DEVELOPING SOLID ORAL DOSAGE FORMS Pharmaceutical Theory & Practice

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✦ Table of Contents

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 release systems
19.3 Rational Design of Modified Release Systems
19.3.1 Identification of the clinical need and definition of the target in vivo product performance
19.3.2 Feasibility study
19.3.3 Selecting the MR system and testing system design
19.3.4 Case studies: impact of drug property and formulation design
19.3.4.1 Case study 1: methylphenidate HCl
19.3.4.2 Case study 2: clarithromycin
19.3.4.3 Case study 3: development compound A
19.3.4.4 Case study 4: development compound B
19.3.4.5 Case study 5: oxybutynin HCl
19.3.4.6 Case study 6: phenylpropanolamine HCl in EOP
19.4 Summary
References
20 Product and Process Development of Solid Oral Dosage Forms
20.1 Introduction
20.2 Development of Solid Dosage Forms
20.2.1 Rational development approach
20.2.2 Integrated formulation and process design
20.2.2.1 Material property consideration
20.2.2.1.1 Physicochemical properties
20.2.2.1.2 Powder and bulk properties
20.2.2.1.3 Biopharmaceutical properties
BCS class I and III compounds
BCS class II and IV compounds
20.2.2.2 Consideration of drug properties in developing a “fit-for-purpose” formulation
20.2.2.3 Product quality and performance considerations
20.2.2.4 Manufacturing considerations
20.2.2.5 Selection of dosage form and production method
20.2.3 Product and process understanding
20.2.4 Process scale-up and optimization
20.3 Technology Transfer
20.3.1 Technology transfer overview
20.3.2 Technology transfer of drug product
20.3.2.1 Technology transfer planning
20.3.2.2 Execution of technology transfer
20.4 Case Studies
20.4.1 Influence of material properties and processing conditions on tablet capping
20.4.2 Understanding formulation design of ER dosage forms of verapamil
20.4.3 Improving process robustness and capability through enhanced process understanding
20.5 Intellectual Property Considerations
20.6 Summary
References
21 Analytical Development and Validation for Solid Oral Dosage Forms
21.1 Analytical Method Development and Validation Strategy
21.2 Category of Analytical Method and Method Development
21.2.1 Identification
21.2.2 Potency assay
21.2.3 Impurities
21.2.4 Dissolution
21.2.5 Blend homogeneity and dosage uniformity
21.2.6 Cleaning test method development
21.2.7 Other analytical techniques
21.3 Analytical Method Validation
21.3.1 Verification of compendial methods
21.3.2 Characterization of reference standard
21.3.3 Stability-indicating method
21.3.4 HPLC coelution peak evaluation
21.3.5 Forced degradation studies (stress studies)
21.3.6 Method validation parameters for chromatographic methods
21.3.6.1 Filter bias
21.3.6.2 System suitability
21.3.6.2.1 Injection repeatability
21.3.6.2.2 Check standard
21.3.6.2.3 Tailing factor
21.3.6.2.4 Theoretical plate number
21.3.6.2.5 System drift
21.3.6.2.6 Resolution
21.3.6.3 Accuracy
21.3.6.4 Precision
21.3.6.4.1 Repeatability
21.3.6.4.2 Intermediate precision
21.3.6.4.3 Reproducibility
21.3.6.5 Linearity
21.3.6.6 Specificity
21.3.6.7 Stability of standard and sample solutions
21.3.6.8 DL and QL
21.3.6.8.1 Visual evaluation
21.3.6.8.2 Signal-to-noise-ratio approach
21.3.6.8.3 Standard deviation of the response and slope approach
21.3.6.9 Robustness
21.3.6.9.1 Robustness on sample preparation
21.3.7 Nonchromatographic method validation
21.3.8 Failure and revalidation
21.3.9 Life cycle management of test procedure
21.4 Method Transfers
21.4.1 Definition
21.4.2 Potency
21.4.3 Related substance assay
21.4.4 Residual solvent assay
21.4.5 Dissolution or release assay
21.5 Case Studies
21.5.1 Case 1
