Pharmaceutical Dissolution Testing, Bioavailability, and Bioequivalence

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 xviiForeword xixPreface xxiAcknowledgments xxvii1 Pharmaceutical Dissolution Testing: Fundamentals and Essential Applications (An Overview) 11.1 Introduction and Objective(s) 11.2 Science of Dissolution Over Past 120+ Years 31.2.1 Journey from Quality Control (QC) to Development 51.3 Fundamentals of Dissolution Testing (An Overview) 61.4 Factors Influencing Dissolution Test(ing) 81.5 Pharmaceutical Product Life Cycle: Role of Dissolution (An Overview) 121.6 Dissolution Test(ing): What It Is and What It Is Not! 131.7 Need for This Textbook 141.8 Summary and Concluding Remarks 15References 162 Bioavailability (BA) and Bioequivalence (BE): Fundamentals and Applications in Drug Product Development 202.1 Introduction and Objective(s) 202.2 Definitions 212.3 Bioequivalence (BE) Testing: Basics, Advances, and Global Perspectives 232.3.1 BA/BE Study Designs 262.3.2 Sample Size, n 282.3.3 BE (Acceptance) Criteria and Statistical Considerations 312.3.4 Bioequivalence (BE) Studies: Role of Modeling and Simulations 332.3.5 Surrogates to BE 352.3.6 PD Endpoint-Based and Clinical Endpoint-Based BE Assessment 372.3.7 Regulatory Requirements 402.4 Current Challenges and Solutions (Insight into Chapter 14) 432.5 Summary and Concluding Remarks 44References 443 Solubility, Dissolution, Permeability, and Classification Systems 543.1 Introduction and Objective(s) 543.2 Definitions 563.3 Solubility Versus Solubilization: What Is Critical in Development? 583.3.1 Theories of Solubilization 583.3.2 Solubility: Challenges in Drug Development! 633.3.3 Solubility Enhancement: Purpose, Theoretical and Practical Considerations! 683.4 Dissolution: Intrinsic Versus Apparent! 703.4.1 Theories of Dissolution 703.4.1.1 Noyes–Whitney Theory (1897) 703.4.1.2 Brunner and Tolloczko Theory (1900) 713.4.1.3 Nernst and Brunner Theory (1904) 713.4.2 Intrinsic Versus Apparent Dissolution 723.5 Permeability Versus Permeation (Process): What Is Critical for Bioefficacy! 743.6 Classification Systems: Theoretical Versus Pragmatic Considerations! 753.7 Summary and Concluding Remarks 78References 794 Understanding the Mechanics of Dissolution: Mathematical Models and Simulations 864.1 Introduction and Objective(s) 864.2 Mechanics of Dissolution: Theories, Presumptions, and Reality Check 874.3 Dissolution Theories/Models 914.4 Dissolution Mechanics (Model-Dependent Methods) 924.4.1 Zero Order 924.4.2 First-Order Model (Gibaldi–Feldman Model 1967) 934.4.3 Makoid–Banakar Model (1993) 934.4.4 Hixson and Crowell Model (1931) 954.4.5 Higuchi Model (1961, 1963, 1967) 964.4.6 Baker–Lonsdale (1974) 974.4.7 Korsmeyer–Peppas Model (1983) 984.4.8 Hopfenberg Model (1976) 984.4.9 Gompertz Distribution Model 994.4.10 El-Yazigi Model (1981) 1004.5 Dissolution Mechanics (Model-Independent Methods) 1014.5.1 Weibull Distribution Model (1951) 1014.5.2 Statistical Mean Time Concept/Model (1982) 1014.5.3 (Other) Statistical Regression-Based Models 1024.5.4 Sequential Model 1024.5.5 Density Function Theory (DFT) 1034.6 Relevance of Mathematical Modeling of Dissolution 1044.7 Purposeful Modeling and Simulation 1054.8 Summary and Concluding Remarks 106References 1075 Dissolution Testing Methods: Necessity Is the Mother of Invention! 1105.1 Introduction and Objective(s) 1105.2 Need for Dissolution Testing Method 1125.3 Dissolution Testing Methods 1135.3.1 Science of Dissolution 1145.3.2 Intrinsic and Apparent Dissolution Methods 1165.3.3 Compendial Methods Versus Regulatory Perspective 1205.3.4 Predictive Testing Methods and “Biorelevant Dissolution” Methods 1245.4 Necessity Is the Mother of Invention! 