Developing Solid Oral Dosage Forms : Pharmaceutical Theory and Practice

Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice, Second Edition illustrates how to develop high-quality, safe, and effective pharmaceutical products by discussing the latest techniques, tools, and scientific advances in preformulation investigation, formulation, process design, characterization, scale-up, and production operations. This book covers the essential principles of physical pharmacy, biopharmaceutics, and industrial pharmacy, and their application to the research and development process of oral dosage forms. Chapters have been added, combined, deleted, and completely revised as necessary to produce a comprehensive, well-organized, valuable reference for industry professionals and academics engaged in all aspects of the development process. New and important topics include spray drying, amorphous solid dispersion using hot-melt extrusion, modeling and simulation, bioequivalence of complex modified-released dosage forms, biowaivers, and much more. Written and edited by an international team of leading experts with experience and knowledge across industry, academia, and regulatory settings Includes new chapters covering the pharmaceutical applications of surface phenomenon, predictive biopharmaceutics and pharmacokinetics, the development of formulations for drug discovery support, and much more Presents new case studies throughout, and a section completely devoted to regulatory aspects, including global product regulation and international perspectives Front Cover Developing Solid Oral Dosage Forms Copyright Page Dedication Contents List of Contributors I. Theories and Techniques in the Characterization of Drug Substances and Excipients 1 Solubility of Pharmaceutical Solids 1.1 Introduction 1.1.1 Implication of solubility in dosage form development 1.1.2 Basic concepts of solubility and dissolution 1.1.2.1 Ionic interactions 1.1.2.2 van der Waals interactions 1.1.2.3 Dispersion interactions 1.1.2.4 Hydrogen bonding 1.2 Thermodynamics of Solutions 1.2.1 Volume of mixing 1.2.2 Enthalpy of mixing 1.2.3 Entropy of mixing 1.2.4 Free energy of mixing 1.3 Theoretical Estimation of Solubility 1.3.1 Ideal solutions 1.3.2 Effect of crystallinity 1.3.3 Nonideal solutions 1.3.4 Regular solution theory 1.3.5 Aqueous solution theory 1.3.6 General solubility equation 1.4 Solubilization of Drug Candidates 1.4.1 Solubility enhancement by pH control and salt formation 1.4.1.1 Theoretical expressions to describe pH–solubility profiles 1.4.2 Solubilization using complexation 1.4.2.1 AL-type phase diagrams 1.4.2.2 AP-type phase diagrams 1.4.2.3 BS-type phase diagrams 1.4.3 Solubilization by cosolvents 1.4.4 Solubilization by surfactants (micellar solubilization) 1.4.5 Solubilization by combination of approaches 1.4.5.1 Combined effect of ionization and cosolvency 1.4.5.2 Combined effect of ionization and micellization 1.4.5.3 Combined effect of ionization and complexation 1.4.5.4 Combined effect of cosolvency and complexation 1.4.5.5 Combined effect of complexation and micellar solubilization 1.5 Experimental Determination of Solubility 1.5.1 Stability of solute and solvent 1.5.2 Shakers and containers 1.5.3 Presence of excess undissolved solute 1.5.4 Determination of equilibrium 1.5.5 Phase separation 1.5.6 Determination of solute content in the dissolved phase 1.5.7 Experimental conditions References 2 Crystalline and Amorphous Solids 2.1 Introduction 2.2 Definitions and Categorization of Solids 2.3 Thermodynamics and Phase Diagrams 2.3.1 Polymorphs 2.3.1.1 Enantiotropy and monotropy 2.3.1.2 Methods of determining stability relationships between polymorphs 2.3.1.2.1 Quantitative methods 2.3.1.2.1.1 Using heat of fusion data 2.3.1.2.1.2 Using eutectic fusion data 2.3.1.2.1.3 Using solubility/intrinsic dissolution rate data 2.3.1.2.1.4 Using solubility/intrinsic dissolution rate and heat of solution data 