21.5.1.1 Problem
21.5.1.2 Investigation
21.5.2 Case 2
21.5.2.1 Problem
21.5.2.2 Investigation
21.5.2.2.1 Possibility 1
21.5.2.2.2 Possibility 2
21.5.3 Case 3
21.5.3.1 Problem
21.5.3.2 Investigation
21.5.4 Case 4
21.5.4.1 Problem
21.5.4.2 Investigation
21.5.5 Case 5
21.5.5.1 Problem
21.5.5.2 Investigation
21.5.6 Case 6
21.5.6.1 Problem
21.5.6.2 Investigation
21.6 Conclusions
References
22 Statistical Design and Analysis of Long-Term Stability Studies for Drug Products
22.1 Stability Study Objectives
22.2 Regulatory Guidance
22.3 Test Methods and Data Management
22.4 Modeling Instability
22.4.1 Stability study variables
22.4.1.1 Responses
22.4.1.2 Experimental fixed variables
22.4.1.3 Experimental random variables
22.4.1.4 Variable transformations
22.4.1.5 Controlled variables
22.4.2 A statistical model for instability
22.5 Long-Term Stability Study Design
22.5.1 Full and reduced designs
22.5.2 Bracketing
22.5.3 Matrixing
22.5.4 Stability design generation
22.5.4.1 Matrixing on time points only
22.5.4.2 Matrixing on both time points and other variables
22.5.5 Comparing stability designs
22.5.5.1 Review of preliminary statistical concepts
22.5.5.2 Power to detect slope differences
22.5.5.3 Probability of achieving a shelf-life claim
22.5.5.4 Implementation in R
22.6 Determination of Shelf Life
22.6.1 Definition of shelf life
22.6.2 Model pruning
22.6.2.1 Simple ANCOVA for the fixed batch case
22.6.2.2 Model pruning for more complex studies
22.6.3 Simple fixed batch case
22.6.4 Simple random batch case
22.6.5 Shelf-life estimation in more complex studies
22.7 Release Limit Estimation
22.8 Probability of Future OOS Stability Test Results
22.8.1 Random batch model for prediction
22.8.2 Prior distributions for model parameters
22.8.3 Predicted quantities of interest
22.8.4 Implementation in WinBUGS
22.8.4.1 Model
22.8.4.2 Data
22.8.4.3 Initial values
22.8.4.4 Burn-in period, sample size, and convergence verification
22.8.5 Results
22.8.6 Bayesian prediction using SAS proc MIXED
Appendix A Sample Data
References
23 Packaging Selection for Solid Oral Dosage Forms
23.1 Introduction
23.1.1 Definitions
23.1.2 General considerations
23.2 Material Considerations
23.2.1 Containers
23.2.2 Determination of container MVTR
23.2.3 Gas absorbers
23.2.3.1 Desiccants and fillers
23.2.3.2 Oxygen scavenger
23.2.4 Drug products
23.3 Linking Packaging Property With Drug Property
23.3.1 The use of moisture vapor transmission rate per unit product for container comparison
23.3.2 Modeling of moisture uptake by packaged products
23.4 Postapproval Packaging Changes
References
24 Clinical Supplies Manufacture: Strategy, GMP Considerations, and Cleaning Validation
24.1 Introduction
24.2 Strategy of Clinical Supplies Manufacture
24.3 Clinical Plan
24.4 Clinical Supplies Liaison
24.5 Lean Manufacturing
24.6 Cross-Functional Training
24.7 Outsourcing of Manufacturing and Packaging
24.8 New Technology
24.9 GMP Considerations on Manufacturing Clinical Supplies
24.9.1 cGMP considerations
24.9.2 A risk-based approach
24.10 Cleaning Validation and Verification
24.10.1 Cleaning validation versus cleaning verification
24.10.2 Swab test acceptance criteria
24.10.3 Swab selection
24.10.4 Representative surface selection for method validation
24.10.5 Analytical methodologies
24.10.6 Analytical method validation
24.10.6.1 Specificity
24.10.6.2 Detection and quantitation limits
24.10.6.3 Linearity
24.10.6.4 Accuracy and recovery
24.10.6.5 Intermediate precision
24.10.6.6 Range
24.10.6.7 Standard and sample stability
24.11 Case Study
24.11.1 Example
24.11.2 Acceptance criteria
24.12 Summary
Acknowledgments
References
25 Specification Setting and Manufacturing Process Control for Solid Oral Drug Products
