Umesh V. Banakar, PhD, is an independent consultant and advisor to the pharmaceutical industry and academia. He's made extensive contributions to drug product development, evaluation (both in vitro and clinical), and regulatory affairs. He is the founding Board Member and Principal Scientific Adviser of the Society for Pharmaceutical Dissolution Science [SPDS] and Founding Chairperson of two International Contract Research Organizations. Dr. Banakar is the Founder of Goa - Center for Excellence in Intellectual Property [G-CEIP] in Panaji, Goa, India. He has served as a worldwide testifying/non-testifying expert in over 65 patent litigations in the disciplines of pharmaceutical formulations/technology, clinical investigations, and dissolution testing. Dr. Banakar has received numerous awards for excellence in teaching, research, and scholarly activity along with two Service to Country Awards from the United Nations and a nomination for the distinguished Fulbright Scholar Award for Teaching.

Foreword xvii

Foreword xix

Preface xxi

Acknowledgments xxvii

1 Pharmaceutical Dissolution Testing: Fundamentals and Essential Applications (An Overview) 1

1.1 Introduction and Objective(s) 1

1.2 Science of Dissolution Over Past 120+ Years 3

1.2.1 Journey from Quality Control (QC) to Development 5

1.3 Fundamentals of Dissolution Testing (An Overview) 6

1.4 Factors Influencing Dissolution Test(ing) 8

1.5 Pharmaceutical Product Life Cycle: Role of Dissolution (An Overview) 12

1.6 Dissolution Test(ing): What It Is and What It Is Not! 13

1.7 Need for This Textbook 14

1.8 Summary and Concluding Remarks 15

References 16

2 Bioavailability (BA) and Bioequivalence (BE): Fundamentals and Applications in Drug Product Development 20

2.1 Introduction and Objective(s) 20

2.2 Definitions 21

2.3 Bioequivalence (BE) Testing: Basics, Advances, and Global Perspectives 23

2.3.1 BA/BE Study Designs 26

2.3.2 Sample Size, n 28

2.3.3 BE (Acceptance) Criteria and Statistical Considerations 31

2.3.4 Bioequivalence (BE) Studies: Role of Modeling and Simulations 33

2.3.5 Surrogates to BE 35

2.3.6 PD Endpoint-Based and Clinical Endpoint-Based BE Assessment 37

2.3.7 Regulatory Requirements 40

2.4 Current Challenges and Solutions (Insight into Chapter 14) 43

2.5 Summary and Concluding Remarks 44

References 44

3 Solubility, Dissolution, Permeability, and Classification Systems 54

3.1 Introduction and Objective(s) 54

3.2 Definitions 56

3.3 Solubility Versus Solubilization: What Is Critical in Development? 58

3.3.1 Theories of Solubilization 58

3.3.2 Solubility: Challenges in Drug Development! 63

3.3.3 Solubility Enhancement: Purpose, Theoretical and Practical Considerations! 68

3.4 Dissolution: Intrinsic Versus Apparent! 70

3.4.1 Theories of Dissolution 70

3.4.1.1 Noyes-Whitney Theory (1897) 70

3.4.1.2 Brunner and Tolloczko Theory (1900) 71

3.4.1.3 Nernst and Brunner Theory (1904) 71

3.4.2 Intrinsic Versus Apparent Dissolution 72

3.5 Permeability Versus Permeation (Process): What Is Critical for Bioefficacy! 74

3.6 Classification Systems: Theoretical Versus Pragmatic Considerations! 75

3.7 Summary and Concluding Remarks 78

References 79

4 Understanding the Mechanics of Dissolution: Mathematical Models and Simulations 86

