage Forms 7
1.2.1 Dilution 7
1.2.2 Dispersion and Drug Release 9
1.2.3 Digestion 13
1.2.4 Assessing Direct Uptake from the Vehicle 16
1.3 Case Examples 16
1.3.1 Compendial or Fed State Biorelevant Media to Evaluate Fenofibrate Lipid-based Formulations? 17
1.3.2 Paddle or Biodis Method for Testing a Lipid-based Formulation? 17
1.3.3 Does Nifedipine Precipitate after Administration as a Soft Gelatin Capsule? 19
1.3.4 Screening of Indomethacin Lipid-Based Formulations 19
1.3.5 Effect of Supersaturation on In Vivo Performance 22
1.4 Conclusions and Future Directions 22
References 23
2 Chewable Oral Drug Products 27 Johannes Kramer, Jayachandar Gajendran, Alexis Guillot, and Abdulwahab Barakat
2.1 Introduction 27
2.1.1 Dosage Forms for Which Drug Release Occurs in the Oral Cavity 27
2.1.2 Chewable Dosage Forms Classification 28
2.2 The Oral Cavity 30
2.2.1 Anatomy of the Oral Cavity 30
2.2.2 Physiological Conditions from the Perspective of In Vivo Performance 30
2.2.3 Mechanical Forces 31
2.2.4 Need for Masticatory Action 31
2.2.5 Saliva Composition 32
2.2.6 Oral Absorption vs. Subsequent Absorption in the GI Tract 32
2.3 Drug Substances Used in Chewable Dosage Forms 33
2.4 Technology 33
2.4.1 Chewable Tablets 34
2.4.2 Medicated Gums 34
2.4.2.1 Conventional Method (Extrusion) 34
2.4.2.2 Direct Compression Method 34
2.4.3 Soft Gel Capsules as Chewable Dosage Forms 35
2.5 Pharmacopoeial Requirements 35
2.5.1 Chewable Tablets and Capsules 35
2.5.1.1 US FDA and USP Requirements for In Vitro Performance Testing of Chewable Tablets 35
2.5.1.2 Rationale for Use of the Reciprocating Cylinder Apparatus (USP Apparatus 3) 36
2.5.1.3 Current Status of Drug Release/Dissolution Testing Apparatus for Chewable Drug Products 36
2.5.2 Medicated Gums 36
2.5.2.1 Rationale for In Vitro Performance Testing of Medicated Gums 41
2.5.3 Apparatus for In Vitro Drug Release Testing of Medicated Gums 41
2.5.3.1 Non-Compendial Setup: A USP Apparatus 2-based Method with Modified Gums 41
2.5.4 Compendial Apparatus 44
2.5.4.1 Ph.Eur. Chewing Apparatus A (Chapter 2.9.25) 44
2.5.4.2 Ph.Eur. Chewing Apparatus B (Chapter 2.9.25) 44
2.5.5 In Vitro-In Vivo Correlation (IVIVC) 45
2.6 Summary and Conclusion 49
References 50
Part II Non-oral Dosage Forms 55
3 Injectables 57 Susan D'Souza
3.1 Introduction 57
3.2 Significance of In Vitro Release Testing 60
3.3 Considerations in Method Development 61
3.3.1 Sink Conditions 63
3.3.2 Burst Release 63
3.3.3 Stability of Drug 64
3.3.4 Completeness of In Vitro Release 64
3.3.5 Robustness of Technique 65
3.3.6 Accelerated Release 65
3.3.7 In Vitro - In Vivo Correlations (IVIVCs) 66
3.4 In Vitro Release Methods 66
3.4.1 Sample and Separate 67
3.4.1.1 Volume of Release Media 67
3.4.1.2 Agitation Conditions 67
3.4.1.3 Sampling Techniques 67
3.4.1.4 Sampling Volume 68
3.4.2 Continuous Flow 68
3.4.2.1 CF Setups 69
3.4.2.2 Pumps and Flow Rates 70
3.4.2.3 Sampling Techniques 70
3.5 Dialysis Method 71
3.5.1 Dialysis Setup 72
3.5.2 Volume of Release Media 73
3.5.3 Sampling Technique and Volume 73
3.6 Accelerated In Vitro Release 74
3.7 In Vitro - In Vivo Correlations (IVIVCs) 76
References 78
4 Drug-Eluting Stents 87 Anne Seidlitz
4.1 Drug-Eluting Stents: Combination Products at the Interface of Medical Devices and Medicinal Products 87