25.1 Introduction
25.2 Specifications for the Drug Substance
25.3 Specifications for Clinical Trial Materials
25.3.1 Early development stage (Phases 1 and 2)
25.3.2 Late development stage (Phase 3)
25.4 Specifications for Commercial Drug Products
25.4.1 Product in-house release specifications and regulatory specifications
25.4.2 Product stability and expiration date
25.5 Process Control for Solid Oral Drug Products
25.5.1 In-process material tests and quality attributes
25.5.2 Powder blending uniformity
25.5.3 Statistical methodology for process control
25.5.4 PAT and in-process controls
25.6 Analytical Procedures
25.7 Conclusions
Acknowledgments
References
26 Process Development, Optimization, and Scale-Up: Providing Reliable Powder Flow and Product Uniformity
26.1 Introduction
26.1.1 Introduction to flowability
26.1.2 Introduction to blending
26.1.3 Introduction to segregation
26.2 Common Powder Handling Equipment
26.2.1 Processing steps prior to final blending
26.2.2 Final blending
26.2.2.1 Discharge from a blender or processing vessel
26.2.3 Intermediate bulk containers
26.2.3.1 Transfer from intermediate bulk containers to the press/encapsulator
26.2.3.2 Feed from the press hopper to the die cavity
26.3 Typical Flow and Segregation Concerns
26.3.1 Common flow problems
26.3.2 Flow patterns
26.3.3 Common segregation mechanisms
26.3.3.1 Material properties that affect segregation
26.3.3.2 Sifting segregation
26.3.3.3 Fluidization segregation
26.3.3.4 Dusting segregation
26.4 Measurement of Flow Properties
26.4.1 Cohesive strength tests: preventing arching and ratholing
26.4.1.1 Test methods
26.4.1.2 Calculation of minimum required outlet dimensions to prevent arching (mass flow bin)
26.4.1.3 Calculation of minimum required outlet dimensions to prevent ratholing (funnel flow bin)
26.4.1.4 Wall friction: determining hopper angles for mass flow
26.4.1.5 Calculation of recommended mass flow hopper angles
26.4.2 Bulk density
26.4.3 Permeability
26.4.4 Segregation tests
26.4.4.1 Sifting segregation test method
26.4.4.2 Fluidization segregation test method
26.5 Basic Equipment Design Techniques
26.5.1 Reliable funnel flow design (preventing a rathole)
26.5.2 Reliable mass flow designs for the bin, chute, and press hopper
26.5.3 Minimizing adverse two-phase flow effects
26.5.4 Minimizing segregation in the blender-to-press transfer steps
References
27 Capsules Dosage Form: Formulation and Manufacturing Considerations
27.1 Introduction—Capsules as a Dosage Form
27.2 Gelatin and Capsule Shell Composition
27.2.1 Capsule storage
27.2.2 Gelatin cross-linking during storage
27.2.3 Capsule shell additives
27.2.4 Mad cow disease
27.3 Capsule Shell Manufacturing
27.4 Alternatives to Gelatin
27.5 Hard Shell
27.5.1 Capsule sizes
27.5.2 Use in preclinical and clinical studies
27.5.3 Animal testing
27.6 Capsule Filling
27.6.1 Hand-filling capsules
27.6.2 Liquid filling two-piece capsules
27.6.3 Powder in capsule automated filling
27.6.4 Semiautomatic
27.6.5 Commercial production methods
27.6.5.1 Dosing disk
27.6.5.2 Dosator
27.7 Capsule Formulation Requirements
27.7.1 Flowability
27.7.2 Compressibility and compactability of capsule plugs
27.7.3 Lubricity
27.8 Capsule Formulations
27.8.1 Filler binders
27.8.2 Disintegrants
27.8.3 Lubricants and flow aids
27.8.4 Surfactants
References
28 Design, Development, and Scale-Up of the High-Shear Wet Granulation Process
28.1 Introduction
28.2 Rate Processes in Wet Granulation
28.2.1 Liquid distribution and nucleation
28.2.2 Consolidation
28.2.3 Coalescence and growth
28.2.4 Attrition and breakage
28.3 Material Properties in Wet Granulation
28.3.1 Powder properties
28.3.1.1 Particle size
28.3.1.2 Surface area
28.3.1.3 Contact angle
