- ホーム
- > 洋書
- > 英文書
- > Science / Mathematics
Full Description
Updated and expanded information on the properties of pharmaceutical solids and their impact on drug product performance, quality, and stability
Solid-State Materials in Pharmaceutical Chemistry provides readers with a comprehensive and up-to-date resource for understanding and controlling the solid-state properties of pharmaceutical materials, enabling the development of safe and effective medicines including small molecule compounds, peptides, proteins, and nucleotides. This new edition covers the significant transformations in the landscape of pharmaceutical research, development, and manufacturing since the previous edition was published, presenting both novel challenges and unprecedented opportunities.
New chapters in this edition cover physical and chemical properties of RNA therapeutics, a frontier to many life-saving medicines and vaccines including Covid vaccines, and final stage drug substance manufacturing and control, addressing challenges in API process development including impurity purging, chiral separation, final form preparation, particle size reduction, and nitrosamine control. Readers will also find other updated topics including bulk and surface properties of solids, lipid nanoparticles, applications of pharmaceutical solvates in impurity purging and final form preparation, pharmaceutical cocrystal engineering to enable chiral separation, the emerging technique of microcrystal electron diffraction in solid form characterization, poor wettability of APIs, oral delivery of peptides such as semaglutide, injectable drug-device combination products, and N-nitrosamine control in drug product.
This updated and revised Second Edition still features:
Physical and chemical properties of solid-state pharmaceuticals such as amorphous forms, mesophases, polymorphs, hydrates/solvates, salts, co-crystals, nano-particles, and solid dispersions
Characterization techniques for solid form identification and physical attribute analysis such as X-Ray powder diffraction, thermal analysis, microscopy, spectroscopy, solid state NMR, particle analysis, water sorption, mechanical property testing, solubility, and dissolution
Applications of pharmaceutical chemistry and physical characterization techniques in developing and testing drug substances and drug products for small molecules and biopharmaceuticals
This book is an essential resource on the subject for formulation scientists, process chemists, medicinal chemists, and analytical chemists. The book will also appeal to quality control, quality assurance, and regulatory affair specialists and advanced undergraduate and graduate students in pharmaceutical chemistry, drug delivery, material science, crystal engineering, pharmaceutics, and biopharmaceutics.
Contents
Table of Contents
Chapter 1 Solid-State Properties and Pharmaceutical Development
1.1 Introduction
1.2 Solid-State Forms
1.3 Bulk and Surface Properties of Solids
1.4 ICH Q6A Decision Trees
1.5 "Big Questions" for Drug Development
1.6 Accelerating Drug Development
1.7 Solid-State Chemistry in Preformulation and Formulation
1.8 Solid-Lipid Nanoparticles
1.9 Learning Before Doing and Quality by Design
1.10 Performance and Stability in Pharmaceutical Development
1.11 Moisture Uptake
1.12 Solid-State Reactions
1.13 Noninteracting Formulations - Physical Characterizations
Chapter 2 Polymorphs
2.1 Introduction
2.2 How are Polymorphs Formed?
2.3 Structure Aspect of Polymorphs
2.4 Physical, Chemical, and Mechanical Properties
2.5 Thermodynamic Stability of Polymorphs
2.6 Polymorph Conversion
2.7 Control of Polymorphs
2.8 Polymorph Screening
2.9 Polymorph Prediction
Chapter 3 Pseudopolymorphs: Hydrates and Solvates
3.1 Introduction
3.2 Pharmaceutical Importance of Hydrates
3.3 Classification of Pharmaceutical Hydrates
3.4 Water Activity
3.5 Stoichiometric Hydrates
3.6 Nonstoichiometric Hydrates
3.7 Emerging Interests in Organic Solvates
3.8 Isostructural Solvates
3.9 Dehydration and Desolvation
3.10 Preparation and Characterization of Hydrates and Solvates
Chapter 4 Pharmaceutical Salts
4.1 Introduction
4.2 Importance of Pharmaceutical Salts
4.3 Weak Acid, Weak Base, and Salt