4.2 DES Characteristics 88
4.3 In Vivo Stent Position and the Resulting Challenges for In Vitro Release Testing of Coronary Stents 90
4.4 Guidelines, Prerequisites, and General Recommendations on DES Testing 92
4.5 Currently Used Test Methods 93
4.5.1 Media 93
4.5.2 Apparatus 96
4.6 Toward More Biorelevant Testing Conditions and New Challenges for DES Testing 101
4.7 Non-Vascular Stents 107
4.8 Drug-Coated Balloons: An Alternative to DESs for a Wide Range of Indications? 108
4.9 Concluding Remarks 109
References 110
5 In Vitro Dissolution for Inhalation Products 119 Annalisa Mercuri and Nikoletta Fotaki
5.1 Introduction 119
5.2 The Environment of the Human Lungs 120
5.2.1 The Anatomy of Bronchi and Alveoli 121
5.2.2 Airway Surface Liquid (ASL) 121
5.2.2.1 The Composition of Humans Lung Fluids in the Disease State 123
5.2.2.2 Surface Tension 125
5.2.2.3 Mucus Production and Mucociliary Clearance 125
5.3 Regulatory Perspectives and Current Practices for Testing Inhaled Products 125
5.3.1 Compendial Methods for Testing Inhaled Products 126
5.3.1.1 Andersen Cascade Impactor (ACI) 127
5.3.1.2 Glass Twin Impinger 127
5.3.1.3 Marple-Miller Impactor (MMI) 129
5.3.1.4 Multi-Stage Liquid Impinger (MSLI) 129
5.3.1.5 Next Generation Impactor (NGI) 130
5.3.1.6 Analysis of the In Vitro Deposition Data of Inhaled Particles 130
5.3.1.7 In Vitro-In Vivo Deposition Correlations 131
5.3.2 Dissolution Methods for Inhaled Products 132
5.3.2.1 Two-Stage Impinger 133
5.3.2.2 Horizontal Diffusion Cell 133
5.3.2.3 Static Dissolution Cell 133
5.3.2.4 Shaking Incubator 133
5.3.2.5 Paddle Dissolution Apparatus (USP II Apparatus) 135
5.3.2.6 Dialysis Membranes 136
5.3.2.7 Flow-through Cell (USP IV Apparatus) 137
5.3.2.8 Transwell(TM) Method 137
5.3.2.9 Franz Cell Method 137
5.3.3 Dissolution Methods with Integrated Deposition and Cell Permeation Models 138
5.4 Simulated Lung Fluids 139
5.5 Pulmonary Biopharmaceutical Classification System 143
5.6 Conclusions 143
References 144
6 Topicals and Transdermals 155 Kailas Thakker
6.1 Introduction 155
6.2 In Vitro Release Studies for Topical Dosage Forms 156
6.2.1 Drug Release from Semisolid Dosage Forms - Theory and Calculations 157
6.2.2 Compendial Apparatus 158
6.2.2.1 Vertical Diffusion Cell 158
6.2.2.2 Immersion Cell 160
6.2.2.3 USP Apparatus 4 163
6.2.3 Method Development: Points to Consider 163
6.2.3.1 Selection of the Receiving Medium 165
6.2.3.2 Selection of the Membrane 166
6.2.3.3 Apparatus Qualification 166
6.2.3.4 Test Procedure 166
6.2.4 Custom-Designed Cells 167
6.3 In Vitro Release Studies for Transdermal Systems 167
6.3.1 Compendial Apparatus 168
6.3.1.1 The Paddle over Disc Apparatus 168
6.3.1.2 The Reciprocating Holder Apparatus 168
6.4 Conclusions 171
References 171
7 Vaginal and Intrauterine Delivery Systems 177 Sandra Klein and Katharina Tietz
7.1 Vaginal and Uterine Anatomy and Physiology Relevant to Drug Delivery 177
7.1.1 Vaginal Anatomy 177
7.1.2 Vaginal Secretions/Vaginal Fluid 179
7.1.3 Vaginal Microflora and pH 179
7.1.4 Uterine Anatomy 179
7.1.5 Cervix Anatomy 180
7.1.6 Uterine and Cervical Secretions/Cervical and Uterine Fluid 180
7.2 Vaginal and Intrauterine Drug Delivery 182
7.3 Standard Dissolution Test Methods for Vaginal and Intrauterine Delivery Systems 183