28.3.1.4 Solubility
28.3.2 Granulating liquid properties
28.3.2.1 Viscosity
28.3.2.2 Surface tension
28.4 Design of the Pharmaceutical Wet Granulation Process
28.4.1 Impeller and chopper speeds
28.4.2 Amount of granulating liquid
28.4.3 Process duration
28.5 Quality Attributes of Wet Granulated Products
28.5.1 Solid state form
28.5.2 Chemical stability
28.5.3 Dissolution and bioavailability
28.5.4 Compaction and flow properties
28.6 Scale-Up of the High-Shear Wet Granulation Process
28.6.1 Challenges in scale-up of high-shear wet granulation
28.6.2 Scale-up principles
28.6.2.1 Parameter-based process scale-up strategies
28.6.2.1.1 Water Amount
28.6.2.1.2 Impeller Speed
28.6.2.1.3 Wet Massing Time
28.6.2.1.4 Spray-related Parameters
28.6.2.2 Attribute-based process scale-up: granulation endpoint
28.7 Modeling and Simulation in High-Shear Wet Granulation
28.7.1 Population balance modeling
28.7.2 Discrete element modeling
28.7.3 Combined PBM/DEM approach
28.8 Summary
References
29 Process Development, Optimization, and Scale-Up: Fluid-Bed Granulation
29.1 Overview of the Fluid-Bed Granulation Process
29.2 Equipment Design
29.2.1 Batchwise models
29.2.1.1 Top spray
29.2.1.2 Bottom spray
29.2.1.3 Tangential spray
29.2.2 Semicontinuous design
29.2.3 Continuous models
29.3 Fluid-Bed Hydrodynamics
29.3.1 Product temperature and moisture content profiles through fluid-bed processing
29.3.2 Moisture mass balance during the fluid-bed process
29.3.2.1 Drying process
29.3.2.2 Wet-granulation process
29.3.2.3 Prediction of moisture profile during the fluid-bed process
29.4 Mechanisms of Agglomeration
29.4.1 Phases in granule growth
29.4.2 Bonding mechanisms
29.5 Formulation and Process Variables and Their Control
29.5.1 Formulation variables
29.5.2 Key process variables
29.5.2.1 Inlet air conditions
29.5.2.2 Spray rate, droplet size, and spray pattern
29.5.3 Granule growth under drier conditions (low moisture content of wet granules during the granulation process)
29.5.4 Granule growth under wetter conditions (high moisture content of wet granules)
29.6 Scale-Up Considerations
29.6.1 Batch size and equipment selection
29.6.2 Spray rate scale-up
29.6.3 Rotary disk speed scale-up
29.6.4 Rational scale-up
29.6.5 Scale-up via semicontinuous (batch-continuous) processing
29.6.6 Scale-up via continuous processing
29.7 Application of Quality-by-Design to Fluid-Bed Granulation
29.8 Summary
References
30 Formulation, Process Development, and Scale-Up: Spray-Drying Amorphous Solid Dispersions for Insoluble Drugs
30.1 Introduction
30.2 Background
30.2.1 Background: assessment of ASD applicability
30.2.2 SDD key considerations
30.3 SDD Formulation Composition
30.3.1 API properties
30.3.2 Polymer choice
30.3.3 Additional excipients
30.3.4 Drug loading
30.3.5 Spray solvent
30.4 SDD Process Considerations: Manufacturing and Scale-Up
30.4.1 Spray-solution preparation and considerations
30.4.2 Warm and hot spray drying processes
30.4.3 Atomization and drying of spray solutions
30.4.3.1 Atomization
30.4.3.2 Drying
30.4.3.3 Scale-up considerations
30.4.3.3.1 Atomization
30.4.3.3.2 Product accumulation
30.4.3.3.3 Bearding
30.4.3.3.4 Condensation
30.4.4 Secondary drying
30.4.5 SDD process and impact on bulk material properties
30.4.6 Scale-up considerations
30.5 SDD Characterization
30.5.1 Physical characteristics
30.5.2 Speciation testing
30.5.3 In vitro dissolution testing
30.5.4 Physical/chemical stability during storage as suspension or powder
30.6 Dosage Form Considerations
30.6.1 Aqueous SDD suspension formulations
30.6.2 Solid dosage forms
30.6.3 Effect of formulation and process on performance (physical, chemical, dissolution)
30.7 Concluding Remarks
References
