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| Preface | |
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| List of Abbreviations | |
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| Introduction | |
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| An Illustrative Description of Oral Drug Absorption: The Whole Story | |
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| Three Regimes of Oral Drug Absorption | |
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| Physiology of the Stomach, Small Intestine, and Colon | |
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| Drug and API Form | |
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| Undissociable and Free Acid Drugs | |
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| Free Base Drugs | |
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| Salt Form Cases | |
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| The Concept of Mechanistic Modeling | |
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| References | |
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| Theoretical Framework I: Solubility | |
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| Definition of Concentration | |
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| Total Concentration | |
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| Dissolved Drug Concentration | |
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| Effective Concentration | |
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| Acid-Base and Bile-Micelle-Binding Equilibriums | |
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| Monoprotic Acid and Base | |
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| Multivalent Cases | |
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| Bile-Micelle Partitioning | |
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| Modified Henderson-Hasselbalch Equation | |
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| Kbm from Log Poct | |
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| Equilibrium Solubility | |
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| Definition of Equilibrium Solubility | |
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| pH-Solubility Profile (pH-Controlled Region) | |
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| Solubility in a Biorelevant Media with Bile Micelles (pH-Controlled Region) | |
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| Estimation of Unbound Fraction from the Solubilities with and without Bile Micelles | |
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| Common Ionic Effect | |
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| Important Conclusion from the pH-Equilibrium Solubility Profile Theory | |
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| Yalkowsky's General Solubility Equation | |
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| Solubility Increase by Converting to an Amorphous Form | |
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| Solubility Increase by Particle Size Reduction (Nanoparticles) | |
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| Cocrystal | |
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| References | |
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| Theoretical Framework II: Dissolution | |
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| Diffusion Coefficient | |
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| Monomer | |
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| Bile Micelles | |
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| Effective Diffusion Coefficient | |
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| Dissolution and Particle Growth | |
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| Mass Transfer Equations: Pharmaceutical Science Versus Fluid Dynamics | |
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| Dissolution Equation with a Lump Sum Dissolution Rate Coefficient (kdiss) | |
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| Particle Size and Surface Area | |
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| Monodispersed Particles | |
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| Polydispersed Particles | |
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| Diffusion Layer Thickness I: Fluid Dynamic Model | |
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| Reynolds and Sherwood Numbers | |
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| Disk (Levich Equation) | |
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| Tube (Graetz Problem) | |
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| Particle Fixed to Space (Ranz-Marshall Equation) | |
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| Floating Particle | |
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| Nonspherical Particle | |
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| Minimum Agitation Speed for Complete Suspension | |
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| Other Factors | |
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| Diffusion Layer Thickness II: Empirical Models for Particles | |
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| Solid Surface pH and Solubility | |
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| Nucleation | |
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| General Description of Nucleation and Precipitation Process | |
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| Classical Nucleation Theory | |
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| Concept of Classical Nucleation Theory | |
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| Mathematical Expressions | |
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| Application of a Nucleation Theory for Biopharmaceutical Modeling | |
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| References | |
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| Theoretical Framework III: Biological Membrane Permeation | |
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| Overall Scheme | |
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| General Permeation Equation | |
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| Permeation Rate Constant, Permeation Clearance, and Permeability | |
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| Intestinal Tube Flatness and Permeation Parameters | |
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| Effective Concentration for Intestinal Membrane Permeability | |
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| Effective Concentration for Unstirred Water Layer Permeation | |
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| Effective Concentration for Epithelial Membrane Permeation: the Free Fraction Theory | |
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| Surface Area Expansion by Plicate and Villi | |
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| Unstirred Water Layer Permeability | |
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| Basic Case | |
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| Particles in the UWL (Particle Drifting Effect) | |
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| Epithelial Membrane Permeability (Passive Processes) | |
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| Passive Transcellular Membrane Permeability: pH Partition Theory | |
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| Intrinsic Passive Transcellular Permeability | |
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| Solubility-Diffusion Model | |
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| Flip-Flop Model | |
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| Relationship between Ptrans,0 and log Poct | |
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| Paracellular Pathway | |
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| Relationship between log Doct, MW, and Fa% | |
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| Enteric Cell Model | |
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| Definition of Papp | |
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| Enzymatic Reaction: Michaelis-Menten Equation | |
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| First-Order Case 1: No Transporter and Metabolic Enzymes | |
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| First-Order Case 2: Efflux Transporter in Apical Membrane | |
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| Apical Efflux Transporter with Km and Vmax | |
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| Apical Influx Transporter with Km and Vmax | |
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| UWL and Transporter | |
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| No Transporter | |
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| Influx Transporter and UWL | |
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| Efflux Transporter | |
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| Gut Wall Metabolism | |
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| The Qgut Model | |
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| Simple Fg Models | |
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| Theoretical Consideration on Fg | |
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| Derivation of the Fg Models | |
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| Derivation of the Anatomical Fg Model | |
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| Interplay between CYP3A4 and P-gp | |
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| Hepatic Metabolism and Excretion | |
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| References | |
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| Theoretical Framework IV: Gastrointestinal Transit Models and Integration | |
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| GI Transit Models | |
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| One-Compartment Model/Plug Flow Model | |
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| Plug Flow Model | |
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| Three-Compartment Model | |
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| S1I7CX (X = 1-4) Compartment Models | |
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| Convection-Dispersion Model | |
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| Tapered Tube Model | |
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| Time-Dependent Changes of Physiological Parameters | |
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| Gastric Emptying | |
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| Water Mass Balance | |
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| Bile Concentration | |
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| Integration 1: Analytical Solutions | |
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| Dissolution Under Sink Condition | |
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| Monodispersed Particles | |
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| Polydispersed Particles | |