4.4 pH-Solubility Profiles of Ionizable Compounds
4.5 Solubility, Dissolution, and Bioavailability of Pharmaceutical Salts
4.6 Physical Stability of Pharmaceutical Salts
4.7 Strategies for Salt Selection
Chapter 5 Pharmaceutical Cocrystals
5.1 Introduction
5.2 Cocrystals and Crystal Engineering
5.3 Solubility Phase Diagram for Cocrystals
5.4 Preparation of Cocrystals
5.5 Dissolution and Bioavailability of Cocrystals
5.6 Pharmaceutical Applications of Cocrystals
5.7 Comparison of Pharmaceutical Salts and Cocrystals
Chapter 6 Amorphous Solids
6.1 Introduction
6.2 The Formation of Amorphous Solids
6.3 Methods of Preparing Amorphous Solids
6.4 The Glass Transition Temperature
6.5 Structural Features of Amorphous Solids
6.6 Molecular Mobility
6.7 Mixtures of Amorphous Solids
Chapter 7 Crystal Mesophases and Nanocrystals
7.1 Introduction
7.2 Overview of Crystal Mesophases
7.3 Liquid Crystals
7.4 Conformationally Disordered (Condis) Crystals
7.5 Plastic Crystals
7.6 Nanocrystals
Chapter 8 X-Ray Crystallography and Crystal Packing Analysis
8.1 Introduction
8.2 Crystals
8.3 Miller Indices and Crystal Faces
8.4 Determination of the Miller Indices of the Faces of a Crystal
8.5 Determination of Crystal Structures
Chapter 9 X-Ray Powder Diffraction
9.1 Introduction
9.2 X-Ray Powder Diffraction of Crystalline Materials
9.3 Qualitative Analysis of Crystalline Materials
9.4 Phase Transformations
9.5 Quantitative Phase Analysis Using XRPD
9.6 Solving Crystal Structures using X-Ray Powder Diffraction
9.7 X-Ray Diffraction of Amorphous and Crystal Mesophases Forms
9.8 Pair Distribution Function
9.9 X-Ray Diffractometers
9.10 Variable Temperature XRPD
Chapter 10 Differential Scanning Calorimetry and Thermogravimetric Analysis
10.1 Introduction
10.2 The Basics of Differential Scanning Calorimetry
10.3 Thermal Transitions of Pharmaceutical Materials
10.4 DSC Instrumentation
10.5 Thermogravimetric Analysis
10.6 Operating a TGA Instrument
10.7 Evolved Gas Analysis
10.8 Applications of DSC and TGA
10.9 Summary of Using DSC and TGA
Chapter 11 Microscopy
11.1 Introduction
11.2 Light Microscopy
11.3 Polarized Light Microscopy
11.4 Thermal Microscopy
11.5 Functionality of Light Microscopy
11.6 Digital Microscope
11.7 Application of Light Microscopy to Pharmaceutical Materials
11.8 Scanning Electron Microscope
11.9 Environmental Scanning Electron Microscopy
11.10 Transmission Electron Microscopy and Electron Diffraction
11.11 Atomic Force Microscopy
Chapter 12 Vibrational Spectroscopy
12.1 Introduction
12.2 The Nature of Molecular Vibrations
12.3 Fourier Transformed Infrared Spectroscopy
12.4 Material Characterization by FT-IR Spectroscopy
12.5 FT-IR Instrumentation
12.6 Diffuse Reflectance FT-IR
12.7 Attenuated Total Reflectance FT-IR
12.8 FT-IR Microscopy
12.9 Near Infrared Spectroscopy
12.10 Raman Spectroscopy
12.11 Raman Instrumentation and Sampling
12.12 Raman Microscopy
12.13 Terahertz Spectroscopy
12.14 Comparison of FT-IR, NIR, Raman, and Terahertz Spectroscopy
Chapter 13 Solid-State NMR Spectroscopy
13.1 Introduction
13.2 An Overview of Solid-State 13C CP/MAS NMR Spectroscopy
13.3 Solid-State NMR Studies of Pharmaceuticals
13.4 Phase Identification in Dosage Forms
13.5 Other Basic Solid-State NMR Experiments Useful for Pharmaceutical Analysis
13.6 Determination of the Domain Structure of Amorphous Dispersions Using Solid-State NMR
13.7 Solid-State NMR of Amorphous Materials
13.8 Summary
Chapter 14 Particle and Powder Analysis
14.1 Introduction
14.2 Particles in Pharmaceutical Systems
14.3 Particle Size and Shape
14.4 Particle Size Distribution
14.5 Dynamic Light Scattering
14.6 Zeta Potential
14.7 Laser Diffraction
14.8 Acoustic Spectroscopy
14.9 Dynamic Image Analysis
14.10 Sieve Analysis
14.11 Bulk Properties of Pharmaceutical Particulates and Powders
14.12 Surface Area Measurement
Chapter 15 Hygroscopic Properties of Solids
15.1 Introduction
15.2 Water Vapor Sorption-Desorption
15.3 Water Vapor Sorption Isotherms, Relative Humidity, and Water Activity
15.4 Measurement of Water Content and Water Vapor Sorption/Desorption Isotherms
15.5 Modes of Water Vapor Sorption
Chapter 16 Mechanical Properties of Pharmaceutical Materials
16.1 Introduction