7.3.1 Official Dissolution Methods 183
7.4 Predictive Dissolution Test Methods for Vaginal and Intrauterine Delivery Systems 186
7.4.1 Test Equipment 187
7.4.2 Test Media 188
7.4.2.1 Simulated Vaginal Fluids 188
7.4.2.2 Simulated Intrauterine Fluids 192
7.4.2.3 Other Genital Fluids 193
7.4.2.4 Summary 194
7.4.3 Case Studies 194
7.4.3.1 Dissolution Test Methods for Vaginal Tablets 195
7.4.3.2 Dissolution Test Methods for Vaginal Suppositories 198
7.4.3.3 Dissolution Test Methods for Vaginal Gels 199
7.4.3.4 Dissolution Test Methods for Vaginal Films 201
7.4.3.5 Dissolution Test Methods for Vaginal Rings 202
7.4.3.6 Dissolution Test Methods for Intrauterine Delivery Systems 205
7.4.4 Conclusion and Future Directions 205
References 206
8 Rectal Dosage Forms 211 Sandra Klein
8.1 Rectal Anatomy and Physiology Relevant to Drug Delivery 211
8.1.1 Rectal Anatomy and Physiology 211
8.1.2 Rectal Secretions and Rectal Fluid Properties 213
8.2 Rectal Drug Delivery 213
8.3 Standard Dissolution Test Methods for Rectal Dosage Forms 215
8.3.1 Official Dissolution Methods 215
8.4 Predictive Dissolution Test Methods for Rectal Dosage Forms 218
8.4.1 Test Equipment 218
8.4.2 Test Media 219
8.4.3 Case Studies 219
8.4.3.1 Dissolution Test Methods for Suppositories 220
8.4.3.2 Dissolution Test Methods for Rectal Capsules 229
8.4.3.3 Dissolution Test Methods for Rectal Gels 229
8.4.4 Conclusion and Future Directions 230
References 231
9 Ophthalmic Dosage Forms 235 Christian Simroth-Loch, Werner Weitschies, and Clive G. Wilson
9.1 Introduction 235
9.2 The Tear Film 236
9.2.1 Tear Characteristics 236
9.2.2 Tear Secretion: Enzymes and Proteins 237
9.2.3 Tear Secretion: Lipids 237
9.2.4 Osmolality 237
9.2.5 Tear Secretion: pH 237
9.2.6 Tear Secretion: Surface Tension 237
9.2.7 Tear Viscosity 238
9.3 Delivery Volume 238
9.4 Ophthalmic Formulations 239
9.4.1 Drug Salts 239
9.4.2 Tonicity Adjusters 240
9.4.3 Buffers 240
9.4.4 Preservatives 240
9.4.5 Polymers 240
9.4.6 Ethylenediaminepentaacetic acid (EDTA) 241
9.5 In Vitro Testing for Ophthalmic Formulations 241
9.5.1 Media to Simulate Ocular Fluids 241
9.5.2 Topical Ocular Delivery Systems and In Vitro Testing 242
9.5.3 Intraocular Delivery Systems and In Vitro Testing 243
9.5.3.1 Periocular Injections and Implants 243
9.5.3.2 Intravitreal Injections and Implants 245
9.6 Concluding Remarks 246
References 247
10 Regulatory Considerations 253 Vivian A. Gray
10.1 Introduction 253
Part One: Review of Documents Related to In Vitro Release Testing 253
10.2 Compendial Chapters with Legal Implications 253
10.2.1 USP General Chapter <711> Dissolution 254
10.2.2 Ph.Eur. Chapters on Dissolution 254
10.2.2.1 Ph.Eur. 2.9.3 Dissolution Test for Solid Dosage Forms 254
10.2.2.2 Ph.Eur. 2.9.42 Dissolution Test for Lipophilic Solid Dosage Forms 255
10.2.3 JP 6.10 Dissolution Test 255
10.2.4 Harmonization of Dissolution Chapters 256
10.2.5 The International Pharmacopoeia 256
10.2.6 Testing of Transdermal Dosage Forms 257
10.2.6.1 USP General Chapter Drug Release <724> 257
10.2.6.2 Dissolution Testing for Transdermal Patches EP 2.9.4 257
10.2.7 Dissolution Test for Medicated Chewing Gums, EP 2.9.25 258
10.2.8 Disintegration Testing 258
10.2.8.1 USP General Chapter Disintegration <701> 258
10.2.8.2 Ph.Eur. Disintegration Testing 259
