In Vitro Drug Release Testing of Special Dosage Forms

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 xviiSeries Preface xixPreface xxiPart I Oral Dosage Forms 11 Lipid‐Based Oral Formulations 3Murat Kilic, Aikaterini Avzoti, Jennifer Dressman, and Christos Reppas1.1 Introduction 31.2 Levels of Release Testing for Lipid‐Based Dosage Forms 71.2.1 Dilution 71.2.2 Dispersion and Drug Release 91.2.3 Digestion 131.2.4 Assessing Direct Uptake from the Vehicle 161.3 Case Examples 161.3.1 Compendial or Fed State Biorelevant Media to Evaluate Fenofibrate Lipid‐based Formulations? 171.3.2 Paddle or Biodis Method for Testing a Lipid‐based Formulation? 171.3.3 Does Nifedipine Precipitate after Administration as a Soft Gelatin Capsule? 191.3.4 Screening of Indomethacin Lipid‐Based Formulations 191.3.5 Effect of Supersaturation on In Vivo Performance 221.4 Conclusions and Future Directions 22References 232 Chewable Oral Drug Products 27Johannes Kramer, Jayachandar Gajendran, Alexis Guillot, and Abdulwahab Barakat2.1 Introduction 272.1.1 Dosage Forms for Which Drug Release Occurs in the Oral Cavity 272.1.2 Chewable Dosage Forms Classification 282.2 The Oral Cavity 302.2.1 Anatomy of the Oral Cavity 302.2.2 Physiological Conditions from the Perspective of In Vivo Performance 302.2.3 Mechanical Forces 312.2.4 Need for Masticatory Action 312.2.5 Saliva Composition 322.2.6 Oral Absorption vs. Subsequent Absorption in the GI Tract 322.3 Drug Substances Used in Chewable Dosage Forms 332.4 Technology 332.4.1 Chewable Tablets 342.4.2 Medicated Gums 342.4.2.1 Conventional Method (Extrusion) 342.4.2.2 Direct Compression Method 342.4.3 Soft Gel Capsules as Chewable Dosage Forms 352.5 Pharmacopoeial Requirements 352.5.1 Chewable Tablets and Capsules 352.5.1.1 US FDA and USP Requirements for In Vitro Performance Testing of Chewable Tablets 352.5.1.2 Rationale for Use of the Reciprocating Cylinder Apparatus (USP Apparatus 3) 362.5.1.3 Current Status of Drug Release/Dissolution Testing Apparatus for Chewable Drug Products 362.5.2 Medicated Gums 362.5.2.1 Rationale for In Vitro Performance Testing of Medicated Gums 412.5.3 Apparatus for In Vitro Drug Release Testing of Medicated Gums 412.5.3.1 Non‐Compendial Setup: A USP Apparatus 2‐based Method with Modified Gums 412.5.4 Compendial Apparatus 442.5.4.1 Ph.Eur. Chewing Apparatus A (Chapter 2.9.25) 442.5.4.2 Ph.Eur. Chewing Apparatus B (Chapter 2.9.25) 442.5.5 In Vitro–In Vivo Correlation (IVIVC) 452.6 Summary and Conclusion 49References 50Part II Non-oral Dosage Forms 553 Injectables 57Susan D’Souza3.1 Introduction 573.2 Significance of In Vitro Release Testing 603.3 Considerations in Method Development 613.3.1 Sink Conditions 633.3.2 Burst Release 633.3.3 Stability of Drug 643.3.4 Completeness of In Vitro Release 643.3.5 Robustness of Technique 653.3.6 Accelerated Release 653.3.7 In Vitro – In Vivo Correlations (IVIVCs) 663.4 In Vitro Release Methods 663.4.1 Sample and Separate 673.4.1.1 Volume of Release Media 673.4.1.2 Agitation Conditions 673.4.1.3 Sampling Techniques 673.4.1.4 Sampling Volume 683.4.2 Continuous Flow 683.4.2.1 CF Setups 693.4.2.2 Pumps and Flow Rates 703.4.2.3 Sampling Techniques 703.5 Dialysis Method 713.5.1 Dialysis Setup 723.5.2 Volume of Release Media 733.5.3 Sampling Technique and Volume 