16.2 Stress and Strain
16.3 Elasticity
16.4 Plasticity
16.5 Viscoelasticity
16.6 Brittleness
16.7 Hardness
16.8 Powder Compression
16.9 Powder Compression Models and Compressibility
16.10 Compatibility and Tensile Strength
16.11 Effect of Solid Form on Mechanical Properties
16.12 Effect of Moisture on Mechanical Properties
16.13 Methods for Testing Mechanical Properties
Chapter 17 Solubility and Dissolution
17.1 Introduction
17.2 Principal Concepts Associated with Solubility
17.3 Prediction of Aqueous Drug Solubility
17.4 Solubility of Pharmaceutical Solid Forms
17.5 Solubility Determination Using the Shake Flask Method
17.6 High Throughput Screening of Solubility
17.7 Solubility Measurement of Metastable Forms
17.8 Kinetic Solubility Measurement
17.9 Solubility Determination of Drugs in Polymer Matrices
17.10 Dissolution Testing
17.11 Nonsink Dissolution Test
17.12 Biorelevant Dissolution Test
17.13 Intrinsic Dissolution Studies
17.14 Summary
Chapter 18 Physical Stability of Solids
18.1 Introduction
18.2 Underlying Basis for Physical Instability in Pharmaceutical Systems
18.3 Disorder in Crystals
18.4 Quantitative Determination of Partially Amorphous Material in Crystals
18.5 Phase Transformation
18.6 Examples of the Role of Process-Induced Disorder in Solid-State Physical Instability in Pharmaceutical Systems
18.7 Poor Wettability of Solids During Dosage Form Processing and Administration
18.8 Considerations inEvaluating Solid-State Physical Stability
Chapter 19 Chemical Stability of Solids
19.1 Introduction
19.2 Examples of Chemical Reactivity in the Solid State
19.3 Some General Principles that Establish the Rate of Chemical Reactions in Solution
19.4 Some General Principles Governing the Rates of Solid-State Reactions
19.5 The Role of Crystal Defects in Solid-State Reactions
19.6 Chemical Reactivity in the Amorphous Solid State
19.7 Chemical Reactivity and Process-Induced Disorder
19.8 The Effects of Residual Water on Solid-State Chemical Reactivity
19.9 Drug-Excipient Interactions
19.10 Summary
Chapter 20 Solid-State Properties of Proteins
20.1 Introduction
20.2 Solution Properties of Proteins
20.3 Amorphous Properties of Proteins
20.4 Crystalline Properties of Proteins
20.5 Local Molecular Motions and Dynamical Transitional Temperature, Td
20.6 Solid-State Physical and Chemical Stability of Proteins
20.7 Cryoprotection and Lyoprotection
Chapter 21 Physical and Chemical Properties of RNA Therapeutics
21.1 Introduction
21.2 Mode of Action
21.3 Building Blocks and Primary Structure
21.4 RNA Structure in Solution
21.5 RNA Stability in Solution
21.6 Solid-State Properties
21.7 Pharmaceutical Development
21.8 Summary
Chapter 22 Solid Form Selection of Active Pharmaceutical Ingredients
22.1 Introduction
22.2 Solid Form Selection
22.3 Amorphous Form Screening
22.4 Salt Selection
22.5 Cocrystal Screening
22.6 Polymorph Screening
22.7 Slurrying
22.8 High Throughput Screening
22.9 Crystallization in Confined Space
22.10 Nonsolvent-Based Polymorph Screening
22.11 Polymer-Induced Heteronucleation
22.12 Physical Characterization
22.13 Thermodynamic Stability and Solid Form Selection
22.14 Summary
Chapter 23 Final Stage Drug Substance Manufacturing and Control
23.1 Introduction
23.2 Crystallization and Impurity Purge
23.3 Removal of Residual Solvents
23.4 Control of Genotoxic Impurities
23.5 Control of N-Nitrosamines
23.6 Chiral Separation Through Salt and Cocrystal Formation
23.7 Preparation of the Final Solid Form
23.8 Particle Size and Shape Control During Crystallization
23.9 Powder Agglomeration and Caking
23.10 Milling and Micronization
23.11 Impact of Process Impurities on Crystallization
23.12 Summary
Chapter 24 Solid-State Mixture Analysis
24.1 Introduction
24.2 Limitations of Wet Chemistry
24.3 Pharmaceutical Analysis in the Solid State
24.4 Measurement of Amorphous Content
24.5 Detection of Crystallinity
24.6 Quantification of Mixtures of Polymorphs
24.7 Salt and Free Form Composition
24.8 Analysis of Particulate Contaminants in Drug Products
24.9 Process Analytical Technology
24.10 Summary
Chapter 25 Drug Product Development
25.1 Chemistry, Manufacture, and Control
25.2 Preformulation
25.3 Drug Excipient Compatibility