2.3.1.2.2 Qualitative methods 2.3.1.2.2.1 Using the definition 2.3.1.2.2.2 Using the heat of fusion rule 2.3.1.2.2.3 Using the heat of transition rule 2.3.2 Solvates/Hydrates 2.3.2.1 Anhydrate/Hydrate equilibrium at constant temperature 2.3.2.2 Temperature dependence of anhydrate/hydrate equilibrium 2.3.3 Cocrystals 2.3.4 Amorphous solids 2.4 Pharmaceutical Relevance and Implications 2.4.1 Solubility 2.4.2 Dissolution rate and bioavailability 2.4.3 Hygroscopicity 2.4.4 Reactivity and chemical stability 2.4.4.1 Topochemical reactions 2.4.4.2 Nontopochemical reactions 2.4.5 Mechanical properties 2.5 Transformations Among Solids 2.5.1 Induced by heat 2.5.1.1 Polymorphic transitions 2.5.1.2 Dehydration/Desolvation 2.5.1.3 Cocrystal formation 2.5.2 Induced by vapor 2.5.3 Induced by solvents 2.5.4 Induced by mechanical stresses 2.6 Methods of Generating Solids 2.6.1 Through gas 2.6.2 Through liquid 2.6.2.1 Through neat liquid 2.6.2.2 Through solution 2.6.2.2.1 Solvent evaporation 2.6.2.2.2 Antisolvent addition 2.6.2.2.3 Reactive solvent addition 2.6.2.2.4 Temperature gradient 2.6.2.2.5 Suspension method 2.6.3 Through solid 2.7 Amorphous Drugs and Solid Dispersions 2.7.1 Characteristics of amorphous phases 2.7.1.1 Origin of the glass transition 2.7.1.2 Configurational thermodynamic quantities 2.7.1.3 Molecular relaxation in the amorphous state 2.7.2 Characteristics of amorphous solid dispersions 2.7.2.1 Thermodynamic analyses and phase miscibility 2.7.2.1.1 Entropy of mixing 2.7.2.1.2 Enthalpy of mixing 2.7.2.1.3 Free energy of mixing 2.7.2.2 Molecular mobility in amorphous solid dispersions 2.7.2.3 Solubility in polymeric matrix 2.7.3 Crystallization of amorphous drugs and dispersions 2.7.3.1 Molecular mobility 2.7.3.2 Free energy driving force 2.7.3.3 Configurational entropy 2.7.3.4 Crystallization inhibition 2.8 Special Topics 2.8.1 Polymorph screening and stable form screening 2.8.2 High-Throughput crystallization 2.8.3 Miniaturization in crystallization References 3 Solid-State Characterization and Techniques 3.1 Introduction 3.2 Microscopy 3.2.1 Optical microscopy 3.2.2 Electron microscopy 3.2.3 Probe microscopy 3.3 Powder X-ray Diffraction 3.4 Thermal Analysis 3.4.1 Differential scanning calorimetry 3.4.1.1 Instrumentation 3.4.1.2 Applications 3.4.1.2.1 Melting and phase diagram 3.4.1.2.2 Characterization of polymorphs 3.4.1.2.3 Characterization of hydrates 3.4.1.2.4 Characterization of amorphous phases 3.4.2 Thermogravimetric analysis 3.4.3 Microcalorimetry 3.5 Vibrational Spectroscopy 3.5.1 IR and Raman spectroscopy 3.5.1.1 IR spectroscopy 3.5.1.2 Raman spectroscopy 3.5.2 SSNMR spectroscopy 3.6 Moisture Sorption 3.7 Hyphenated Techniques 3.8 Conclusion References 4 API Solid-Form Screening and Selection 4.1 Introduction 4.2 Solid-Form Selection Considerations 4.2.1 Key physicochemical property considerations 4.2.1.1 Solid-form stability 4.2.1.2 Hygroscopicity 4.2.1.3 Solubility, dissolution rate, and bioavailability 4.2.2 Considerations for various forms 4.2.2.1 Salts 4.2.2.1.1 pH-solubility profile and salt solubility 4.2.2.1.2 Selection of counterions and salt formation 4.2.2.1.3 Dissolution and oral absorption of salts 4.2.2.1.4 Toxicity of counterions 4.2.2.1.5 Chemical stability considerations 4.2.2.1.6 Disproportionation of salts 4.2.2.1.7 Dosage form consideration 4.2.2.2 Cocrystals 4.2.2.2.1 Selection of coformer 4.2.2.3 Polymorphs, solvates, and hydrates 4.2.2.4 Amorphous forms 4.3 Screening SOLID-FORMS of API 4.3.1 Screening techniques 4.3.2 High-throughput screening 4.3.3 Manual screens 4.3.4 Alternate screens 4.4 Identification and Analysis of Forms 4.4.1 Single-crystal and PXRD 4.4.2 Thermal techniques 4.4.3 Spectroscopic techniques 4.5 Conclusions 4.6 Case Studies 4.6.1 Case study 1: RPR111423144 4.6.2 Case study 2: LY333531145 4.6.3 Case study 3 References 5 Drug Stability and Degradation Studies 5.1 Introduction 5.2 Chemical Stability 5.2.1 Solution kinetics 