31 Process Development and Scale-Up: Twin-Screw Extrusion
31.1 Introduction
31.2 Twin-Screw Extruder and Extrusion Process
31.2.1 Extruder design and components
31.2.1.1 Barrels
31.2.1.2 Screw elements
31.2.1.2.1 Conveying screws
31.2.1.2.2 Mixing screws
31.2.1.3 Dies
31.2.1.4 Auxiliary systems
31.2.2 Extrusion process design
31.2.2.1 Feed rate
31.2.2.2 Screw speed
31.2.2.3 Barrel temperature
31.3 Hot-Melt Extrusion
31.3.1 Formation mechanisms of ASD
31.3.2 ASD formulation consideration
31.3.2.1 Polymer selection consideration
31.3.2.2 Plasticizer and surfactant selection considerations
31.3.3 HME process consideration
31.4 Continuous Granulation Using a Twin-Screw Extruder
31.4.1 Continuous wet granulation
31.4.1.1 Granulation mechanism inside extruder
31.4.1.2 Effect of screw design on granulation
31.4.1.2.1 Conveying
31.4.1.2.2 Kneading element
31.4.1.2.3 DMEs
31.4.1.2.4 Screw mixing element
31.4.1.2.5 Screw configuration
31.4.1.3 Effect of extrusion process parameters on granulation
31.4.2 Continuous melt granulation
31.4.3 Scale-up/scale-down considerations
31.4.4 Modeling of continuous granulation
31.5 Process Scale-Up
31.5.1 Extrusion process scale-up
31.5.1.1 Geometric similarity
31.5.1.2 Classic scale-up strategies
31.5.1.2.1 Volumetric scale-up
31.5.1.2.2 Power scale-up
31.5.1.2.3 Heat transfer scale-up
31.5.1.2.4 Simulation-assisted scale-up strategies
31.5.2 Product and process understanding, control strategy, and PAT
31.6 Case Studies
31.6.1 Improving oral absorption of BCS class II drugs
31.6.2 Improving processing characteristics through modification of API surface
31.6.3 Continuous granulation for manufacturing extended-release tablets using a twin-screw extruder
31.6.4 Extended-release opioid tablets with abuse-deterrent properties
31.7 Summary
References
32 Development, Scale-Up, and Optimization of Process Parameters: Roller Compaction Theory and Practice
32.1 Introduction
32.1.1 Overview of roller compaction materials and operation
32.1.1.1 Material considerations
32.1.1.2 Key operating parameters and product attributes
32.1.1.2.1 Ribbon solid fraction
32.1.1.2.2 Ribbon tensile strength
32.1.1.2.3 Roll gap and ribbon thickness
32.1.1.3 Operating principles
32.1.1.4 Roller compaction equipment design
32.2 In-Process Analytical Characterization Tools
32.2.1 Instrumented roll
32.2.1.1 Mechanistic understanding
32.2.1.2 Modeling contributions using instrumented roll
32.2.2 Uniaxial compaction to simulate roller compaction
32.2.3 Density characterization tools
32.2.3.1 Envelope density analyzer
32.2.3.2 Arc punch
32.2.3.3 Laser profilometer
32.2.4 Ribbon strength characterization
32.2.4.1 Three-point bending flexural test
32.2.5 Process analytical technology tools
32.3 Roller Compaction Models
32.3.1 Johanson’s rolling theory for granular solids
32.3.2 Modified approaches to Johanson’s theory
32.3.2.1 Johanson’s model comparisons with experimental data (instrumented roll)
32.3.3 Slab analysis
32.3.3.1 Slab model comparisons with experimental data (instrumented roll)
32.3.4 Finite element method
32.3.4.1 Comparison of FEM to Johanson’s theory
32.3.5 Neural networks and other artificial intelligence approaches
32.4 Approaches to Developing a Roller Compaction Process
32.4.1 Material assessment: appropriateness for roller compaction
32.4.1.1 Roll selection
32.4.1.2 Optimizing roller compaction parameters: targeting a ribbon solid fraction
32.4.1.3 Optimizing roller compaction parameters: establishing the design space
32.4.1.4 Output characterization
32.5 Illustrative Example Detailing the Typical Drug Product Development Process for a Roller Compacted Product
32.5.1 Selection of rolls
32.5.1.1 Experimental set-up
32.5.1.2 Outcome