25.4 Solid Dispersions
25.5 Abuse-Deterrent Dosage Forms
25.6 Drug-Eluting Stents
25.7 Dry Powder Inhaler
25.8 Lyophilization and Biopharmaceutical Products
25.9 Oral Delivery of Peptides
25.10 Injectable Drug-Device Combination Products
25.11 Control of N-Nitrosamine in Drug Product
25.12 Summary
Chapter 26 Quality by Design
26.1 Introduction
26.2 Quality by Design Wheel
26.3 Learning before Doing
26.4 Risk-Based Orientation
26.5 API Attributes and Process Design
26.6 Development and Design Space
26.7 Process Design - Crystallization
26.8 Phase Transformations during Wet Granulation
26.9 Dissolution Tests with an IVIVC for Quality by Design
26.10 SummaryTable of Contents Chapter 1Solid-State Properties and Pharmaceutical Development 1.1Introduction 1.2Solid-State Forms 1.3Bulk and Surface Properties of Solids 1.4ICH Q6A Decision Trees 1.5"Big Questions" for Drug Development 1.6Accelerating Drug Development 1.7Solid-State Chemistry in Preformulation and Formulation 1.8Solid-Lipid Nanoparticles 1.9Learning Before Doing and Quality by Design 1.10Performance and Stability in Pharmaceutical Development 1.11Moisture Uptake 1.12Solid-State Reactions 1.13Noninteracting Formulations - Physical Characterizations Chapter 2Polymorphs 2.1Introduction 2.2How are Polymorphs Formed? 2.3Structure Aspect of Polymorphs 2.4Physical, Chemical, and Mechanical Properties 2.5Thermodynamic Stability of Polymorphs 2.6Polymorph Conversion 2.7Control of Polymorphs 2.8Polymorph Screening 2.9Polymorph Prediction Chapter 3Pseudopolymorphs: Hydrates and Solvates 3.1Introduction 3.2Pharmaceutical Importance of Hydrates 3.3Classification of Pharmaceutical Hydrates 3.4Water Activity 3.5Stoichiometric Hydrates 3.6Nonstoichiometric Hydrates 3.7Emerging Interests in Organic Solvates 3.8Isostructural Solvates 3.9Dehydration and Desolvation 3.10Preparation and Characterization of Hydrates and Solvates Chapter 4Pharmaceutical Salts 4.1Introduction 4.2Importance of Pharmaceutical Salts 4.3Weak Acid, Weak Base, and Salt 4.4pH-Solubility Profiles of Ionizable Compounds 4.5Solubility, Dissolution, and Bioavailability of Pharmaceutical Salts 4.6Physical Stability of Pharmaceutical Salts 4.7Strategies for Salt Selection Chapter 5Pharmaceutical Cocrystals 5.1Introduction 5.2Cocrystals and Crystal Engineering 5.3Solubility Phase Diagram for Cocrystals 5.4Preparation of Cocrystals 5.5Dissolution and Bioavailability of Cocrystals 5.6Pharmaceutical Applications of Cocrystals 5.7Comparison of Pharmaceutical Salts and Cocrystals Chapter 6Amorphous Solids 6.1Introduction 6.2The Formation of Amorphous Solids 6.3Methods of Preparing Amorphous Solids 6.4The Glass Transition Temperature 6.5Structural Features of Amorphous Solids 6.6Molecular Mobility 6.7Mixtures of Amorphous Solids Chapter 7Crystal Mesophases and Nanocrystals 7.1Introduction 7.2Overview of Crystal Mesophases 7.3Liquid Crystals 7.4Conformationally Disordered (Condis) Crystals 7.5Plastic Crystals 7.6Nanocrystals Chapter 8X-Ray Crystallography and Crystal Packing Analysis 8.1Introduction 8.2Crystals 8.3Miller Indices and Crystal Faces 8.4Determination of the Miller Indices of the Faces of a Crystal 8.5Determination of Crystal Structures Chapter 9X-Ray Powder Diffraction 9.1Introduction 9.2X-Ray Powder Diffraction of Crystalline Materials 9.3Qualitative Analysis of Crystalline Materials 9.4Phase Transformations 9.5Quantitative Phase Analysis Using XRPD 9.6Solving Crystal Structures using X-Ray Powder Diffraction 9.7X-Ray Diffraction of Amorphous and Crystal Mesophases Forms 9.8Pair Distribution Function 9.9X-Ray Diffractometers 9.10Variable Temperature XRPD Chapter 10Differential Scanning Calorimetry and Thermogravimetric Analysis 10.1Introduction 10.2The Basics of Differential Scanning Calorimetry 10.3Thermal Transitions of Pharmaceutical Materials 10.4DSC Instrumentation 10.5Thermogravimetric Analysis 10.6Operating a TGA Instrument 10.7Evolved Gas Analysis 10.8Applications of DSC and TGA 10.9Summary of Using DSC and TGA Chapter 11Microscopy 11.1Introduction 11.2Light Microscopy 11.3Polarized Light Microscopy 11.4Thermal Microscopy 11.5Functionality of Light Microscopy 11.6Digital Microscope 11.7Application of Light