733.6 Accelerated In Vitro Release 743.7 In Vitro – In Vivo Correlations (IVIVCs) 76References 784 Drug‐Eluting Stents 87Anne Seidlitz4.1 Drug‐Eluting Stents: Combination Products at the Interface of Medical Devices and Medicinal Products 874.2 DES Characteristics 884.3 In Vivo Stent Position and the Resulting Challenges for In Vitro Release Testing of Coronary Stents 904.4 Guidelines, Prerequisites, and General Recommendations on DES Testing 924.5 Currently Used Test Methods 934.5.1 Media 934.5.2 Apparatus 964.6 Toward More Biorelevant Testing Conditions and New Challenges for DES Testing 1014.7 Non‐Vascular Stents 1074.8 Drug‐Coated Balloons: An Alternative to DESs for a Wide Range of Indications? 1084.9 Concluding Remarks 109References 1105 In Vitro Dissolution for Inhalation Products 119Annalisa Mercuri and Nikoletta Fotaki5.1 Introduction 1195.2 The Environment of the Human Lungs 1205.2.1 The Anatomy of Bronchi and Alveoli 1215.2.2 Airway Surface Liquid (ASL) 1215.2.2.1 The Composition of Humans Lung Fluids in the Disease State 1235.2.2.2 Surface Tension 1255.2.2.3 Mucus Production and Mucociliary Clearance 1255.3 Regulatory Perspectives and Current Practices for Testing Inhaled Products 1255.3.1 Compendial Methods for Testing Inhaled Products 1265.3.1.1 Andersen Cascade Impactor (ACI) 1275.3.1.2 Glass Twin Impinger 1275.3.1.3 Marple‐Miller Impactor (MMI) 1295.3.1.4 Multi‐Stage Liquid Impinger (MSLI) 1295.3.1.5 Next Generation Impactor (NGI) 1305.3.1.6 Analysis of the In Vitro Deposition Data of Inhaled Particles 1305.3.1.7 In Vitro–In Vivo Deposition Correlations 1315.3.2 Dissolution Methods for Inhaled Products 1325.3.2.1 Two‐Stage Impinger 1335.3.2.2 Horizontal Diffusion Cell 1335.3.2.3 Static Dissolution Cell 1335.3.2.4 Shaking Incubator 1335.3.2.5 Paddle Dissolution Apparatus (USP II Apparatus) 1355.3.2.6 Dialysis Membranes 1365.3.2.7 Flow‐through Cell (USP IV Apparatus) 1375.3.2.8 Transwell™ Method 1375.3.2.9 Franz Cell Method 1375.3.3 Dissolution Methods with Integrated Deposition and Cell Permeation Models 1385.4 Simulated Lung Fluids 1395.5 Pulmonary Biopharmaceutical Classification System 1435.6 Conclusions 143References 1446 Topicals and Transdermals 155Kailas Thakker6.1 Introduction 1556.2 In Vitro Release Studies for Topical Dosage Forms 1566.2.1 Drug Release from Semisolid Dosage Forms – Theory and Calculations 1576.2.2 Compendial Apparatus 1586.2.2.1 Vertical Diffusion Cell 1586.2.2.2 Immersion Cell 1606.2.2.3 USP Apparatus 4 1636.2.3 Method Development: Points to Consider 1636.2.3.1 Selection of the Receiving Medium 1656.2.3.2 Selection of the Membrane 1666.2.3.3 Apparatus Qualification 1666.2.3.4 Test Procedure 1666.2.4 Custom‐Designed Cells 1676.3 In Vitro Release Studies for Transdermal Systems 1676.3.1 Compendial Apparatus 1686.3.1.1 The Paddle over Disc Apparatus 1686.3.1.2 The Reciprocating Holder Apparatus 1686.4 Conclusions 171References 1717 Vaginal and Intrauterine Delivery Systems 177Sandra Klein and Katharina Tietz7.1 Vaginal and Uterine Anatomy and Physiology Relevant to Drug Delivery 1777.1.1 Vaginal Anatomy 1777.1.2 Vaginal Secretions/Vaginal Fluid 1797.1.3 Vaginal Microflora and pH 1797.1.4 Uterine Anatomy 1797.1.5 Cervix Anatomy 1807.1.6 Uterine and Cervical Secretions/Cervical and Uterine Fluid 