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| Fraction of a Dose Absorbed (Fa%) | |
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| Approximate Fa% Analytical Solutions 1: Case-by-Case Solution | |
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| Permeability-Limited Case | |
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| Solubility-Permeability-Limited Case | |
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| Dissolution-Rate-Limited Case | |
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| Approximate Fa% Analytical Solutions 2: Semi-General Equations | |
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| Sequential First-Order Kinetics of Dissolution and Permeation | |
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| Minimum Fa% Model | |
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| Approximate Fa% Analytical Solutions 3: FaSS Equation | |
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| Application Range | |
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| Derivation of Fa Number Equation | |
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| Refinement of the FaSS Equation | |
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| Advantage of FaSS Equation | |
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| Limitation of FaSS Equation | |
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| Interpretations of Fa Equations | |
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| Approximate Analytical Solution for Oral PK Model | |
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| Integration 2: Numerical Integration | |
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| Virtual Particle Bins | |
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| The Mass Balance of Dissolved Drug Amount in Each GI Position | |
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| Controlled Release of Virtual Particle Bin | |
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| In Vivo FA From PK Data | |
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| Absolute Bioavailability and Fa | |
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| Relative Bioavailability Between Solid and Solution Formulations | |
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| Relative Bioavailability Between Low and High Dose | |
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| Convolution and Deconvolution | |
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| Convolution | |
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| Deconvolution | |
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| Other Administration Routes | |
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| Skin | |
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| References | |
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| Physiology Of Gastrointestinal Tract And Other Administration Sites In Humans and Animals | |
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| Morphology of Gastrointestinal Tract | |
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| Length and Tube Radius | |
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| Surface Area | |
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| Small Intestine | |
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| Colon | |
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| Degree of Flatness | |
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| Small Intestine | |
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| Colon | |
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| Epithelial Cells | |
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| Apical and Basolateral Lipid Bilayer Membranes | |
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| Tight Junction | |
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| Mucous Layer | |
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| Movement of the Gastrointestinal Tract | |
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| Transit Time | |
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| Gastric Emptying Time (GET) | |
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| Small Intestinal Transit Time | |
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| Colon Transit Time | |
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| Migrating Motor Complex | |
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| Agitation | |
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| Mixing Pattern | |
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| Agitation Strength | |
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| Unstirred Water Layer on the Intestinal Wall | |
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| Fluid Character of the Gastrointestinal Tract | |
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| Volume | |
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| Stomach | |
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| Small Intestine | |
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| Colon | |
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| Bulk Fluid pH and Buffer Concentration | |
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| Stomach | |
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| Small Intestine | |
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| Colon | |
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| Microclimate pH | |
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| Small Intestine | |
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| Colon | |
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| Bile Micelles | |
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| Stomach | |
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| Small Intestine | |
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| Colon | |
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| Enzymes and Bacteria | |
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| Viscosity, Osmolality, and Surface Tension | |
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| Transporters and Drug-Metabolizing Enzymes in the Intestine | |
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| Absorptive Drug Transporters | |
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| PEP-T1 | |
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| OATP | |
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| Efflux Drug Transporters | |
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| P-gp | |
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| Drug-Metabolizing Enzymes | |
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| CYP3A4 | |
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| Glucuronyl Transferase and Sulfotransferase | |
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| Intestinal and Liver Blood Flow | |
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| Absorption Sites Connected to Portal Vein | |
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| Villous Blood Flow (Qvilli) | |
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| Hepatic Blood Flow (Qh) | |
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| Physiology Related to Enterohepatic Recirculation | |
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| Bile Secretion | |
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| Mass Transfer into/from the Hepatocyte | |
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| Sinusoidal Membrane (Blood to Hepatocyte) | |
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| Canalicular Membrane (Hepatocyte to Bile Duct) | |
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| Nasal | |
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| Pulmonary | |
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| Fluid in the Lung | |
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| Mucociliary Clearance | |
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| Absorption into the Circulation | |
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| Skin | |
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| References | |
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| Drug Parameters | |
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| Dissociation Constant (pKa) | |
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| pH Titration | |
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| pH-UV Shift | |
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| Capillary Electrophoresis | |
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| pH-Solubility Profile | |
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| Calculation from Chemical Structure | |
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| Recommendation | |
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| Octanol-Water Partition Coefficient | |
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| Shake Flask Method | |
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| HPLC Method | |
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| Two-Phase Titration Method | |
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| PAMPA-Based Method | |
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| In Silico Method | |
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| Recommendation | |
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| Bile Micelle Partition Coefficient (Kbm) | |
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| Calculation from Solubility in Biorelevant Media | |
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| Spectroscopic Method | |
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| Recommendations | |
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| Particle Size and Shape | |
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| Microscope | |
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| Laser Diffraction | |
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| Dynamic Laser Scattering (DLS) | |
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| Recommendations | |
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| Solid Form | |
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| Nomenclature | |
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| Crystalline and Amorphous | |
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| Salts, Cocrystals, and Solvates | |
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| Hydrate | |
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| Crystal Polymorph | |
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| True Polymorph and Pseudopolymorph | |
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| Kinetic Resolution versus Stable Form | |
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| Dissolution Profile Advantages of Less Stable Forms | |
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| Enantiotropy | |
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| Solid Form Characterization | |
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| Polarized Light Microscopy (PLM) | |