32.5.2 Selection of operating parameters
32.5.2.1 Experimental set-up
32.5.2.2 Outcome
32.6 Scale-Up Considerations of Roller Compaction
32.7 Illustrative Example Detailing a Possible Approach to Scaling-Up a Roller Compaction Process
32.7.1 Experimental design
32.7.2 Results
32.8 Trouble-Shooting
32.9 Conclusions
References
33 Development, Optimization, and Scale-Up of Process Parameters: Tablet Compression
33.1 Introduction
33.2 Operation Principles of Compression by Rotary Press
33.3 Tool Design
33.3.1 Terminology
33.3.2 Common tooling standards
33.3.3 EU, TSM, B, and D type punches
33.3.4 Recent innovations
33.3.5 Cup depth, overall length, and working length
33.3.6 Tooling options
33.3.6.1 Common tooling options
33.3.6.1.1 Domed heads
33.3.6.1.2 Punch head flats
33.3.6.1.3 Rotating heads
33.3.6.1.4 Mirror-finished heads
33.3.6.1.5 Bakelite relief and double-deep relief
33.3.6.1.6 Short lower punch tip straight
33.3.6.1.7 Punch-barrel chamfers
33.3.6.1.8 Key types and positions
33.3.7 Tool configuration for small and micro tablets
33.3.8 Tapered dies
33.4 Tablet Designs
33.4.1 Tablet shapes
33.4.2 Tablet face configurations
33.4.3 Undesirable shapes
33.4.4 Tablet identification
33.4.5 Bisects
33.4.6 Steel types
33.4.7 Inserted dies
33.4.8 Multitip tooling
33.4.9 Punch-tip pressure guide
33.5 Care of Punches and Dies
33.6 Tooling Inspection
33.7 Tooling Reworking
33.8 Press Wear
33.9 Purchasing Tablet Compression Tooling
33.10 Consideration of Tooling
33.11 Application of Quality by Design and Tools (Case Study)
33.11.1 Objective
33.11.2 Methods
33.11.3 DOE design
33.11.4 Results
33.11.5 Conclusions
33.11.6 Application of britest tool in troubleshooting
33.12 Scale-Up of Compression
33.12.1 Compaction and compression
33.12.2 Tableting failure
33.12.3 Main factors of tableting
33.12.4 Compaction event
33.12.5 Tableting time definitions
33.12.6 Dwell time and contact time
33.12.7 Tableting geometry
33.12.8 Tableting scale-up
References
34 Development, Optimization, and Scale-Up of Process Parameters: Pan Coating
34.1 Introduction
34.1.1 The basis of film coating
34.1.2 Evolution of pharmaceutical-coating technology development
34.1.3 Coating equipment introduction
34.2 Film-Coating Formulations
34.2.1 Overview of types of film-coating formulations
34.2.2 Overview of types of materials used in film-coating formulations
34.2.2.1 Polymers
34.2.2.2 Plasticizers
34.2.2.3 Colorants
34.2.2.4 Other additives
34.2.2.5 Solvents/vehicles
34.2.3 Film-coating formulations used for immediate-release applications
34.2.3.1 Characteristics of polymers used
34.2.3.2 Examples of types of polymers used
34.2.3.2.1 Cellulosic polymers
34.2.3.2.2 Vinyl pyrrolidone polymers
34.2.3.2.3 Vinyl alcohol polymers
34.2.3.2.4 Acrylic polymers
34.2.3.3 Formulation strategies used
34.2.4 Film coatings used for modified-release applications
34.2.4.1 Delayed-release (enteric) coatings
34.2.4.2 Extended-release coatings
34.3 Design and Development of Film-Coating Processes
34.3.1 General introduction to coating processes and equipment
34.3.1.1 Overview
34.3.2 Batch coating systems
34.3.3 Continuous-coating systems
34.3.4 System components
34.3.4.1 Overview
34.3.4.2 Pan units
34.3.4.2.1 Comparison of batch-type coating pans
34.3.4.2.2 Comparison of continuous-coating equipment
34.3.4.3 Process air equipment
34.3.4.4 Spray systems
34.3.4.4.1 Comparison of different spray guns
34.3.4.4.2 Pneumatic spray guns
34.3.4.4.3 Hydraulic spray guns
34.3.4.4.4 Solution delivery pump
34.3.4.4.5 Delivery control
34.3.4.4.6 System controls
34.3.5 General characteristics of the pharmaceutical coating process
34.3.5.1 Typical process steps
34.3.5.1.1 Coating pan set-up
34.3.5.1.2 Loading/charging
