Pharmaceutical Dissolution Testing, Bioavailability, and Bioequivalence: Science, Applications, and Beyond

Explore the cutting-edge of dissolution testing in an authoritative, one-stop resource In Pharmaceutical Dissolution Testing, Bioavailability, and Bioequivalence: Science, Applications, and Beyond, distinguished pharmaceutical advisor and consultant Dr. Umesh Banakar delivers a comprehensive and up-to-date reference covering the established and emerging roles of dissolution testing in pharmaceutical drug development. After discussing the fundamentals of the subject, the included resources go on to explore common testing practices and methods, along with their associated challenges and issues, in the drug development life cycle. Over 19 chapters and 1100 references allow practicing scientists to fully understand the role of dissolution, apart from mere quality control. Readers will discover a wide range of topics, including automation, generic and biosimilar drug development, patents, and clinical safety. This volume offers a one-stop resource for information otherwise scattered amongst several different regulatory regimes. It also includes: A thorough introduction to the fundamentals and essential applications of pharmaceutical dissolution testing Comprehensive explorations of the foundations and drug development applications of bioavailability and bioequivalence Practical discussions about solubility, dissolution, permeability, and classification systems in drug development In-depth examinations of the mechanics of dissolution, including mathematical models and simulations An elaborate assessment of biophysiologically relevant dissolution testing and IVIVCs, and their unique applications A complete understanding of the methods, requirements, and global regulatory expectations pertaining to dissolution testing of generic drug products Ideal for drug product development and formulation scientists, quality control and assurance professionals, and regulators, Pharmaceutical Dissolution Testing, Bioavailability, and Bioequivalence is also the perfect resource for intellectual property assessors.

Table of Contents:
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 <1088> 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 Complex Generics 386 13.4 Generics: Finished Products – Role of Dissolution Testing 388 13.4.1 Tentative Approval to Final Approval: Setting QC Specifications! 388 13.4.2 Biowaivers: Global Considerations and Perspectives! 389 13.4.3 Regulatory Queries and Responses 392 13.5 Summary and Concluding Remarks 396 References 396 14 Successful Bioequivalence Investigations: Current Challenges and Possible Solutions! 400 14.1 Introduction and Objective(s) 400 14.2 Understanding Challenges and Approaches to Overcome Them! 402 14.2.1 Oral Dosage Forms 404 14.2.1.1 Highly Variable Drugs (HVDs) 405 14.2.1.2 Oral Dosage Forms: Locally Acting 406 14.2.2 Narrow Therapeutic Index (NTI) Drugs 409 14.2.3 Topical Dosage Forms 411 14.2.3.1 Ophthalmic Dosage Forms 413 14.2.4 Oral Inhalation Products 417 14.2.5 Complex Generics 420 14.2.6 Nutraceuticals and Natural Products 422 14.3 Concluding Remarks 423 References 424 15 Beyond Guidance(s): Convincing Regulatory Authorities Through Creative Dissolution Data Interpretation 434 15.1 Introduction and Objective(s) 434 15.2 Regulatory Guidance(s): Reading Versus Understanding! 435 15.3 Regulatory Submission: Premise and Expectation(s) 438 15.4 Handling Regulatory Query/Deficiency: Efficient and Satisfying Response 440 15.5 Winning an Argument: Three Cs to Succeed! 443 15.6 Sample Case Study(ies) 444 15.7 Summary and Concluding Remarks 447 References 447 16 Biosimilars: The Emerging Frontier for Generics – Role of Dissolution Testing! 449 16.1 Introduction and Objective(s) 449 16.2 Generics, (Bio)betters, and Biosimilars: What Are They? 451 16.3 Regulatory Approval Process (Brief): Focus on Efficacy! 453 16.4 Role of Solubility and Dissolution 456 16.5 Concluding Remarks 458 References 459 17 Patentability of Drug Product Based on Dissolution Data: Intellectual Property Considerations! 461 17.1 Introduction and Objective(s) 461 17.2 Patentability and the Patent Process (Brief): Scientist’s Perspective 462 17.2.1 Is Solubility and Dissolution Patentable: Scientist’s Perspective 465 17.3 Pharmaceutical Product: Patentability and Role of Dissolution Testing 466 17.4 Patentability: Double-Edged Sword! 468 17.5 Concluding Remarks 471 References 471 18 Setting Up Clinical Therapeutics Safety-Based QC Specifications for Dissolution Testing of a Finished Product 473 18.1 Introduction and Objective(s) 473 18.2 Critical Quality Attributes (CQA): Role of In vitro Dissolution as a QC Test! 475 18.3 Clinical Drug Product Performance: Adequate or Predictable! 476 18.4 Clinically Relevant Specifications (CRS): Basics and Challenges! 478 18.4.1 Setting Up CRDS or CRS 481 18.5 Idealism and Pragmatism Versus Realism! 484 18.6 Concluding Remarks 489 References 490 19 Unlocking the Mystery(ies) While Predicting Bioavailability from Dissolution 493 19.1 Introduction and Objective(s) 493 19.2 The IVIVC Model and Objective(s) of IVIVC 494 19.3 Challenges Encountered in Predicting Bioavailability from Dissolution 495 19.4 What Are We Doing Now? 499 19.4.1 Mathematical Modeling: Limitations and Feel Good Phenomena! 499 19.4.2 BCS and Its Relation to Drug Formulation’s Dissolution Performance 500 19.4.3 The Application (or the Lack) of f 1 and f 2 Parameters 501 19.4.4 Dissolution Data Banks, Agency Recommendations, and Compendial Monographs 502 19.4.5 Dissolution Testing Apparatuses (Choice Versus Selection!) 503 19.4.6 Advent of Biophysiologically Relevant Dissolution Media(um) 504 19.4.7 What Are We Missing in This Picture? 505 19.5 What We Should Be Doing! The Way Forward: The Missing Link! 506 19.6 Advent of IVRT, IVPT, PBPK, and PBAM 508 19.6.1 Role of IVRT, IVPT, and PBAM in Predicting In Vivo Absorption of Drug from Oral Solid Dosage Forms 510 19.7 Summary and Concluding Remarks 511 References 512 Index 515