Microscopy to Pharmaceutical Materials 11.8Scanning Electron Microscope 11.9Environmental Scanning Electron Microscopy 11.10Transmission Electron Microscopy and Electron Diffraction 11.11Atomic Force Microscopy Chapter 12Vibrational Spectroscopy 12.1Introduction 12.2The Nature of Molecular Vibrations 12.3Fourier Transformed Infrared Spectroscopy 12.4Material Characterization by FT-IR Spectroscopy 12.5FT-IR Instrumentation 12.6Diffuse Reflectance FT-IR 12.7Attenuated Total Reflectance FT-IR 12.8FT-IR Microscopy 12.9Near Infrared Spectroscopy 12.10Raman Spectroscopy 12.11Raman Instrumentation and Sampling 12.12Raman Microscopy 12.13Terahertz Spectroscopy 12.14Comparison of FT-IR, NIR, Raman, and Terahertz Spectroscopy Chapter 13Solid-State NMR Spectroscopy 13.1Introduction 13.2An Overview of Solid-State 13C CP/MAS NMR Spectroscopy 13.3Solid-State NMR Studies of Pharmaceuticals 13.4Phase Identification in Dosage Forms 13.5Other Basic Solid-State NMR Experiments Useful for Pharmaceutical Analysis 13.6Determination of the Domain Structure of Amorphous Dispersions Using Solid-State NMR 13.7Solid-State NMR of Amorphous Materials 13.8Summary Chapter 14Particle and Powder Analysis 14.1Introduction 14.2Particles in Pharmaceutical Systems 14.3Particle Size and Shape 14.4Particle Size Distribution 14.5Dynamic Light Scattering 14.6Zeta Potential 14.7Laser Diffraction 14.8Acoustic Spectroscopy 14.9Dynamic Image Analysis 14.10Sieve Analysis 14.11Bulk Properties of Pharmaceutical Particulates and Powders 14.12Surface Area Measurement Chapter 15Hygroscopic Properties of Solids 15.1Introduction 15.2Water Vapor Sorption-Desorption 15.3Water Vapor Sorption Isotherms, Relative Humidity, and Water Activity 15.4Measurement of Water Content and Water Vapor Sorption/Desorption Isotherms 15.5Modes of Water Vapor Sorption Chapter 16Mechanical Properties of Pharmaceutical Materials 16.1Introduction 16.2Stress and Strain 16.3Elasticity 16.4Plasticity 16.5Viscoelasticity 16.6Brittleness 16.7Hardness 16.8Powder Compression 16.9Powder Compression Models and Compressibility 16.10Compatibility and Tensile Strength 16.11Effect of Solid Form on Mechanical Properties 16.12Effect of Moisture on Mechanical Properties 16.13Methods for Testing Mechanical Properties Chapter 17Solubility and Dissolution 17.1Introduction 17.2Principal Concepts Associated with Solubility 17.3Prediction of Aqueous Drug Solubility 17.4Solubility of Pharmaceutical Solid Forms 17.5Solubility Determination Using the Shake Flask Method 17.6High Throughput Screening of Solubility 17.7Solubility Measurement of Metastable Forms 17.8Kinetic Solubility Measurement 17.9Solubility Determination of Drugs in Polymer Matrices 17.10Dissolution Testing 17.11Nonsink Dissolution Test 17.12Biorelevant Dissolution Test 17.13Intrinsic Dissolution Studies 17.14Summary Chapter 18Physical Stability of Solids 18.1Introduction 18.2Underlying Basis for Physical Instability in Pharmaceutical Systems 18.3Disorder in Crystals 18.4Quantitative Determination of Partially Amorphous Material in Crystals 18.5Phase Transformation 18.6Examples of the Role of Process-Induced Disorder in Solid-State Physical Instability in Pharmaceutical Systems 18.7Poor Wettability of Solids During Dosage Form Processing and Administration 18.8Considerations in Evaluating Solid-State Physical Stability Chapter 19Chemical Stability of Solids 19.1Introduction 19.2Examples of Chemical Reactivity in the Solid State 19.3Some General Principles that Establish the Rate of Chemical Reactions in Solution 19.4Some General Principles Governing the Rates of Solid-State Reactions 19.5The Role of Crystal Defects in Solid-State Reactions 19.6Chemical Reactivity in the Amorphous Solid State 19.7Chemical Reactivity and Process-Induced Disorder 19.8The Effects of Residual Water on Solid-State Chemical Reactivity 19.9Drug-Excipient Interactions 19.10Summary Chapter 20Solid-State Properties of Proteins 20.1Introduction 20.2Solution Properties of Proteins 20.3Amorphous Properties of Proteins 20.4Crystalline Properties of Proteins 20.5Local Molecular Motions and Dynamical Transitional Temperature, Td 20.6Solid-State Physical and Chemical Stability of Proteins 