5.2.2 Rate equations 5.2.3 Elemental reactions and reaction mechanism 5.2.4 Typical simple order kinetics 5.2.4.1 Zero-order reactions 5.2.4.2 First-order reactions 5.2.4.3 Second-order reactions 5.2.4.4 Apparent pseudokinetic orders 5.2.5 Complex reactions 5.2.5.1 Reversible reactions 5.2.5.2 Parallel reactions 5.2.5.3 Consecutive reactions 5.2.6 Arrhenius equation, collision theory, and transition state theory 5.2.6.1 Arrhenius equation 5.2.6.2 Classic collision theory of reaction rates 5.2.6.3 Transition state theory 5.2.7 Catalysts and catalysis 5.2.7.1 Specific acid-base catalysis 5.2.7.2 General acid-base catalysis 5.2.8 pH-rate profiles 5.2.8.1 V-shaped, U-shaped, and other truncated pH-rate profiles 5.2.8.2 Sigmoidal pH-rate profiles 5.2.8.3 Bell-shaped pH-rate profiles 5.2.8.4 More complicated pH-rate profiles 5.2.9 Solid-state reaction kinetics 5.2.10 Solid-state kinetic models 5.2.10.1 Reactions involving nucleation 5.2.10.2 Avrami–Erofeev equation 5.2.10.3 Prout–Tompkins equation 5.2.10.4 Reactions controlled by diffusion 5.2.10.5 Reactions governed by phase boundaries 5.2.10.6 Higher (nth)–order reactions 5.2.10.7 Bawn kinetics 5.2.10.8 Model-fitting versus model-free approaches 5.2.11 Physical parameters affecting solid-state kinetics 5.2.12 The role of moisture 5.2.13 Topochemical reactions 5.3 Common Pathways of Drug Degradation 5.3.1 Hydrolysis 5.3.1.1 Hydrolysis of carboxylic acid derivatives 5.3.1.2 Hydrolysis of acetals and ketals 5.3.1.3 Hydrolysis of other carbonyl derivatives 5.3.1.4 Miscellaneous hydrolysis reactions 5.3.2 Oxidative degradation 5.3.2.1 Mechanisms of oxidation 5.3.2.2 Prediction of oxidative stability 5.3.2.3 Functional groups susceptible to oxidation 5.3.3 Photochemical degradation 5.3.3.1 Light 5.3.3.2 Light absorption, excitation, and photochemical reactions 5.3.3.3 Photooxidation 5.3.4 Other degradation pathways 5.4 Experimental Approaches to Studying the Chemical Degradation of Drugs 5.4.1 Solution thermal degradation studies 5.4.2 Solid-state thermal degradation studies 5.4.3 Oxidative degradation studies 5.4.4 Photodegradation studies 5.5 Physical Stability and Phase Transformations 5.5.1 Types of phase transformations 5.5.2 Mechanisms of phase transformations 5.5.2.1 Solid-state transitions 5.5.2.2 Melt transitions 5.5.2.3 Solution transitions 5.5.2.4 Solution-mediated transitions 5.6 Phase Transformations During Pharmaceutical Processing 5.6.1 Processes for preparing solid dosage forms and associated potential phase transformations 5.6.1.1 Size reduction 5.6.1.2 Granulation/size enlargement 5.6.1.2.1 Wet granulation and drying 5.6.1.2.2 Dry granulation 5.6.1.2.3 Melt granulation 5.6.1.2.4 Spray drying and freeze-drying 5.6.1.3 Granulation milling/sizing and blending 5.6.1.4 Compression and encapsulation 5.6.1.5 Coating 5.6.2 Anticipating and preventing phase transformations in process development References 6 Excipient Compatibility and Functionality 6.1 Introduction 6.2 Excipient Functionality 6.2.1 Compendial standards 6.2.2 Determining FRCs 6.2.3 Identification of CMAs 6.3 Excipient Compatibility 6.3.1 Chemistry of drug-excipient interactions 6.3.1.1 Influence of water and microenvironmental pH 6.3.1.2 Reactions with excipients and their impurities 6.3.1.3 Stabilizing excipients 6.3.2 Current practices 6.3.2.1 Experimental design 6.3.2.1.1 Two-component or multicomponent systems 6.3.2.1.2 The n−1 design and mini-formulations 6.3.2.2 Sample preparation and storage 6.3.2.2.1 Sample preparation 6.3.2.2.2 Thermal stresses 6.3.2.2.3 Humidity and water content 6.3.2.2.4 Mechanical stress 6.3.2.2.5 Oxidative stress 6.3.2.3 Sample analysis and data interpretation 6.3.2.3.1 Monitoring for drug degradation 6.3.2.3.2 Thermal methods 6.3.2.3.3 Monitoring for form changes 6.4 Excipient Variability 6.4.1 Identification of critical excipients 6.4.2 Understanding the mechanistic basis of functional role 6.4.3 Understanding the range of