1807.2 Vaginal and Intrauterine Drug Delivery 1827.3 Standard Dissolution Test Methods for Vaginal and Intrauterine Delivery Systems 1837.3.1 Official Dissolution Methods 1837.4 Predictive Dissolution Test Methods for Vaginal and Intrauterine Delivery Systems 1867.4.1 Test Equipment 1877.4.2 Test Media 1887.4.2.1 Simulated Vaginal Fluids 1887.4.2.2 Simulated Intrauterine Fluids 1927.4.2.3 Other Genital Fluids 1937.4.2.4 Summary 1947.4.3 Case Studies 1947.4.3.1 Dissolution Test Methods for Vaginal Tablets 1957.4.3.2 Dissolution Test Methods for Vaginal Suppositories 1987.4.3.3 Dissolution Test Methods for Vaginal Gels 1997.4.3.4 Dissolution Test Methods for Vaginal Films 2017.4.3.5 Dissolution Test Methods for Vaginal Rings 2027.4.3.6 Dissolution Test Methods for Intrauterine Delivery Systems 2057.4.4 Conclusion and Future Directions 205References 2068 Rectal Dosage Forms 211Sandra Klein8.1 Rectal Anatomy and Physiology Relevant to Drug Delivery 2118.1.1 Rectal Anatomy and Physiology 2118.1.2 Rectal Secretions and Rectal Fluid Properties 2138.2 Rectal Drug Delivery 2138.3 Standard Dissolution Test Methods for Rectal Dosage Forms 2158.3.1 Official Dissolution Methods 2158.4 Predictive Dissolution Test Methods for Rectal Dosage Forms 2188.4.1 Test Equipment 2188.4.2 Test Media 2198.4.3 Case Studies 2198.4.3.1 Dissolution Test Methods for Suppositories 2208.4.3.2 Dissolution Test Methods for Rectal Capsules 2298.4.3.3 Dissolution Test Methods for Rectal Gels 2298.4.4 Conclusion and Future Directions 230References 2319 Ophthalmic Dosage Forms 235Christian Simroth‐Loch, Werner Weitschies, and Clive G. Wilson9.1 Introduction 2359.2 The Tear Film 2369.2.1 Tear Characteristics 2369.2.2 Tear Secretion: Enzymes and Proteins 2379.2.3 Tear Secretion: Lipids 2379.2.4 Osmolality 2379.2.5 Tear Secretion: pH 2379.2.6 Tear Secretion: Surface Tension 2379.2.7 Tear Viscosity 2389.3 Delivery Volume 2389.4 Ophthalmic Formulations 2399.4.1 Drug Salts 2399.4.2 Tonicity Adjusters 2409.4.3 Buffers 2409.4.4 Preservatives 2409.4.5 Polymers 2409.4.6 Ethylenediaminepentaacetic acid (EDTA) 2419.5 In Vitro Testing for Ophthalmic Formulations 2419.5.1 Media to Simulate Ocular Fluids 2419.5.2 Topical Ocular Delivery Systems and In Vitro Testing 2429.5.3 Intraocular Delivery Systems and In Vitro Testing 2439.5.3.1 Periocular Injections and Implants 2439.5.3.2 Intravitreal Injections and Implants 2459.6 Concluding Remarks 246References 24710 Regulatory Considerations 253Vivian A. Gray10.1 Introduction 253Part One: Review of Documents Related to In Vitro Release Testing 25310.2 Compendial Chapters with Legal Implications 25310.2.1 USP General Chapter <711> Dissolution 25410.2.2 Ph.Eur. Chapters on Dissolution 25410.2.2.1 Ph.Eur. 2.9.3 Dissolution Test for Solid Dosage Forms 25410.2.2.2 Ph.Eur. 2.9.42 Dissolution Test for Lipophilic Solid Dosage Forms 25510.2.3 JP 6.10 Dissolution Test 25510.2.4 Harmonization of Dissolution Chapters 25610.2.5 The International Pharmacopoeia 25610.2.6 Testing of Transdermal Dosage Forms 25710.2.6.1 USP General Chapter Drug Release <724> 25710.2.6.2 Dissolution Testing for Transdermal Patches EP 2.9.4 25710.2.7 Dissolution Test for Medicated Chewing Gums, EP 2.9.25 25810.2.8 Disintegration Testing 25810.2.8.1 USP General Chapter Disintegration <701> 25810.2.8.2 Ph.Eur. Disintegration Testing 25910.2.8.3 JP Disintegration Test 6.09 26010.3 Compendial Chapters, Non‐binding 26110.3.1 The Dissolution Procedure: Development and Validation USP General Chapter <1092> 26110.3.2 Ph.Eur. Recommendations on Dissolution Testing 5.17.1 26110.3.3 USP General Chapter In Vitro and In Vivo Evaluation of Dosage Forms <1088> 26210.3.4 USP General Chapter Semisolid Drug Products‐Performance Tests <1724> 26210.3.5 Capsules‐Dissolution Testing and Related Quality Attributes USP General Chapter <1094> 26210.3.6 Assessment of Drug Performance‐Bioavailability, Bioequivalence, and Dissolution USP General Chapter <1090> 26310.4 Guidances Related to In Vitro Release Testing 26310.4.1 FDA Guidances 26410.4.1.1 Dissolution Testing of Immediate‐Release Solid Oral Dosage Forms 26410.4.1.2 Extended‐Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro–In Vivo Correlations 26510.4.1.3 Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate‐Release Solid Oral Dosage Forms Based on a BCS 26510.4.1.4 Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations 26610.4.1.5 SUPAC Guidances for Immediate‐Release [36], Extended‐Release [37], and Non‐Sterile Semisolids [19] 26610.4.1.6 Orally Disintegrating Tablets 26810.4.1.7 The Use of MC of Dissolution Apparatus 1 and 2 – Current Good Manufacturing Practice (CGMP) 26810.4.1.8 Dissolution Testing and Specification Criteria for Immediate‐Release Solid Oral Dosage Forms Containing BCS Class 1 and 3 Drugs 26810.4.1.9 Quality Attribute Considerations for Chewable Tablets 26910.4.2 EMA Guidances 26910.4.2.1 Guideline on Quality of Oral Modified‐Release Products 26910.4.2.2 Guideline on Quality of Transdermal Patches 27010.4.2.3 Guideline on the Investigation of Bioequivalence 27010.4.3 Japanese Guidelines 27110.4.3.1 Guideline for the Design and Evaluation of Oral Prolonged‐Release Dosage Forms 27110.4.3.2 Guideline for Bioequivalence Studies of Generic Products 27110.4.3.3 Guideline for Bioequivalence Studies for Different Strengths of Oral Solid Dosage Forms 27210.4.3.4 Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid Dosage Forms 27210.4.3.5 Guideline for Bioequivalence Studies for Different Oral Solid Dosage Forms 27210.4.4 ICH Guidelines 27210.4.4.1 Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances 27310.4.4.2 Evaluation and Recommendation of Pharmacopeial Texts for Use in the ICH Regions on Dissolution Test General Chapter Q4B Annex 7(R2) 27310.4.4.3 Evaluation and Recommendation of Pharmacopeial Texts for Use in the ICH Regions on Disintegration Test General Chapter Q4B Annex 5(R1) 27310.4.5 Other Guidelines 27310.4.5.1 FIP Guidelines for Dissolution Testing of Solid Oral Products 27310.4.5.2 FIP/AAPS Guidelines for Dissolution/In Vitro Release Testing of Novel/Special Dosage Forms 27410.4.5.3 Specifications for Pharmaceutical Preparations (Forty‐Sixth Report), WHO Technical Report Series 970 274Part Two: Role of Method Development in Setting Clinically Relevant Specifications 27510.5 Considerations in Early Method Development 27510.6 Choice of Media 27610.7 Discriminatory Power of the Method 27710.8 In Vitro Release Testing for Special Dosage Forms 27810.9 Resources 278Useful Web Sites 278Bibliography 279Acknowledgments 279References 279Index 285