1375.4.1 Controlled Release Parenteral Systems Including Drug-Eluting Stents 1385.4.2 Pharmaceutical Formulations for the Oral Cavity 1395.4.2.1 Soft Gelatin Capsules (SGC): Oral Delivery and Rectal Inserts 1445.4.3 Inhalation Products 1455.4.4 Semisolid Pharmaceutical Systems Including Transdermal Drug Delivery Systems (TDDSs) 1485.4.5 Nanotechnology-Based Systems: Nanobiomedicine Formulations 1495.4.6 Others 1505.5 The Perpetual Struggle 1525.6 Concluding Remarks 154References 1556 Essentials of Dissolution Testing of Pharmaceutical Systems 1666.1 Introduction and Objective(s) 1666.2 Objectives of Dissolution Testing of Pharmaceutical Systems 1676.3 Oral Solid Dosage Forms (SDFs) 1686.3.1 Immediate Release/Rapid Release SDFs 1706.3.1.1 Conventional IR SDFs (Focus: Recent Advances in Solubility Enhancement!) 1716.3.1.2 Chewable: Tablets and Gums 1756.3.2 Modified Release (MR) SDFs 1796.3.3 Advanced/Innovative MR-SDFs 1936.4 Oral Liquid Dosage Forms 1976.4.1 Rapid Release Systems (RRSs) 1986.5 Non-oral Dosage Forms 2016.5.1 Topical Dosage Forms 2026.5.1.1 Traditional Topical Dosage Forms 2036.5.1.2 Transdermal Drug Delivery Systems 2046.5.1.3 Nasal, Ocular, Otic, Vaginal, and Rectal Dosage Forms 2056.5.2 Parenteral Dosage Forms 2136.6 Nanotechnology-Based Pharmaceutical Systems 2206.7 Nutraceuticals and Natural Products 2216.8 Concluding Remarks: Need for Purposeful Dissolution/Release Testing! 225References 2267 Dissolution/Release Test Data (Profile): Requirements, Analyses, and Regulatory Expectations 2377.1 Introduction and Objective(s) 2377.2 Academic Curiosity 2397.3 Early Development 2417.4 Product Development Stage 2427.5 Comparative Analyses 2447.6 Summary and Concluding Remarks 248References 2508 Automation in Dissolution Testing: Recent Advances and Continuing Challenges! 2548.1 Introduction and Objective(s) 2548.2 Automated Dissolution Testing: Why and What to Automate? 2558.3 Challenges in Automation of Dissolution Test(ing) 2638.4 Automation in Dissolution Testing: Looking Forward! 2648.5 Concluding Remarks 266References 2679 In vitro–In vivo Correlations (IVIVCs): What Makes Them Challenging! 2699.1 Introduction and Objective(S) 2699.2 Basic Model, Scheme, and Assumptions 2709.3 Mechanics for Determination of IVIVC 2779.4 BCS and IVIVC 2809.5 IVIVC in New Drug Development vis-à-vis Generic Drug Development 2839.6 IVIVCs in Topical/Transdermal Drug Delivery Systems (TDDSs) 2849.7 Nonlinear IVIVCs 2869.8 Validation of IVIVC Prediction Error (PE) 2869.9 IVIVC in Drug Product Life Cycle: What Is the Ultimate Objective? 2879.10 Summary and Conclusions 289References 28910 Biorelevant Dissolution/Release Test Method Development for Pharmaceutical Dosage Forms 29410.1 Introduction and Objective(s) 29410.2 General Considerations in BDM Development 29510.3 Oral Drug Delivery Systems 29610.3.1 Challenges in the Simulation of GI Biorelevant Factors: Motility and Hydrodynamics 29910.3.2 Biorelevant Dissolution Media for Oral Drug Delivery Systems 30110.4 Inhalation Drug Delivery Systems 30310.5 Parenteral Drug Delivery Systems 30610.6 Other Drug Delivery Systems 30810.7 The Roadmap 30910.8 Summary and Concluding Remarks 310References 31111 Bioavailability Prediction Software: Hype or Reality! 32011.1 Introduction and Objective(s) 32011.2 The Need for Simulations and Predictions in Drug Product Development 32211.3 Simulation and Prediction of In Vivo Performance: The Catch- 22 Situation!32511.4 Bioavailability (BA)/Bioequivalence (BE) Simulation Software: What They Do and Do Not! 32711.5 Appreciating and Depreciating Potential Utility of BA Prediction Software 33511.6 Concluding Remarks 336References 33712 Challenges and Unique Applications of IVIVC in Drug Development 34012.1 Introduction and Objective(s) 34012.2 USP <1088> and US FDA Guidance for Industry (1997): Operational Challenges 34212.3 Applications of IVIVC(s) 34712.4 Prospective IVIVC(s) 34912.4.1 Background 34912.4.2 Process 34912.4.3 Application 35212.4.3.1 Unique Application of IVIVC 35312.5 Retrospective IVIVC(s): Responding to Agency Queries! 35512.6 Summary and Concluding Remarks 361References 36213 Dissolution Testing in Generic Drug Development: Methods, Requirements, and Regulatory Expectations/Requirements 36613.1 Introduction and Objective(s) 36613.2 Generic Drug Development Process: Role of Dissolution Testing 36813.2.1 Preformulation 36913.2.2 Prototype Formulation 37113.2.3 Prospective Development: IVIVC with BE as the Objective! 