variability of excipient attributes 6.4.4 Generating or obtaining excipient lots with a range of known MAs 6.4.4.1 Different grades or suppliers of excipients as a worst-case scenario 6.4.4.2 Mixtures of different grades of excipients 6.4.4.3 Spiking or using storage conditions to modify MAs 6.4.5 Controlled experiments with a range of known MAs 6.4.5.1 MA comparison at target formulation and process parameters 6.4.5.2 Statistical DoE studies that combine MAs with formulation and/or process parameters 6.5 Risk Assessment of Drug-Excipient Incompatibilities and Mitigation Strategies 6.6 Conclusions References 7 Polymer Properties and Characterization 7.1 Introduction 7.1.1 Definition, structure, and nomenclature 7.1.2 Types of homopolymers and copolymers 7.2 Basic Concepts and Characterization of Polymeric Materials 7.2.1 Polymer composition 7.2.2 Molecular weight 7.2.3 Rheological properties 7.2.4 Polymers in solution 7.2.5 Polymer morphology and physical properties 7.2.6 Structure–property relationships 7.2.6.1 Molecular weight effects 7.2.6.1.1 Effect of molecular weight on solution viscosity 7.2.6.1.2 Effect of molecular weight on mechanical and thermoplastic properties 7.2.6.1.3 Mechanical strength of films 7.2.6.1.4 Mechanical strength of tablets 7.2.6.1.5 Glass transition temperature, melting point, and melt index 7.2.6.1.6 Effect of molecular weight on gel strength 7.2.6.2 Side-chain substitution effects 7.2.6.2.1 Side-chain structure (substituent type) 7.2.6.2.2 Extent of side-chain substitution 7.2.6.2.3 Effect of extent of substitution on solubility 7.2.6.2.4 Effect of extent of substitution on amorphous solid dispersion properties 7.2.6.2.5 Effect of extent of substitution on mechanical properties 7.2.6.3 Copolymerization 7.2.6.3.1 Thermal properties of copolymers 7.2.6.3.2 Mechanical properties of copolymers 7.3 Commonly Used Polymer Excipients in Solid Oral Products 7.3.1 Cellulose and cellulose derivatives 7.3.1.1 Hydroxypropyl cellulose 7.3.1.2 Hydroxypropyl methylcellulose 7.3.1.3 Hydroxyethyl cellulose 7.3.1.4 Ethyl cellulose 7.3.1.5 Methyl cellulose 7.3.1.6 Sodium carboxymethyl cellulose 7.3.1.7 Cellulose acetate 7.3.1.8 Cellulose derivatives with pH-dependent solubility 7.3.2 Synthetic polymers 7.3.2.1 Acrylic acid polymers 7.3.2.1.1 Polyacrylic acid (carbomer; carbopol) 7.3.2.1.2 Polymethacrylate 7.3.2.2 Polyvinylpyrrolidone 7.3.2.2.1 Povidone 7.3.2.2.2 Crospovidone 7.3.2.3 Polyvinyl alcohol (PVA) 7.3.2.4 Polyethylene oxide (PEO) and polyethylene glycol (PEG) 7.3.2.4.1 Polyethylene glycol (PEG) 7.3.2.4.2 Polyethylene oxide (PEO) 7.3.2.5 Ion-exchange resins 7.4 Conclusion References 8 Interfacial Phenomena 8.1 Interfaces 8.2 Fundamental Intermolecular Forces 8.2.1 Van der waals forces 8.2.2 Thermodynamics of dispersion forces 8.2.2.1 Hamaker’s approach 8.2.2.2 Lifshitz’s approach 8.3 Thermodynamics of Particles in Electrolyte Solutions 8.3.1 DLVO theory 8.3.2 Steric stabilization of particles 8.4 Surface Tension and Surface Energy 8.4.1 Fundamentals 8.4.2 Surface energy components 8.4.2.1 Acid-base interactions 8.4.3 Fundamentals of self-assembly of soft Structures 8.5 Thermodynamics of Wetting 8.5.1 Fundamentals 8.5.2 Experimental techniques 8.5.2.1 Sessile drop contact angle 8.5.2.2 Beyond the sessile drop measurements 8.5.2.3 Effects of surface roughness 8.5.3 Implications of solid–liquid interfaces 8.5.3.1 Interfacial thermodynamics in dissolution 8.5.3.2 Surfactant enhanced wetting 8.5.3.3 Effect of additives in crystallization 8.6 Solid–Vapor Interface 8.6.1 Introduction 8.6.2 Adsorption fundamentals 8.6.3 Heterogeneous adsorption 8.6.3.1 Mapping of energetic surface Heterogeneity 8.6.4 Inverse gas chromatography (IGC) 8.6.5 Implications of solid–vapor interfaces 8.6.5.1 Moisture content in solid-state materials 8.6.5.2 Drying 8.7 Interfacial Phenomenon (Solid–Solid) 8.7.1 Fundamental thermodynamics 8.7.2 Experimental techniques 8.7.2.1 Atomic force