20.7Cryoprotection and Lyoprotection Chapter 21Physical and Chemical Properties of RNA Therapeutics 21.1Introduction 21.2Mode of Action 21.3Building Blocks and Primary Structure 21.4RNA Structure in Solution 21.5RNA Stability in Solution 21.6Solid-State Properties 21.7Pharmaceutical Development 21.8Summary Chapter 22 Solid Form Selection of Active Pharmaceutical Ingredients 22.1Introduction 22.2Solid Form Selection 22.3Amorphous Form Screening 22.4Salt Selection 22.5Cocrystal Screening 22.6Polymorph Screening 22.7Slurrying 22.8High Throughput Screening 22.9Crystallization in Confined Space 22.10Nonsolvent-Based Polymorph Screening 22.11Polymer-Induced Heteronucleation 22.12Physical Characterization 22.13Thermodynamic Stability and Solid Form Selection 22.14Summary Chapter 23Final Stage Drug Substance Manufacturing and Control 23.1Introduction 23.2Crystallization and Impurity Purge 23.3Removal of Residual Solvents 23.4Control of Genotoxic Impurities 23.5Control of N-Nitrosamines 23.6Chiral Separation Through Salt and Cocrystal Formation 23.7Preparation of the Final Solid Form 23.8Particle Size and Shape Control During Crystallization 23.9Powder Agglomeration and Caking 23.10Milling and Micronization 23.11Impact of Process Impurities on Crystallization 23.12Summary Chapter 24Solid-State Mixture Analysis 24.1Introduction 24.2Limitations of Wet Chemistry 24.3Pharmaceutical Analysis in the Solid State 24.4Measurement of Amorphous Content 24.5Detection of Crystallinity 24.6Quantification of Mixtures of Polymorphs 24.7Salt and Free Form Composition 24.8Analysis of Particulate Contaminants in Drug Products 24.9Process Analytical Technology 24.10Summary Chapter 25Drug Product Development 25.1Chemistry, Manufacture, and Control 25.2Preformulation 25.3Drug Excipient Compatibility 25.4Solid Dispersions 25.5Abuse-Deterrent Dosage Forms 25.6Drug-Eluting Stents 25.7Dry Powder Inhaler 25.8Lyophilization and Biopharmaceutical Products 25.9Oral Delivery of Peptides 25.10Injectable Drug-Device Combination Products 25.11Control of N-Nitrosamine in Drug Product 25.12Summary Chapter 26Quality by Design 26.1Introduction 26.2Quality by Design Wheel 26.3Learning before Doing 26.4Risk-Based Orientation 26.5API Attributes and Process Design 26.6Development and Design Space 26.7Process Design - Crystallization 26.8Phase Transformations during Wet Granulation 26.9Dissolution Tests with an IVIVC for Quality by Design 26.10SummaryTable of Contents Chapter 1Solid-State Properties and Pharmaceutical Development 1.1Introduction 1.2Solid-State Forms 1.3Bulk and Surface Properties of Solids 1.4ICH Q6A Decision Trees 1.5"Big Questions" for Drug Development 1.6Accelerating Drug Development 1.7Solid-State Chemistry in Preformulation and Formulation 1.8Solid-Lipid Nanoparticles 1.9Learning Before Doing and Quality by Design 1.10Performance and Stability in Pharmaceutical Development 1.11Moisture Uptake 1.12Solid-State Reactions 1.13Noninteracting Formulations - Physical Characterizations Chapter 2Polymorphs 2.1Introduction 2.2How are Polymorphs Formed? 2.3Structure Aspect of Polymorphs 2.4Physical, Chemical, and Mechanical Properties 2.5Thermodynamic Stability of Polymorphs 2.6Polymorph Conversion 2.7Control of Polymorphs 2.8Polymorph Screening 2.9Polymorph Prediction Chapter 3Pseudopolymorphs: Hydrates and Solvates 3.1Introduction 3.2Pharmaceutical Importance of Hydrates 3.3Classification of Pharmaceutical Hydrates 3.4Water Activity 3.5Stoichiometric Hydrates 3.6Nonstoichiometric Hydrates 3.7Emerging Interests in Organic Solvates 3.8Isostructural Solvates 3.9Dehydration and Desolvation 3.10Preparation and Characterization of Hydrates and Solvates Chapter 4Pharmaceutical Salts 4.1Introduction 4.2Importance of Pharmaceutical Salts 4.3Weak Acid, Weak Base, and Salt 4.4pH-Solubility Profiles of Ionizable Compounds 4.5Solubility, Dissolution, and Bioavailability of Pharmaceutical Salts 4.6Physical Stability of Pharmaceutical Salts 4.7Strategies for Salt Selection Chapter 5Pharmaceutical Cocrystals 5.1Introduction 5.2Cocrystals and Crystal Engineering 5.3Solubility Phase Diagram for Cocrystals 5.4Preparation of Cocrystals 5.5Dissolution and Bioavailability of Cocrystals 5.6Pharmaceutical