Absorption and Drug Development, 2ed: Solubility, Permeability, and Charge State

Alex Avdeef

ISBN: 9788126577613




This book shows the reader how to examine a compound's pharmaceutical properties, emphasizing oral absorption. It explains the different physicochemical methods currently used to analyze drug candidates and how to interpret these methods. In the new edition, Dr. Avdeef adds to the extensive compilations of solubility (Ch 6), permeability (Ch 7), and pKas (Ch 3), to reflect the new measurements published and the recent developments in the three absorption core areas of the book, with major emphasis placed on the updating of permeability section, expanding the original Chapter 7 on permeability into two major chapters (8 and 9) on cell assays and blood-brain-barrier, respectively.


Preface to the First Edition

List of Abbreviations


Commercial Trademarks


1 Introduction

1.1 Bulldozer Searching for a Needle 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 7

1.6 The "Absorption" in 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 32

3.2 Methods of Choice for the Determination of 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 Standardization

3.10 Bjerrum Plot: Most Useful Graphical Tool in pKa Analysis

3.11 Cosolvent Methods for pKa Determination of Practically Insoluble Substances

3.12 Other Methods for pKa Measurement

3.13 pKa Micro constants

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 versus Measured log P of Research Compounds

4.13 log D versus pH Case Study: Procaine Structural Analogs

4.14 Database of Octanol--Water log PN log PI 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 PSI M P EM from log PI OCT

5.12 Three Indices of Lipophilicity: Liposomes IAM and Octanol

5.13 Getting It Wrong from One-Point log DMEM Measurement

5.14 Partitioning into Charged Liposomes

5.15 pKa MEM Shifts in Charged Liposomes and Micelles

5.16 Prediction of Absorption from Liposome Partition Studies?

5.17 Database of log PMEM and log PSI M P EM


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 "Δ-Shift" Method

6.6 Case Studies (Solubility--pH Profiles)

6.7 Limits of Detection--Precision versus 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 Drug 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 pKa FLUX-Optimized Design (pOD)

7.8 Cosolvent PAMPA

7.9 UV versus LC/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 in Formulation: Solubilizing Excipient Effects

7.18 Database of Double-Sink PAMPA log P0 log Pm 6.5 and log Pm 7.4


8 Permeability: Caco-2/MDCK

8.1 Permeability in the Gastrointestinal Tract

8.2 Cell-Based In Vitro Permeability Model

8.3 In Situ Human Jejunum Permeability (HJP) Model

8.4 Passive Intrinsic Permeability Coefficients of Caco-2 and MDCK Compared

8.5 Theory (Stage 1): Paracellular Leakiness and Size Exclusion in Caco-2 MDCK and 2/4/A1 Cell Lines

8.6 Theory (Stage 2): Regression Method for In Vitro Cellular Permeability

8.7 Case Studies of Cell-Based Permeability as a Function of pH

8.8 Human Jejunal Permeability Predicted Directly from Caco-2/MDCK

8.9 Caco-2/MDCK Database and Its In Combo PAMPA Prediction


9 Permeability: Blood--Brain Barrier

9.1 The Blood--Brain Barrier: A Key Element for Drug Access to the Central Nervous System

9.2 The Blood--Brain Barrier

9.3 Noncellular BBB Models

9.4 In Vitro BBB Cell-Based Models

9.5 In Vivo BBB Models

9.6 Paradigm Shift

9.7 In Silico BBB Models

9.8 Biophysical Analysis of In Vitro Endothelial Cell Models

9.9 In Situ Brain Perfusion Analysis of Flow

9.10 In Combo PAMPA--BBB Model for Passive BBB Permeability


10 Summary and Some Simple Approximations