Absorption and Drug Development - Solubility, Permeability, and Charge State

Informationen zum Autor ALEX AVDEEF , PhD, is the founder of in-ADME Research. He has more than thirty years of experience in chemical instrumentation and software development. Internationally recognized as an authority in the field of solution chemistry, Dr. Avdeef has an extensive list of scholarly publications to his credit. Klappentext Explains how to perform and analyze the results of the latest physicochemical methodsWith 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 bookWell 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. Zusammenfassung 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. Inhaltsverzeichnis 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 3.1...

List of contents

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 lo

Product details

• Authors: Avdeef, A Avdeef, Alex Avdeef, Alex (Pion Avdeef, Avdeef Alex
• Publisher: Wiley, John and Sons Ltd
• Languages: English
• Product format: Hardback
• Released: 08.06.2012
• EAN: 9781118057452
• ISBN: 978-1-118-05745-2
• No. of pages: 744
• Subjects: Natural sciences, medicine, IT, technology > Chemistry > Miscellaneous; Chemie, Physikalische Chemie, Analytische Chemie, Wirkstoffforschung, chemistry, Physical Chemistry, Analytical Chemistry, Wirkstoffforschung u. -entwicklung, Drug Discovery & Development