Ibuprofen_ Discovery, Development and Therapeutics.pdf

IbuprofenIbuprofen Discovery, Development and Therapeutics E D I TED BY . RA I NSFO RD Biomedical Research Centre, Sheffield Hallam University, UK v Contents List of Contributors xiii Preface xv 1 History and Development of Ibuprofen 1 . Rainsford Summary 1 Introduction 1 Historical Background 5 Initial Stages 7 in Development 10 Ibufenac – Almost There, but for Liver Toxicity 12 More Setbacks 12 More Learning 12 Ibuprofen 12 First Clinical Trials 12 Gastrointestinal Safety 14 Achievements and Rewards at Last 15 Ultimate Recognition of Safety – OTC Status 17 Worldwide Developments 19 Evolving Applications of Ibuprofen 19 Acknowledgements 20 References 20 2 The Medicinal Chemistry of Ibuprofen 22 h J. Nichol and David W. Allen Introduction 22 The Discovery of Ibuprofen 22 Synthetic Routes to Ibuprofen 27 Biological Activities of Ibuprofen Analogues 31 Metabolites of Ibuprofen 36 Metabolites and Enantiomer Inversion 36 Synthesis of Metabolites 37 Ibuprofen Enantiomers 38 Physicochemical Aspects 42 Acknowledgements 43 References 43 vi Contents 3 The Pharmaceutics of Ibuprofen 51 Fred Higton Summary 51 Physical and Chemical Characteristics of Ibuprofen 51 Products Available Worldwide 55 Solid Dose Presentations 55 Conventional Ibuprofen Tablets 57 In vitro/in vivo Testing 59 Sustained Release Preparations 61 Ibuprofen Fast Acting: Ibuprofen Salts and Derivatives 65 Liquids 68 Taste‐Masking of Ibuprofen 68 Suppositories 70 Topical Presentations 71 Conclusion 73 References 73 4 The ics of Ibuprofen in Humans and Animals 81 Fakhreddin Jamali and Dion R. Brocks Summary 81 Absorption 82 Distribution 83 Protein Binding 83 Tissue Distribution 88 Clearance 92 Metabolism of Ibuprofen 93 Excretion of Ibuprofen 104 Interspecies Differences in ics of ( R )‐ and ( S)‐Ibupr