34.3.5.1.3 Preheat/de-dusting
34.3.5.1.4 Application of a seal/barrier coat
34.3.5.1.5 Application of the film coating
34.3.5.1.6 Gloss coat
34.3.5.1.7 Wax addition
34.3.5.1.8 Product discharge
34.3.6 Understanding process thermodynamics
34.3.6.1 Adequate evaporative rate
34.3.6.2 Process air
34.3.6.2.1 Volume
34.3.6.2.2 Humidity
34.3.6.2.3 Temperatures
34.3.7 Understanding spray dynamics
34.3.7.1 Spray rate
34.3.7.2 Droplet size distribution
34.3.7.3 Coating zone/pattern
34.3.7.4 Coating analysis
34.3.8 Controlling coating processes—critical factors
34.3.8.1 Uniformity of the spray application
34.3.8.1.1 Spray gun design
34.3.8.1.2 Number of spray guns
34.3.8.1.3 Uniform gun-to-gun solution delivery
34.3.8.1.4 Atomization air volume/droplet size
34.3.8.1.5 Spray gun angle
34.3.8.2 Uniformity of product movement
34.3.8.2.1 Pan speed
34.3.8.2.2 Tablet size and shape
34.3.8.2.3 Baffle type/size/number
34.3.8.2.4 Batch size
34.3.8.3 Adequate evaporative capacity
34.3.8.3.1 Process air volume
34.3.8.3.2 Spray rate
34.3.8.3.3 Spray gun-to-tablet-bed distance
34.3.8.3.4 Product/exhaust temperature
34.3.8.3.5 Dew-point temperature
34.3.9 Scale-up
34.3.9.1 Batch size
34.3.9.2 Pan speed (angular pan velocity)
34.3.9.3 Available coating zone
34.3.9.4 Spray-rate-to-pan-speed ratio
34.3.9.5 Airflow-to-spray ratio
34.4 Troubleshooting
34.4.1 Introduction to troubleshooting
34.4.2 Up-front approaches to avoid troubleshooting issues
34.5 Consideration of Product Substrate
34.5.1 Hardness/friability
34.5.2 Weight variation
34.5.3 Stability
34.5.4 Compatibility
34.5.5 Shape
34.5.6 Logo design
34.5.7 Core porosity
34.5.8 Disintegration/dissolution
34.6 Coating Formulation
34.6.1 Film mechanical strength
34.6.2 Plasticizer level
34.6.3 Pigment level
34.6.4 Film solution solids
34.6.5 Solution viscosity
34.6.6 Stability
34.6.7 Compatibility
34.6.8 Processing issues as they relate to troubleshooting
34.6.8.1 Equipment maintenance issues
34.6.8.2 Process adjustment as a troubleshooting initiative
34.6.9 Troubleshooting: summary
34.6.10 Film-coating defects/troubleshooting—summary
34.7 Application of Systematic and Statistical Tools for Trouble Shooting and Process Optimization
References
35 Development, Optimization, and Scale-Up of Process Parameters: Wurster Coating
35.1 Introduction
35.2 Basic Design
35.3 HS Wurster Considerations
35.4 Coating and Process Characteristics
35.5 Processing Examples
35.6 Process Variables
35.6.1 Batch size
35.6.2 Fluidization pattern
35.6.3 Atomizing air pressure and volume
35.6.4 Nozzle port size
35.6.5 Evaporation rate
35.6.6 Product temperature
35.7 Case Studies for Layering and Fine Particle Coating
35.8 Scale-Up of Wurster Processing
35.8.1 Batch size
35.8.2 Spray rate
35.8.3 Droplet size and nozzle considerations
35.8.4 Process air volume
35.8.5 Process air and product temperatures
35.8.6 Mass effects
35.9 Summary
36 Commercial Manufacturing and Product Quality
36.1 Introduction
36.2 Process Design, Understanding, and Control Strategy Development
36.3 Process Scale-up, Technology Transfer, and Process Qualification
36.3.1 Design of a facility and qualification of utilities and equipment
36.3.2 Number of PPQ batches
36.3.3 Heightened level of monitoring and testing to demonstrate intra- and inter-batch consistency
36.4 Continued Process Verification
36.4.1 Process monitoring program
36.4.2 Tools for process monitoring
36.4.2.1 Using control chart to evaluate if the process is in-control
36.4.2.2 Using process capability and process performance indices to evaluate if the process is capable
36.4.3 Continual improvement
36.4.4 Illustrative Example-1: monitoring key excipient material variability of an extended release tablets and continual i...