37213.2.4 Pilot BE to Pivotal BE 37513.3 Generic Pharmaceutical Systems: Role of Dissolution 37513.3.1 Traditional: Para III Formulations – Rush to “First to File” 37613.3.2 Para IV Formulations 37713.3.3 Exploring 505(b)(2) Opportunities 38013.3.4 Differentiated Products and/or Incremental Innovations 38413.3.5 Supergenerics: Are They? 38513.3.6 Complex Generics 38613.4 Generics: Finished Products – Role of Dissolution Testing 38813.4.1 Tentative Approval to Final Approval: Setting QC Specifications! 38813.4.2 Biowaivers: Global Considerations and Perspectives! 38913.4.3 Regulatory Queries and Responses 39213.5 Summary and Concluding Remarks 396References 39614 Successful Bioequivalence Investigations: Current Challenges and Possible Solutions! 40014.1 Introduction and Objective(s) 40014.2 Understanding Challenges and Approaches to Overcome Them! 40214.2.1 Oral Dosage Forms 40414.2.1.1 Highly Variable Drugs (HVDs) 40514.2.1.2 Oral Dosage Forms: Locally Acting 40614.2.2 Narrow Therapeutic Index (NTI) Drugs 40914.2.3 Topical Dosage Forms 41114.2.3.1 Ophthalmic Dosage Forms 41314.2.4 Oral Inhalation Products 41714.2.5 Complex Generics 42014.2.6 Nutraceuticals and Natural Products 42214.3 Concluding Remarks 423References 42415 Beyond Guidance(s): Convincing Regulatory Authorities Through Creative Dissolution Data Interpretation 43415.1 Introduction and Objective(s) 43415.2 Regulatory Guidance(s): Reading Versus Understanding! 43515.3 Regulatory Submission: Premise and Expectation(s) 43815.4 Handling Regulatory Query/Deficiency: Efficient and Satisfying Response 44015.5 Winning an Argument: Three Cs to Succeed! 44315.6 Sample Case Study(ies) 44415.7 Summary and Concluding Remarks 447References 44716 Biosimilars: The Emerging Frontier for Generics – Role of Dissolution Testing! 44916.1 Introduction and Objective(s) 44916.2 Generics, (Bio)betters, and Biosimilars: What Are They? 45116.3 Regulatory Approval Process (Brief): Focus on Efficacy! 45316.4 Role of Solubility and Dissolution 45616.5 Concluding Remarks 458References 45917 Patentability of Drug Product Based on Dissolution Data: Intellectual Property Considerations! 46117.1 Introduction and Objective(s) 46117.2 Patentability and the Patent Process (Brief): Scientist’s Perspective 46217.2.1 Is Solubility and Dissolution Patentable: Scientist’s Perspective 46517.3 Pharmaceutical Product: Patentability and Role of Dissolution Testing 46617.4 Patentability: Double-Edged Sword! 46817.5 Concluding Remarks 471References 47118 Setting Up Clinical Therapeutics Safety-Based QC Specifications for Dissolution Testing of a Finished Product 47318.1 Introduction and Objective(s) 47318.2 Critical Quality Attributes (CQA): Role of In vitro Dissolution as a QC Test! 47518.3 Clinical Drug Product Performance: Adequate or Predictable! 47618.4 Clinically Relevant Specifications (CRS): Basics and Challenges! 47818.4.1 Setting Up CRDS or CRS 48118.5 Idealism and Pragmatism Versus Realism! 48418.6 Concluding Remarks 489References 49019 Unlocking the Mystery(ies) While Predicting Bioavailability from Dissolution 49319.1 Introduction and Objective(s) 49319.2 The IVIVC Model and Objective(s) of IVIVC 49419.3 Challenges Encountered in Predicting Bioavailability from Dissolution 49519.4 What Are We Doing Now? 49919.4.1 Mathematical Modeling: Limitations and Feel Good Phenomena! 49919.4.2 BCS and Its Relation to Drug Formulation’s Dissolution Performance 50019.4.3 The Application (or the Lack) of f 1 and f 2 Parameters 50119.4.4 Dissolution Data Banks, Agency Recommendations, and Compendial Monographs 50219.4.5 Dissolution Testing Apparatuses (Choice Versus Selection!) 50319.4.6 Advent of Biophysiologically Relevant Dissolution Media(um) 50419.4.7 What Are We Missing in This Picture? 50519.5 What We Should Be Doing! The Way Forward: The Missing Link! 50619.6 Advent of IVRT, IVPT, PBPK, and PBAM 50819.6.1 Role of IVRT, IVPT, and PBAM in Predicting In Vivo Absorption of Drug from Oral Solid Dosage Forms 51019.7 Summary and Concluding Remarks 511References 512Index 515