microscope 8.7.2.2 Scanning electron microscope 8.7.3 Pharmaceutical implications 8.7.3.1 Flowability 8.7.3.2 Mixing or blending 8.7.3.3 High-shear mixing or dry coating 8.7.3.4 Milling 8.7.3.5 Tableting 8.7.3.6 Triboelectrification 8.8 Future Directions—Opinions References 9 Fundamental of Diffusion and Dissolution 9.1 Fundamental of Diffusion 9.1.1 Introduction 9.1.2 Basic Equations of Diffusion 9.1.3 Solutions for Diffusion Equations 9.1.3.1 Diffusion from a plane source into an infinite medium 9.1.3.2 Diffusion between two infinite regions in contact 9.1.3.3 Diffusion in semi-infinite systems 9.1.3.4 Diffusion in finite planar systems 9.1.3.5 Diffusion across a planar barrier 9.1.3.6 Diffusion in a sphere 9.1.3.7 Diffusion in a cylinder 9.1.3.8 Diffusion combined with other processes 9.1.4 The Diffusion Coefficient and Its Determination 9.1.4.1 Steady-state flux method 9.1.4.2 Lag time method 9.1.4.3 Sorption and desorption methods 9.1.5 Pharmaceutical Application of Diffusion Theory 9.2 Fundamentals of Dissolution 9.2.1 Introduction 9.2.2 Mechanism and theories of solid dissolution 9.2.2.1 Thermodynamic considerations 9.2.2.2 Dissolution by pure diffusion 9.2.2.3 Diffusion layer model 9.2.2.4 Convective-diffusion model 9.2.3 Planar surface dissolution 9.2.3.1 Convective-diffusion model for a rotating disk 9.2.3.2 Convective-diffusion model for flow past a planar surface 9.2.4 Particulate dissolution 9.2.4.1 Diffusion layer–based dissolution models 9.2.4.2 Convective-diffusion-based particulate dissolution model 9.2.4.3 Dissolution under nonsink conditions 9.2.4.4 Effects of particle shape 9.2.4.5 Polydispersity effects References 10 Particle, Powder, and Compact Characterization 10.1 Introduction 10.2 Particle Size Characterization 10.2.1 Light Microscopy 10.2.2 Scanning Electron Microscopy 10.2.3 Sieving 10.2.4 Light diffraction 10.2.5 Importance/impact of particle size characterization 10.3 Powder Characterization 10.3.1 Density 10.3.1.1 True density 10.3.1.2 Bulk density 10.3.1.3 Tapped density 10.3.2 Flow 10.3.2.1 Compressibility Index and Hausner ratio 10.3.2.2 Angle of repose and flow through an orifice 10.3.2.3 Shear cell methods 10.3.2.4 Additional shear testers 10.3.2.5 Dynamic test methods 10.4 Compact (Mechanical Property) Characterization 10.4.1 Important mechanical properties 10.4.1.1 Elastic deformation 10.4.1.2 Plastic deformation 10.4.1.3 Brittle and ductile fracture 10.4.1.4 Viscoelastic properties 10.4.2 Overview of methods 10.4.3 Quasi-static testing 10.4.3.1 Test specimen preparation 10.4.3.2 Importance of the solid fraction 10.4.3.3 Tensile strength determination 10.4.3.4 Pendulum Impact Device 10.4.3.5 Tableting indices 10.4.3.6 Bonding Index 10.4.3.7 Brittle Fracture Index 10.4.3.8 Viscoelastic index 10.4.3.9 Application of Quasi-static testing to formulation development 10.4.4 Dynamic testing 10.4.4.1 Application of dynamic testing to formulation development 10.5 Conclusions References II. Biopharmaceutical and Pharmacokinetic Evaluations of Drug Molecules and Dosage Forms 11 Oral Absorption Basics: Pathways and Physicochemical and Biological Factors Affecting Absorption 11.1 Barriers to Oral Drug Delivery 11.1.1 Intestinal barrier 11.1.2 Hepatic barrier 11.2 Pathways of Drug Absorption 11.2.1 Paracellular diffusion 11.2.2 Passive diffusion 11.2.3 Carrier-mediated transport 11.2.3.1 Active transport 11.2.3.1.1 Peptide transporters 11.2.3.1.2 Amino acid transporters 11.2.3.1.3 Organic anion-transporting peptides 11.2.3.2 Facilitated transport 11.2.3.2.1 Nucleoside transporters 11.3 Pathways of Drug Metabolism 11.3.1 Phase I metabolism 11.3.1.1 Oxidative metabolism 11.3.1.1.1 Cytochrome P450 enzymes 11.3.1.1.2 Nomenclature of CYP 11.3.1.1.3 Hydroxylation 11.3.1.2 Reductive metabolism 11.3.1.3 Hydrolysis 11.3.1.3.1 Necessity of hydrolysis 11.3.1.3.2 Common hydrolysis substrates 11.3.2 Phase II metabolism 11.3.2.1 UDP-glucuronosyltransferases or