36.4.5 Illustrative Example-2: using PAT and RTRT to monitor and control traditional batch manufacturing process
36.4.6 Illustrative Example-3: using PAT and RTRT to monitor and control a continuous manufacturing process
36.5 Summary
References
37 Emerging Technology for Modernizing Pharmaceutical Production: Continuous Manufacturing
37.1 Introduction
37.2 Challenges for Pharmaceutical Manufacturing
37.3 The Adoption of Emerging Technology to Address Pharmaceutical Manufacturing Challenges
37.4 Technologies for Continuous Drug Product Manufacturing
37.4.1 Feeding
37.4.2 Blending
37.4.3 Granulation
37.4.3.1 Wet granulation
37.4.3.2 Dry granulation
37.4.4 Particle size reduction
37.4.5 Compression
37.4.6 Coating
37.4.7 Emerging technologies for continuous drug product production
37.4.8 Process integration
37.4.9 Process monitoring and control
37.5 Challenges in Implementing Continuous Manufacturing
37.6 Conclusion
References
IV. Regulatory Aspects of Product Development
38 Drug Product Approval in the United States and International Harmonization
38.1 Drug Product Approval and the US Food and Drug Administration
38.1.1 History and background of drug regulations in the United States
38.1.2 Current organization of the FDA
38.1.3 Center for Drug Evaluation and Research (CDER) organization
38.1.4 Pharmaceutical quality oversight
38.1.5 New review initiatives
38.1.5.1 Team-based integrated quality assessment
38.1.5.2 Question-based review (QbR)
38.1.5.3 Emerging technologies
38.1.6 Current drug approval overview
38.2 The New Drug Application Process
38.2.1 INDs and presubmission of NDAs
38.2.2 Format and content of the NDA
38.2.3 The CTD format
38.2.4 NDA review practices
38.2.4.1 Filing
38.2.4.2 Review
38.2.4.3 Labeling
38.2.4.4 FDA-sponsor communications during NDA review
38.2.4.5 Advisory committee
38.2.5 Special approval pathways for NDAs/BLAs
38.2.5.1 Expedited approval pathways
38.2.5.2 Orphan drug designation program
38.2.5.3 Pediatric exclusivity
38.3 The Abbreviated New Drug Application Process
38.3.1 Format and content of the ANDA
38.3.2 The CTD format of an ANDA
38.3.3 ANDA review practices
38.3.3.1 Filing
38.3.3.2 Review
38.3.4 Special considerations for ANDAs
38.3.4.1 ANDA filing and market exclusivity
38.3.4.2 Drug master files (DMFs)
38.4 The Biologic License Application Process
38.4.1 Format and content of the BLA
38.4.2 BLA review practices
38.4.3 Special considerations for BLAs
38.4.3.1 Biosimilars
38.4.3.2 Biosimilars and market exclusivity
38.4.3.3 BPCI act and protein products under NDA
38.5 Postapproval Activities and Life Cycle Management of NDAs, ANDAs, and BLAs
38.5.1 Prior-approval Supplements
38.5.2 Changes being effected (CBE-30 and CBE-0 supplements)
38.5.3 Annual reports
38.5.4 Supplements to BLAs
38.6 Global Perspectives on Product Registration and Drug Approval
38.6.1 ICH harmonization in drug marketing submissions: the CTD format
38.6.2 EMA and comparison to FDA
Acknowledgments
References
39 Modern Pharmaceutical Regulations: Quality Assessment for Drug Substances
39.1 Introduction
39.2 Origin of the QbR
39.3 Evolution of the Drug Substance Review Process
39.4 Quality Assessment for Drug Substances
39.5 Conclusion
Appendix QbR Questions—Drug Substance
References
40 Modern Pharmaceutical Regulations: Quality Assessment for Drug Products
40.1 Introduction
40.2 QbR History
40.3 Current Status of QbR
40.4 QbR Questions
40.5 Future Direction
40.6 Conclusions
Appendix: QbR Questions
References
Index
Back Cover