Buch, Englisch, 744 Seiten, Format (B × H): 161 mm x 240 mm, Gewicht: 1267 g
Buch, Englisch, 744 Seiten, Format (B × H): 161 mm x 240 mm, Gewicht: 1267 g
ISBN: 978-1-118-05745-2
Verlag: Wiley
Explains how to perform and analyze the results of the latest physicochemical methods
With this book as their guide, readers have access to all the current information needed to thoroughly investigate and accurately determine a compound's pharmaceutical properties and their effects on drug absorption. The book emphasizes oral absorption, explaining all the physicochemical methods used today to analyze drug candidates. Moreover, the author provides expert guidance to help readers analyze the results of their studies in order to select the most promising drug candidates.
This Second Edition has been thoroughly updated and revised, incorporating all the latest research findings, methods, and resources, including:
- Descriptions and applications of new PAMPA models, drawing on more than thirty papers published by the author's research group
- Two new chapters examining permeability and Caco-2/MDCK and permeability and the blood-brain barrier
- Expanded information and methods to support pKa determination
- New examples explaining the treatment of practically insoluble test compounds
- Additional case studies demonstrating the use of the latest physicochemical techniques
- New, revised, and expanded database tables throughout the book
Well over 200 drawings help readers better understand difficult concepts and provide a visual guide to complex procedures. In addition, over 800 references serve as a gateway to the primary literature in the field, facilitating further research into all the topics covered in the book.
This Second Edition is recommended as a reference for researchers in pharmaceutical R&D as well as in agrochemical, environmental, and other related areas of research. It is also recommended as a supplemental text for graduate courses in pharmaceutics.
Autoren/Hrsg.
Fachgebiete
Weitere Infos & Material
Preface xxiii
Preface to the First Edition xxvii
List of Abbreviations xxxi
Nomenclature xxxv
Commercial Trademarks xli
1 Introduction 1
1.1 Bulldozer Searching for a Needle in the Haystack? 1
1.2 As the Paradigm Turns 4
1.3 Screen for the Target or ADME First? 5
1.4 ADME and Multimechanism Screens 6
1.5 ADME and the Medicinal Chemist 7
1.6 The “Absorption” in ADME 8
1.7 It Is Not Just a Number It Is a Multimechanism 9
References 9
2 Transport Model 12
2.1 Permeability–Solubility–Charge State and pH-Partition Hypothesis 12
2.2 Properties of the Gastrointestinal Tract (GIT) 17
2.3 pH Microclimate 22
2.4 Intracellular pH Environment 23
2.5 Tight Junction Complex 23
2.6 Structure of Octanol 23
2.7 Biopharmaceutics Classification System 25
References 26
3 pKa Determination 31
3.1 Charge State and the pKa 32
3.2 Methods of Choice for the Determination of the pKa 34
3.3 Titration with a Glass-Membrane pH Electrode 34
3.4 Equilibrium Equations and the Ionization Constant 38
3.5 “Pure Solvent” Activity Scale 41
3.6 Ionic Strength and Debye–Hückel/Davies Equation 41
3.7 “Constant Ionic Medium” Activity Scale 43
3.8 Temperature Dependence of pKa Values 47
3.9 Electrode Calibration and Standardization 55
3.10 Bjerrum Plot: Most Useful Graphical Tool in pKa Analysis 66
3.11 Cosolvent Methods for pKa Determination of Practically Insoluble Substances 78
3.12 Other Methods for pKa Measurement 96
3.13 pKa Microconstants 102
3.14 pKa Compilations 107
3.15 pKa Prediction Programs 107
3.16 Database of pKa (25°C and 37°C) 107
Appendix 3.1 Quick Start: Determination of the pKa of Codeine 127
Appendix 3.2 Tutorial for Measurements with Glass-Membrane pH Electrode 130
Appendix 3.3 pH Convention Adopted by IUPAC and Supported by NIST 137
Appendix 3.4 Liquid-Junction Potentials (LJP) 140
Appendix 3.5 pKa Refi nement by Weighted Nonlinear Regression 146
Appendix 3.6 Molality to Molarity Conversion 157
References 158
4 Octanol–Water Partitioning 174
4.1 Overton–Hansch Model 175
4.2 Tetrad of Equilibria 175
4.3 Conditional Constants 177
4.4 log P Data Sources 178
4.5 log D Lipophilicity Profile 178
4.6 Ion-Pair Partitioning 183
4.7 Micro-log P 187
4.8 Methods for log P Determination 188
4.9 Dyrssen Dual-Phase Titration log P Method 189
4.10 Ionic Strength Dependence of log P 194
4.11 Temperature Dependence of log P 194
4.12 Calculated versus Measured log P of Research Compounds 194
4.13 log D versus pH Case Study: Procaine Structural Analogs 196
4.14 Database of Octanol–Water log PN log PI and log D7.4 201
References 209
5 Liposome–Water Partitioning 220
5.1 Biomimetic Lipophilicity 221
5.2 Tetrad of Equilibria and Surface Ion-Pairing (SIP) 221
5.3 Data Sources 222
5.4 Location of Drugs Partitioned into Bilayers 222
5.5 Thermodynamics of Partitioning: Entropy- or Enthalpy-Driven? 223
5.6 Electrostatic and Hydrogen Bonding in a Low Dielectric Medium 224
5.7 Water Wires H+/OH- Currents and Permeability of Amino Acids and Peptides 227
5.8 Preparation Methods: MLV SUV FAT LUV ET 228
5.9 Experimental Methods 229
5.10 Prediction of log PMEM from log POCT 229
5.11 log DMEM diff log PMEM and Prediction of log PSI M P EM from log PI OCT 233
5.12 Three Indices of Lipophilicity: Liposomes IAM and Octanol 238
5.13 Getting It Wrong from One-Point log DMEM Measurement 239
5.14 Partitioning into Charged Liposomes 240
5.15 pKa MEM Shifts in Charged Liposomes and Micelles 240
5.16 Prediction of Absorption from Liposome Partition Studies? 241
5.17 Database of log PMEM and log PS