10.2.8.3 JP Disintegration Test 6.09 260
10.3 Compendial Chapters, Non-binding 261
10.3.1 The Dissolution Procedure: Development and Validation USP General Chapter <1092> 261
10.3.2 Ph.Eur. Recommendations on Dissolution Testing 5.17.1 261
10.3.3 USP General Chapter In Vitro and In Vivo Evaluation of Dosage Forms <1088> 262
10.3.4 USP General Chapter Semisolid Drug Products-Performance Tests <1724> 262
10.3.5 Capsules-Dissolution Testing and Related Quality Attributes USP General Chapter <1094> 262
10.3.6 Assessment of Drug Performance-Bioavailability, Bioequivalence, and Dissolution USP General Chapter <1090> 263
10.4 Guidances Related to In Vitro Release Testing 263
10.4.1 FDA Guidances 264
10.4.1.1 Dissolution Testing of Immediate-Release Solid Oral Dosage Forms 264
10.4.1.2 Extended-Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro-In Vivo Correlations 265
10.4.1.3 Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BCS 265
10.4.1.4 Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations 266
10.4.1.5 SUPAC Guidances for Immediate-Release [36], Extended-Release [37], and Non-Sterile Semisolids [19] 266
10.4.1.6 Orally Disintegrating Tablets 268
10.4.1.7 The Use of MC of Dissolution Apparatus 1 and 2 - Current Good Manufacturing Practice (CGMP) 268
10.4.1.8 Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing BCS Class 1 and 3 Drugs 268
10.4.1.9 Quality Attribute Considerations for Chewable Tablets 269
10.4.2 EMA Guidances 269
10.4.2.1 Guideline on Quality of Oral Modified-Release Products 269
10.4.2.2 Guideline on Quality of Transdermal Patches 270
10.4.2.3 Guideline on the Investigation of Bioequivalence 270
10.4.3 Japanese Guidelines 271
10.4.3.1 Guideline for the Design and Evaluation of Oral Prolonged-Release Dosage Forms 271
10.4.3.2 Guideline for Bioequivalence Studies of Generic Products 271
10.4.3.3 Guideline for Bioequivalence Studies for Different Strengths of Oral Solid Dosage Forms 272
10.4.3.4 Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid Dosage Forms 272
10.4.3.5 Guideline for Bioequivalence Studies for Different Oral Solid Dosage Forms 272
10.4.4 ICH Guidelines 272
10.4.4.1 Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances 273
10.4.4.2 Evaluation and Recommendation of Pharmacopeial Texts for Use in the ICH Regions on Dissolution Test General Chapter Q4B Annex 7(R2) 273
10.4.4.3 Evaluation and Recommendation of Pharmacopeial Texts for Use in the ICH Regions on Disintegration Test General Chapter Q4B Annex 5(R1) 273
10.4.5 Other Guidelines 273
10.4.5.1 FIP Guidelines for Dissolution Testing of Solid Oral Products 273
10.4.5.2 FIP/AAPS Guidelines for Dissolution/In Vitro Release Testing of Novel/Special Dosage Forms 274
10.4.5.3 Specifications for Pharmaceutical Preparations (Forty-Sixth Report), WHO Technical Report Series 970 274
Part Two: Role of Method Development in Setting Clinically Relevant Specifications 275
10.5 Considerations in Early Method Development 275
10.6 Choice of Media 276
10.7 Discriminatory Power of the Method 277
10.8 In Vitro Release Testing for Special Dosage Forms 278
10.9 Resources 278
Useful Web Sites 278
Bibliography 279
Acknowledgments 279
References 279
Index 285
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