4.1 Introduction and Objective(s) 86

4.2 Mechanics of Dissolution: Theories, Presumptions, and Reality Check 87

4.3 Dissolution Theories/Models 91

4.4 Dissolution Mechanics (Model-Dependent Methods) 92

4.4.1 Zero Order 92

4.4.2 First-Order Model (Gibaldi-Feldman Model 1967) 93

4.4.3 Makoid-Banakar Model (1993) 93

4.4.4 Hixson and Crowell Model (1931) 95

4.4.5 Higuchi Model (1961, 1963, 1967) 96

4.4.6 Baker-Lonsdale (1974) 97

4.4.7 Korsmeyer-Peppas Model (1983) 98

4.4.8 Hopfenberg Model (1976) 98

4.4.9 Gompertz Distribution Model 99

4.4.10 El-Yazigi Model (1981) 100

4.5 Dissolution Mechanics (Model-Independent Methods) 101

4.5.1 Weibull Distribution Model (1951) 101

4.5.2 Statistical Mean Time Concept/Model (1982) 101

4.5.3 (Other) Statistical Regression-Based Models 102

4.5.4 Sequential Model 102

4.5.5 Density Function Theory (DFT) 103

4.6 Relevance of Mathematical Modeling of Dissolution 104

4.7 Purposeful Modeling and Simulation 105

4.8 Summary and Concluding Remarks 106

References 107

5 Dissolution Testing Methods: Necessity Is the Mother of Invention! 110

5.1 Introduction and Objective(s) 110

5.2 Need for Dissolution Testing Method 112

5.3 Dissolution Testing Methods 113

5.3.1 Science of Dissolution 114

5.3.2 Intrinsic and Apparent Dissolution Methods 116

5.3.3 Compendial Methods Versus Regulatory Perspective 120

5.3.4 Predictive Testing Methods and "Biorelevant Dissolution" Methods 124

5.4 Necessity Is the Mother of Invention! 137

5.4.1 Controlled Release Parenteral Systems Including Drug-Eluting Stents 138

5.4.2 Pharmaceutical Formulations for the Oral Cavity 139

5.4.2.1 Soft Gelatin Capsules (SGC): Oral Delivery and Rectal Inserts 144

5.4.3 Inhalation Products 145

5.4.4 Semisolid Pharmaceutical Systems Including Transdermal Drug Delivery Systems (TDDSs) 148

5.4.5 Nanotechnology-Based Systems: Nanobiomedicine Formulations 149

5.4.6 Others 150

5.5 The Perpetual Struggle 152

5.6 Concluding Remarks 154

References 155

6 Essentials of Dissolution Testing of Pharmaceutical Systems 166

6.1 Introduction and Objective(s) 166

6.2 Objectives of Dissolution Testing of Pharmaceutical Systems 167

6.3 Oral Solid Dosage Forms (SDFs) 168

6.3.1 Immediate Release/Rapid Release SDFs 170

6.3.1.1 Conventional IR SDFs (Focus: Recent Advances in Solubility Enhancement!) 171

6.3.1.2 Chewable: Tablets and Gums 175

6.3.2 Modified Release (MR) SDFs 179

6.3.3 Advanced/Innovative MR-SDFs 193

6.4 Oral Liquid Dosage Forms 197

6.4.1 Rapid Release Systems (RRSs) 198

6.5 Non-oral Dosage Forms 201

6.5.1 Topical Dosage Forms 202

6.5.1.1 Traditional Topical Dosage Forms 203

6.5.1.2 Transdermal Drug Delivery Systems 204

6.5.1.3 Nasal, Ocular, Otic, Vaginal, and Rectal Dosage Forms 205

6.5.2 Parenteral Dosage Forms 213

6.6 Nanotechnology-Based Pharmaceutical Systems 220

6.7 Nutraceuticals and Natural Products 221

6.8 Concluding Remarks: Need for Purposeful Dissolution/Release Testing! 225

References 226

7 Dissolution/Release Test Data (Profile): Requirements, Analyses, and Regulatory Expectations 237

7.1 Introduction and Objective(s) 237

7.2 Academic Curiosity 239

7.3 Early Development 241

7.4 Product Development Stage 242

7.5 Comparative Analyses 244