Applications of Cocrystals 5.7Comparison of Pharmaceutical Salts and Cocrystals Chapter 6Amorphous Solids 6.1Introduction 6.2The Formation of Amorphous Solids 6.3Methods of Preparing Amorphous Solids 6.4The Glass Transition Temperature 6.5Structural Features of Amorphous Solids 6.6Molecular Mobility 6.7Mixtures of Amorphous Solids Chapter 7Crystal Mesophases and Nanocrystals 7.1Introduction 7.2Overview of Crystal Mesophases 7.3Liquid Crystals 7.4Conformationally Disordered (Condis) Crystals 7.5Plastic Crystals 7.6Nanocrystals Chapter 8X-Ray Crystallography and Crystal Packing Analysis 8.1Introduction 8.2Crystals 8.3Miller Indices and Crystal Faces 8.4Determination of the Miller Indices of the Faces of a Crystal 8.5Determination of Crystal Structures Chapter 9X-Ray Powder Diffraction 9.1Introduction 9.2X-Ray Powder Diffraction of Crystalline Materials 9.3Qualitative Analysis of Crystalline Materials 9.4Phase Transformations 9.5Quantitative Phase Analysis Using XRPD 9.6Solving Crystal Structures using X-Ray Powder Diffraction 9.7X-Ray Diffraction of Amorphous and Crystal Mesophases Forms 9.8Pair Distribution Function 9.9X-Ray Diffractometers 9.10Variable Temperature XRPD Chapter 10Differential Scanning Calorimetry and Thermogravimetric Analysis 10.1Introduction 10.2The Basics of Differential Scanning Calorimetry 10.3Thermal Transitions of Pharmaceutical Materials 10.4DSC Instrumentation 10.5Thermogravimetric Analysis 10.6Operating a TGA Instrument 10.7Evolved Gas Analysis 10.8Applications of DSC and TGA 10.9Summary of Using DSC and TGA Chapter 11Microscopy 11.1Introduction 11.2Light Microscopy 11.3Polarized Light Microscopy 11.4Thermal Microscopy 11.5Functionality of Light Microscopy 11.6Digital Microscope 11.7Application of Light Microscopy to Pharmaceutical Materials 11.8Scanning Electron Microscope 11.9Environmental Scanning Electron Microscopy 11.10Transmission Electron Microscopy and Electron Diffraction 11.11Atomic Force Microscopy Chapter 12Vibrational Spectroscopy 12.1Introduction 12.2The Nature of Molecular Vibrations 12.3Fourier Transformed Infrared Spectroscopy 12.4Material Characterization by FT-IR Spectroscopy 12.5FT-IR Instrumentation 12.6Diffuse Reflectance FT-IR 12.7Attenuated Total Reflectance FT-IR 12.8FT-IR Microscopy 12.9Near Infrared Spectroscopy 12.10Raman Spectroscopy 12.11Raman Instrumentation and Sampling 12.12Raman Microscopy 12.13Terahertz Spectroscopy 12.14Comparison of FT-IR, NIR, Raman, and Terahertz Spectroscopy Chapter 13Solid-State NMR Spectroscopy 13.1Introduction 13.2An Overview of Solid-State 13C CP/MAS NMR Spectroscopy 13.3Solid-State NMR Studies of Pharmaceuticals 13.4Phase Identification in Dosage Forms 13.5Other Basic Solid-State NMR Experiments Useful for Pharmaceutical Analysis 13.6Determination of the Domain Structure of Amorphous Dispersions Using Solid-State NMR 13.7Solid-State NMR of Amorphous Materials 13.8Summary Chapter 14Particle and Powder Analysis 14.1Introduction 14.2Particles in Pharmaceutical Systems 14.3Particle Size and Shape 14.4Particle Size Distribution 14.5Dynamic Light Scattering 14.6Zeta Potential 14.7Laser Diffraction 14.8Acoustic Spectroscopy 14.9Dynamic Image Analysis 14.10Sieve Analysis 14.11Bulk Properties of Pharmaceutical Particulates and Powders 14.12Surface Area Measurement Chapter 15Hygroscopic Properties of Solids 15.1Introduction 15.2Water Vapor Sorption-Desorption 15.3Water Vapor Sorption Isotherms, Relative Humidity, and Water Activity 15.4Measurement of Water Content and Water Vapor Sorption/Desorption Isotherms 15.5Modes of Water Vapor Sorption Chapter 16Mechanical Properties of Pharmaceutical Materials 16.1Introduction 16.2Stress and Strain 16.3Elasticity 16.4Plasticity 16.5Viscoelasticity 16.6Brittleness 16.7Hardness 16.8Powder Compression 16.9Powder Compression Models and Compressibility 16.10Compatibility and Tensile Strength 16.11Effect of Solid Form on Mechanical Properties 16.12Effect of Moisture on Mechanical Properties 16.13Methods for Testing Mechanical Properties Chapter 17Solubility and Dissolution 17.1Introduction 17.2Principal Concepts Associated with Solubility 17.3Prediction of Aqueous Drug Solubility 17.4Solubility of Pharmaceutical