UGTs 11.3.2.2 Sulfotransferases or SULTs 11.3.2.3 Glutathione transferases or GSTs 11.3.2.4 Other conjugating enzymes 11.4 Pathways of Drug Elimination 11.4.1 P-Glycoprotein 11.4.1.1 Introduction to P-gp 11.4.1.2 Structure of P-gp 11.4.1.3 Nomenclature of ABC transporters 11.4.1.4 Substrates for P-gp 11.4.1.5 Disruption of P-gp activity 11.4.2 Multidrug-resistance associated proteins 11.4.2.1 Introduction to MRPs 11.4.2.2 Structure of MRPs 11.4.2.3 Nomenclature of MRPs 11.4.2.4 Substrates for MRPs 11.4.2.5 Disruption of MRP activity 11.4.3 Breast cancer resistance protein 11.4.3.1 Introduction to BCRP 11.4.3.2 Structure of BCRP 11.4.3.3 Nomenclature of BCRP 11.4.3.4 Substrates for BCRP 11.4.3.5 Disruption of BCRP activity 11.4.4 Organic anion transporters 11.4.4.1 Introduction to OATs 11.4.4.2 Structure of OATs 11.4.4.3 Nomenclature of OATs 11.4.4.4 Substrates of OATs 11.4.4.5 Disruption of OAT activity 11.5 Coupling of Enzymes and Efflux Transporters 11.5.1 Double Jeopardy theorem 11.5.1.1 Mechanistic description of the theorem 11.5.1.2 Consequences of disruption 11.5.2 Revolving door theorem 11.5.2.1 Mechanistic description of the theorem 11.5.2.2 Consequences of disruption 11.5.3 Enteric and enterohepatic recycling 11.6 Regulation of Transporters and Enzymes by Nuclear Receptors 11.6.1 Nuclear receptors 11.6.2 Pregnane X receptor and constitutive androstane receptor 11.6.3 Regulation of transporters and enzymes by PXR 11.6.4 Regulation of transporters and enzymes by CAR 11.6.5 Regulation of transporters and enzymes by other NRs 11.7 Physicochemical Factors Affecting Drug Absorption 11.7.1 Lipophilicity 11.7.2 Size 11.7.3 Charge 11.7.4 Solubility 11.7.5 Dissolution 11.7.6 Ionization (pKa) 11.8 Biological Factors Affecting Drug Absorption 11.8.1 Transit time 11.8.2 pH 11.8.3 Food 11.8.4 Luminal enzymes References 12 Oral Drug Absorption: Evaluation and Prediction 12.1 Introduction 12.2 Anatomy and Physiology of the GI Tract 12.3 Biopharmaceutics Classification System 12.3.1 FDA guidance on biowaivers 12.3.1.1 Determination of drug solubility 12.3.1.2 Determination of drug substance permeability 12.3.1.2.1 Mass balance and absolute bioavailability studies 12.3.1.2.2 Intestinal permeability 12.3.1.3 Comparison of dissolution profile 12.3.2 Scientific basis for BCS 12.4 Intestinal Permeability Evaluation: Cultured Cells 12.4.1 Caco-2 cells 12.4.2 Limitations of Caco-2 cell model 12.4.3 MDCK cells 12.4.4 Other cells 12.5 Intestinal Permeability Evaluation: Ex Vivo 12.5.1 The everted gut sac technique 12.5.2 Ussing chamber 12.5.3 In situ intestinal perfusion in rat 12.5.4 Intestinal perfusion in humans 12.6 In Silico Methods 12.6.1 QSAR 12.6.2 QSPR 12.6.3 PBPK modeling 12.7 In Vivo Methods to Determine Oral Drug Absorption 12.7.1 Mass balance study to determine drug absorption 12.7.2 Rate of oral drug absorption into systemic circulation 12.7.2.1 First-order drug absorption 12.7.2.2 Zero-order drug absorption 12.8 Food Effects on Drug Intestinal Absorption 12.8.1 GI physiological changes under fed state 12.8.2 FDA guidance on food-effect bioavailability and bioequivalence studies 12.9 Regional Drug Absorption Along GI 12.9.1 Drug absorption from the stomach 12.9.2 Drug absorption from the small intestine 12.9.3 Drug absorption from colon 12.9.4 Advance in estimation of human in vivo regional intestinal permeability 12.10 Future Trends 12.11 Conclusions Disclaimer References 13 Dissolution Testing of Solid Products 13.1 Introduction 13.2 Theory of Dissolution Test for Solid Drug Products 13.2.1 Dissolution and drug absorption 13.2.2 Dissolution tests for quality control 13.2.3 Mechanism of dissolution 13.3 Current Technology and Instrumentation for Dissolution Testing 13.3.1 Current USP dissolution apparatus for oral dosage forms 13.3.2 Possible variables during dissolution testing 13.3.3 Calibration of dissolution apparatus 13.3.4 Automation 13.3.5 Noncompendial dissolution