7.6 Summary and Concluding Remarks 248

References 250

8 Automation in Dissolution Testing: Recent Advances and Continuing Challenges! 254

8.1 Introduction and Objective(s) 254

8.2 Automated Dissolution Testing: Why and What to Automate? 255

8.3 Challenges in Automation of Dissolution Test(ing) 263

8.4 Automation in Dissolution Testing: Looking Forward! 264

8.5 Concluding Remarks 266

References 267

9 In vitro-In vivo Correlations (IVIVCs): What Makes Them Challenging! 269

9.1 Introduction and Objective(S) 269

9.2 Basic Model, Scheme, and Assumptions 270

9.3 Mechanics for Determination of IVIVC 277

9.4 BCS and IVIVC 280

9.5 IVIVC in New Drug Development vis-à-vis Generic Drug Development 283

9.6 IVIVCs in Topical/Transdermal Drug Delivery Systems (TDDSs) 284

9.7 Nonlinear IVIVCs 286

9.8 Validation of IVIVC Prediction Error (PE) 286

9.9 IVIVC in Drug Product Life Cycle: What Is the Ultimate Objective? 287

9.10 Summary and Conclusions 289

References 289

10 Biorelevant Dissolution/Release Test Method Development for Pharmaceutical Dosage Forms 294

10.1 Introduction and Objective(s) 294

10.2 General Considerations in BDM Development 295

10.3 Oral Drug Delivery Systems 296

10.3.1 Challenges in the Simulation of GI Biorelevant Factors: Motility and Hydrodynamics 299

10.3.2 Biorelevant Dissolution Media for Oral Drug Delivery Systems 301

10.4 Inhalation Drug Delivery Systems 303

10.5 Parenteral Drug Delivery Systems 306

10.6 Other Drug Delivery Systems 308

10.7 The Roadmap 309

10.8 Summary and Concluding Remarks 310

References 311

11 Bioavailability Prediction Software: Hype or Reality! 320

11.1 Introduction and Objective(s) 320

11.2 The Need for Simulations and Predictions in Drug Product Development 322

11.3 Simulation and Prediction of In Vivo Performance: The Catch- 22 Situation!325

11.4 Bioavailability (BA)/Bioequivalence (BE) Simulation Software: What They Do and Do Not! 327

11.5 Appreciating and Depreciating Potential Utility of BA Prediction Software 335

11.6 Concluding Remarks 336

References 337

12 Challenges and Unique Applications of IVIVC in Drug Development 340

12.1 Introduction and Objective(s) 340

12.2 USP and US FDA Guidance for Industry (1997): Operational Challenges 342

12.3 Applications of IVIVC(s) 347

12.4 Prospective IVIVC(s) 349

12.4.1 Background 349

12.4.2 Process 349

12.4.3 Application 352

12.4.3.1 Unique Application of IVIVC 353

12.5 Retrospective IVIVC(s): Responding to Agency Queries! 355

12.6 Summary and Concluding Remarks 361

References 362

13 Dissolution Testing in Generic Drug Development: Methods, Requirements, and Regulatory Expectations/Requirements 366

13.1 Introduction and Objective(s) 366

13.2 Generic Drug Development Process: Role of Dissolution Testing 368

13.2.1 Preformulation 369

13.2.2 Prototype Formulation 371

13.2.3 Prospective Development: IVIVC with BE as the Objective! 372

13.2.4 Pilot BE to Pivotal BE 375

13.3 Generic Pharmaceutical Systems: Role of Dissolution 375

13.3.1 Traditional: Para III Formulations - Rush to "First to File" 376

13.3.2 Para IV Formulations 377

13.3.3 Exploring 505(b)(2) Opportunities 380

13.3.4 Differentiated Products and/or Incremental Innovations 384

13.3.5 Supergenerics: Are They? 385

13.3.6...