Solid Forms 17.5Solubility Determination Using the Shake Flask Method 17.6High Throughput Screening of Solubility 17.7Solubility Measurement of Metastable Forms 17.8Kinetic Solubility Measurement 17.9Solubility Determination of Drugs in Polymer Matrices 17.10Dissolution Testing 17.11Nonsink Dissolution Test 17.12Biorelevant Dissolution Test 17.13Intrinsic Dissolution Studies 17.14Summary Chapter 18Physical Stability of Solids 18.1Introduction 18.2Underlying Basis for Physical Instability in Pharmaceutical Systems 18.3Disorder in Crystals 18.4Quantitative Determination of Partially Amorphous Material in Crystals 18.5Phase Transformation 18.6Examples of the Role of Process-Induced Disorder in Solid-State Physical Instability in Pharmaceutical Systems 18.7Poor Wettability of Solids During Dosage Form Processing and Administration 18.8Considerations in Evaluating Solid-State Physical Stability Chapter 19Chemical Stability of Solids 19.1Introduction 19.2Examples of Chemical Reactivity in the Solid State 19.3Some General Principles that Establish the Rate of Chemical Reactions in Solution 19.4Some General Principles Governing the Rates of Solid-State Reactions 19.5The Role of Crystal Defects in Solid-State Reactions 19.6Chemical Reactivity in the Amorphous Solid State 19.7Chemical Reactivity and Process-Induced Disorder 19.8The Effects of Residual Water on Solid-State Chemical Reactivity 19.9Drug-Excipient Interactions 19.10Summary Chapter 20Solid-State Properties of Proteins 20.1Introduction 20.2Solution Properties of Proteins 20.3Amorphous Properties of Proteins 20.4Crystalline Properties of Proteins 20.5Local Molecular Motions and Dynamical Transitional Temperature, Td 20.6Solid-State Physical and Chemical Stability of Proteins 20.7Cryoprotection and Lyoprotection Chapter 21Physical and Chemical Properties of RNA Therapeutics 21.1Introduction 21.2Mode of Action 21.3Building Blocks and Primary Structure 21.4RNA Structure in Solution 21.5RNA Stability in Solution 21.6Solid-State Properties 21.7Pharmaceutical Development 21.8Summary Chapter 22 Solid Form Selection of Active Pharmaceutical Ingredients 22.1Introduction 22.2Solid Form Selection 22.3Amorphous Form Screening 22.4Salt Selection 22.5Cocrystal Screening 22.6Polymorph Screening 22.7Slurrying 22.8High Throughput Screening 22.9Crystallization in Confined Space 22.10Nonsolvent-Based Polymorph Screening 22.11Polymer-Induced Heteronucleation 22.12Physical Characterization 22.13Thermodynamic Stability and Solid Form Selection 22.14Summary Chapter 23Final Stage Drug Substance Manufacturing and Control 23.1Introduction 23.2Crystallization and Impurity Purge 23.3Removal of Residual Solvents 23.4Control of Genotoxic Impurities 23.5Control of N-Nitrosamines 23.6Chiral Separation Through Salt and Cocrystal Formation 23.7Preparation of the Final Solid Form 23.8Particle Size and Shape Control During Crystallization 23.9Powder Agglomeration and Caking 23.10Milling and Micronization 23.11Impact of Process Impurities on Crystallization 23.12Summary Chapter 24Solid-State Mixture Analysis 24.1Introduction 24.2Limitations of Wet Chemistry 24.3Pharmaceutical Analysis in the Solid State 24.4Measurement of Amorphous Content 24.5Detection of Crystallinity 24.6Quantification of Mixtures of Polymorphs 24.7Salt and Free Form Composition 24.8Analysis of Particulate Contaminants in Drug Products 24.9Process Analytical Technology 24.10Summary Chapter 25Drug Product Development 25.1Chemistry, Manufacture, and Control 25.2Preformulation 25.3Drug Excipient Compatibility 25.4Solid Dispersions 25.5Abuse-Deterrent Dosage Forms 25.6Drug-Eluting Stents 25.7Dry Powder Inhaler 25.8Lyophilization and Biopharmaceutical Products 25.9Oral Delivery of Peptides 25.10Injectable Drug-Device Combination Products 25.11Control of N-Nitrosamine in Drug Product 25.12Summary Chapter 26Quality by Design 26.1Introduction 26.2Quality by Design Wheel 26.3Learning before Doing 26.4Risk-Based Orientation 26.5API Attributes and Process Design 26.6Development and Design Space 26.7Process Design - Crystallization 26.8Phase Transformations during Wet Granulation 26.9Dissolution Tests with an IVIVC for Quality by Design 26.10Summary