methods 13.4 Regulatory Considerations 13.4.1 The role of dissolution in product quality control 13.4.2 Dissolution method development: regulatory considerations 13.4.3 Setting regulatory acceptance criteria for dissolution testing 13.4.4 Biowaiver considerations and comparison of dissolution profiles 13.5 Summary References 14 Bioavailability and Bioequivalence 14.1 General Background 14.2 Definitions and Key Concepts 14.2.1 Bioavailability 14.2.2 Bioequivalence 14.2.3 Pharmaceutical equivalents, pharmaceutical alternatives, and therapeutic equivalents 14.3 General Components of BA and BE Studies 14.3.1 Study population 14.3.2 Study design 14.3.3 Biofluid matrices 14.3.4 Bioanalytical methods 14.3.5 Compounds for bioassay 14.4 Data Analysis for BA and BE Studies 14.4.1 Variables for BA/BE assessment 14.4.2 Statistical analysis for BE studies 14.4.2.1 Average BE 14.4.2.2 Population BE and individual BE 14.4.3 Data analysis for BA studies 14.5 Special Topics for BA and BE Assessment 14.5.1 BE studies requiring pAUCs 14.5.2 BE evaluation for HV drugs 14.5.3 BE evaluation for NTI drugs 14.6 Biowaiver and BCS 14.6.1 BA and BE are self-evident 14.6.2 BA and BE claim based on in vitro data 14.6.3 Biowaivers and BCS 14.7 Summary and Future Perspectives References 15 Predictive Biopharmaceutics and Pharmacokinetics: Modeling and Simulation 15.1 Introduction 15.2 Modeling and Simulation Approaches for Biopharmaceutics and PK 15.2.1 Conventional compartment PK modeling and population PK modeling 15.2.2 Physiologically based PK modeling 15.2.2.1 Absorption 15.2.2.1.1 Compartmental absorption and transit model 15.2.2.1.2 Advanced compartmental absorption and transit model 15.2.2.1.3 Advanced dissolution, absorption, and metabolism model 15.2.2.2 Distribution 15.2.2.3 First-pass intestinal metabolism 15.2.2.4 Hepatic and renal CL 15.2.2.4.1 Drug hepatic CL 15.2.2.4.2 Drug renal CL 15.3 Application of Biopharmaceutics and PK Modeling and Simulation in Drug Development 15.4 Application of Biopharmaceutics and PK Modeling and Simulation in Regulatory Activities 15.4.1 In the new drug evaluation 15.4.2 In generic drug evaluation 15.5 Summary References 16 In Vitro/In Vivo Correlations: Fundamentals, Development Considerations, and Applications 16.1 Introduction 16.1.1 In vitro/in vivo correlation 16.1.2 IVIVC and product development 16.2 Development and Assessment of an IVIVC 16.2.1 Study design and general considerations 16.2.2 IVIVC modeling 16.2.2.1 Convolution and deconvolution approaches used in Level A correlation 16.2.2.1.1 General solution 16.2.2.1.2 Numerical deconvolution 16.2.2.1.3 Model-dependent deconvolution 16.2.2.2 Mean time parameters used in Level B correlation 16.2.2.2.1 In vivo parameters 16.2.2.2.2 In vitro parameters 16.2.2.3 Summary parameters used in Level C correlation 16.2.2.4 Establishment of a Level A IVIVC model 16.2.2.4.1 Two-stage approach 16.2.2.4.2 Single-stage approach 16.2.2.4.3 Compartmental and population approach 16.2.2.5 Establishment of a Level C IVIVC model 16.2.3 Evaluation of a correlation 16.3 Considerations in IVIVC Development 16.3.1 In vivo absorption versus in vitro test considerations 16.3.1.1 Apparent drug absorption from the GI tract 16.3.1.2 In vitro test method 16.3.2 Drug and formulation considerations 16.3.2.1 Immediate-release dosage forms 16.3.2.2 Extended-release (ER) dosage forms 16.4 IVIVC Development Approach 16.4.1 General strategy and approach 16.4.2 Design of a predictive in vitro test 16.5 Applications and Limitations 16.5.1 Setting dissolution specifications 16.5.2 Supporting waiver of in vivo bioavailability study 16.5.3 Limitations and additional considerations 16.6 Case Studies 16.6.1 Influence of API solubility on IVIVC 16.6.2 Developing a predictive in vitro test 16.6.3 Illustration of setting an optimal dissolution specification based on IVIVC using Monte Carlo simulation 16.6.4 Setting clinically relevant specifications 