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This book explains how to examine a compound's pharmaceutical properties, emphasizing oral absorption, detailing different physicochemical methods and how to interpret results for analyzing drug candidates. Now in a new edition, this updated volume now includes more case examples, more entries into properties data tables, updated references, and extensive compilations of solubility, permeability, and pKas. With over 600 references and 100 drawings, this book is well-suited for the practical pharmaceutical chemist and those seeking a better understanding of physicochemical measurements.
1. Introduction. 1.1 Bulldozer Searching for a Need in the Haystack? 1.2 As the Paradigm Turns. 1.3 Screen for the Target or ADME First? 1.4 ADME and Multi-Mechanism Screens. 1.5 ADME and the Medicinal Chemist. 1.6 The 'Absorption' of ADME. 1.7 It is Not Just a Number - It is a Multi-Mechanism. 2. Transport Model. 2.1 Permeability-Solubility-Charge State and pH-Partition Hypothesis. 2.2 Properties of the Gastrointestinal Tract (GIT). 2.3 pH Microclimate. 2.4 Intracellular pH Environment. 2.5 Tight Junction Complex. 2.6 Structure of Octanol. 2.7 Biopharmaceutics Classification System. 3. pKa Determination. 3.1 Charge State and the pKa. 3.3 Titration with a Glass-Membrane pH Electrode. 3.4 Equilibrium Equations and the Ionization Constant. 3.5 'Pure Solvent' Activity Scale. 3.6 Ionic Strength and Debye-Hückel/Davies Equation. 3.7 'Constant Ionic Medium' Activity Scale. 3.8 Temperature Dependence of pKa Values. 3.9 Electrode Calibration and Standarization. 3.10 Bjerrum Plot - Most Useful Graphical Tool in pKa Analysis. 3.11 Cosolvent Method for pKa Determination of Practically-Insoluble Substances. 3.12 Other Methods for pKa Measurement. 3.13 pKa Microconstants. 3.14 pKa Compilations. 3.15 pKa Prediction Programs. 3.16 Database of pKa (25°C and 37°C). 4. Octanol-Water Partitioning. 4.1 Overton-Hansch Model. 4.2 Tetrad of Equilibria. 4.3 Conditional Constants. 4.4 log P Data Sources. 4.5 log D Lipophilicity Profile. 4.6 Ion-Pair Partitioning. 4.7 Micro-log P. 4.8 Methods for log P Determination. 4.9 Dyrssen Dual-Phase Titration log P Method. 4.10 Ionic Strength Dependence of log P. 4.11 Temperature Dependence of log P. 4.12 Calculated vs. Measured log P of Research Compounds. 4.13 log D vs. pH Case Study: Procaine Structural Analogs. 4.14 Database of Octanol-Water log PN, log P1, and log D7.4. 5. Liposome-Water Partitioning. 5.1 Biomimetic Lipophilicity. 5.2 Tetrad of Equilibria and Surface Ion -Pairing (SIP). 5.3 Data Sources. 5.4 Location of Drugs Partitioned into Bilayers. 5.5 Thermodynamics of Partitioning: Entropy- or Enthalpy-Driven? 5.6 Electrostatic and Hydrogen Bonding in a Low Dielectric Medium. 5.7 Water Wires, H+/OH- Currents, and Permeability of Amino Acids and Peptides. 5.8 Preparation Methods: MLV, SUV, FAT, LUV, ET. 5.9 Experimental Methods. 5.10 Prediction of log Pmem from log Poct. 5.11 log Dmem, diff log Pmem, and Prediction of log Psipmem from log P1oct. 5.12 Three Indices of Lipophilicity: Liposomes, IAM, and Octonal. 5.13 Getting It Wrong from One-Point log Dmem Measurement. 5.14 Partitioning into Charged Liposomes. 5.15 pKamem Shifts in Charged Liposomes and Micelles. 5.16 Prediction of Absorption from Liposome Partition Studies? 5.17 Database of log pmem and log Psipmem. 6. Solubility. 6.1 It's Not Just a Number. 6.2 Why is Solubility Measurement Difficult? 6.3 Mathematical Models for Solubility-pH Profiles. 6.4 Experimental Methods. 6.5 Correction for the DMSO Effect by the 'A-Shift' Method. 6.6 Case Studies (Solubility-pH Profiles). 6.7 Limits of Detection - Precision vs. Accuracy. 6.8 Data Sources and the 'Ionizable-Drug Problem'. 6.9 Database of log S0. 7. Permeability - Pampa. 7.1 Permeability in the Gastrointestinal Tract. 7.2 Historical Developments in Permeability Models. 7.3 Rise of Pampa - a Useful Tool in Early Discovery. 7.4 PAMPA-HDM, -DOPC, -DS Models Compared. 7.5 Modeling Biological Membranes. 7.6 Permeability-pH Relationship and the Mitigating Effect of the Aqueous Boundary Layer. 7.7 pKaFlux - Optimized Design (pOD). 7.8 Cosolvent PAMPA. 7.9 UV vs. LS/MS Detection. 7.10 Assay Time Points. 7.11 Buffer Effects. 7.12 Apparent Filter Porosity. 7.13 PAMPA Errors: Intra-Plate and Inter-Plate Reproducibility. 7.14 Human Intestinal Absorption (HIA) and PAMPA. 7.15 Permeation of Permanently Charged Molecules. 7.16 Permeation of Zwitterions/Ampholytes - in combo PAMPA. 7.17 PAMPA on Formulation - Solubilization Excipient Effects. 7.18 Database of Double-Sink PAMPA log Po,log Pm6.5, log Pm7.4. 8. Pereability - Caco-2/MDCK. 8.1 Permeability in the Gastrointestinal Tract. 8.2 Cell-Based in vitro