16.6.5 Setting biorelevant dissolution specification 16.7 Summary References III. Design, Development and Scale-up of Formulation and Manufacturing Process 17 Oral Formulations for Preclinical Studies: Principle, Design, and Development Considerations 17.1 Introduction 17.2 Considerations in Designing Formulations for Preclinical Species 17.2.1 Type and requirements of nonclinical safety assessment studies 17.2.2 Complexities caused by high exposure requirement but minimal adverse effect 17.2.3 Complexities in dosing preclinical species 17.2.4 Complexities due to use-limit of excipients 17.3 Use of API Properties to Guide Formulation Design 17.3.1 Solubility and bioavailability 17.3.1.1 Factors that impact solubility 17.3.1.2 Solid-state properties 17.3.1.3 pH and pKa 17.3.1.4 Lipophilicity 17.3.2 Solubility prediction and screen 17.3.2.1 Solubility prediction 17.3.2.2 Solubility screen and measurement methods 17.3.2.3 Solubility screen in vehicles 17.3.3 Formulation design with solubility information 17.3.4 Stability 17.3.4.1 Implication to formulation design 17.3.5 Evolution of solid forms and batch-to-batch variation 17.4 Formulations for BCS Class I/III Compounds 17.4.1 Aqueous solution formulations 17.4.2 Suspension formulations 17.5 Formulations for BCS Class II/IV Compounds Using Enabling Technologies 17.5.1 Solubilization by changing solution pH 17.5.2 Formulation through suspension of salt 17.5.3 Solubilization through cosolvents 17.5.4 Lipid and surfactant-based formulations 17.5.4.1 Commercially available excipients 17.5.4.2 Selection of excipients 17.5.4.3 Formulation development 17.5.4.4 Formulation characterization and selection 17.5.5 Amorphous solid dispersions 17.5.5.1 Formulation for fast crystallizers 17.5.5.2 Formulation for slow crystallizers 17.5.5.3 Preparation of prototype amorphous solid dispersion formulations 17.5.5.4 Characterization of prototype amorphous solid dispersion formulations 17.5.5.5 Scale-up the amorphous solid dispersion formulations 17.6 Evaluating Formulation Performance by In Vitro Dissolution 17.7 Rationale Selection of Formulations Suitable for Intended Studies 17.8 Case Study 17.8.1 Model compound properties 17.8.2 Crystallization tendency assessment 17.8.3 Development of salt suspension 17.8.4 Development of lipid/surfactant-based formulations 17.8.5 Development of amorphous solid dispersions 17.8.6 In vivo comparison of different formulations Acknowledgments References 18 Rational Design for Amorphous Solid Dispersions 18.1 Introduction 18.2 Key Components of Amorphous Solid Dispersions 18.3 Characterization of Amorphous Dispersions 18.4 Screening and Selection of Amorphous Solid Dispersions 18.5 Stability Considerations 18.6 Solubility and Dissolution Considerations 18.7 Methods of Manufacturing Amorphous Solid Dispersions 18.8 Dosage Form Development Considerations 18.9 Case Studies 18.9.1 Early Development: Vemurafenib 18.9.2 Late Development: Telaprevir 18.9.3 Life Cycle Management 18.9.3.1 Kaletra 18.10 Conclusions References 19 Rational Design of Oral Modified-Release Drug Delivery Systems 19.1 Introduction 19.2 Oral MR Technologies and Drug Delivery Systems 19.2.1 Common oral extended-release systems 19.2.1.1 Matrix systems 19.2.1.1.1 Hydrophobic matrix systems 19.2.1.1.2 Hydrophilic matrix systems 19.2.1.1.3 Modulation of drug release profile 19.2.1.1.3.1 pH-independent drug release 19.2.1.1.3.2 Solubility enhancement 19.2.1.1.3.3 Modification of release kinetics 19.2.1.2 Reservoir polymeric systems 19.2.1.3 Osmotic pump systems 19.2.1.4 Other extended-release systems 19.2.2 Other common oral modified-release systems 19.2.2.1 Enteric release 19.2.2.2 Colonic release 19.2.2.3 Pulsatile release 19.2.2.4 Bimodal release 19.2.3 Materials used for modifying drug release 19.2.3.1 Materials for matrix systems 19.2.3.2 Materials for reservoir systems 19.2.3.3 Materials for osmotic pump systems 19.2.3.4 Materials for delayed rel