Stephen R. Byrn, PhD, Charles B. Jordan Professor of Medicinal Chemistry in the Department of Industrial and Molecular Pharmaceutics, Purdue University. George Zografi, PhD, Edward Kremers Professor Emeritus of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison. Xiaoming (Sean) Chen, PhD, works in the field of pharmaceutical product development and held various positions at Schering-Plough, OSI Pharmaceuticals, Astellas Pharma, Shionogi Inc, Antares Pharma, Arvinas, and Improved Pharma.

• Biography of Authors xvPreface xviiPreface to the First Edition xviiAcknowledgment xix1 Solid-State Properties and Pharmaceutical Development 11.1 Introduction 11.2 Solid-state Forms 11.3 Bulk and Surface Properties of Solids 61.4 ICH Q6A Decision Trees 71.5 “Big Questions” for Drug Development 81.6 Accelerating Drug Development 101.7 Solid-state Chemistry in Preformulation and Formulation 121.8 Solid–Lipid Nanoparticles 151.9 Learning Before Doing and Quality by Design 161.10 Performance and Stability in Pharmaceutical Development 191.11 Moisture Uptake 201.12 Solid-state Reactions 211.13 Noninteracting Formulations – Physical Characterizations 212 Polymorphs 272.1 Introduction 272.2 How Are Polymorphs Formed? 272.3 Structural Aspect of Polymorphs 292.3.1 Configurational Polymorphs 292.3.2 Conformational Polymorphs 302.4 Physical, Chemical, and Mechanical Properties 322.4.1 Solubility 332.4.2 Chemical Stability 342.4.3 Mechanical Properties 342.5 Thermodynamic Stability of Polymorphs 352.5.1 Monotropy and Enantiotropy 362.5.2 Burger and Ramberger’s Rules 372.5.3 van’t Hoff Plot 372.5.4 ​∆G​/temperature diagram 382.6 Polymorph Conversion 392.6.1 Solution-mediated Transformation 402.6.2 Solid-state Conversion 402.7 Control of Polymorphs 422.8 Polymorph Screening 432.9 Polymorph Prediction 443 Pseudopolymorphs: Hydrates and Solvates 493.1 Introduction 493.2 Pharmaceutical Importance of Hydrates 493.3 Classification of Pharmaceutical Hydrates 513.4 Water Activity 523.5 Stoichiometric Hydrates 533.6 Nonstoichiometric Hydrates 543.7 Emerging Interests in Organic Solvates 553.8 Isostructural Solvates 573.9 Dehydration and Desolvation 593.10 Preparation and Characterization of Hydrates and Solvates 614 Pharmaceutical Salts 654.1 Introduction 654.2 Importance of Pharmaceutical Salts 654.3 Weak Acid, Weak Base, and Salt 664.4 pH Solubility Profiles of Ionizable Compounds 694.5 Solubility, Dissolution, and Bioavailability of Pharmaceutical Salts 714.6 Physical Stability of Pharmaceutical Salts 754.7 Strategies for Salt Selection 765 Pharmaceutical Cocrystals 815.1 Introduction 815.2 Cocrystals and Crystal Engineering 815.3 Solubility Phase Diagrams for Cocrystals 835.4 Preparation of Cocrystals 855.5 Dissolution and Bioavailability of Cocrystals 885.6 Pharmaceutical Applications of Cocrystals 905.7 Comparison of Pharmaceutical Salts and Cocrystals 925.7.1 Formation 935.7.2 Preparation 935.7.3 Polymorphism and Pseudopolymorphism 935.7.4 Characterization 935.7.5 Stability 935.7.6 Formulation 945.7.7 Regulatory 946 Amorphous Solids 976.1 Introduction 976.2 The Formation of Amorphous Solids 986.3 Methods of Preparing Amorphous Solids 996.4 The Glass Transition Temperature 1006.5 Structural Features of Amorphous Solids 1036.6 Molecular Mobility 1056.6.1 Overview of Molecular Mobility 1056.6.2 Viscosity and Molecular Mobility 1066.6.3 Relaxation Time 1076.6.4 Fragility in Supercooled Liquids 1086.6.5 Diffusive Relaxation Time in the Glassy State 1106.6.6 Secondary Relaxations in Amorphous Solids 1126.7 Mixtures of Amorphous Solids 1146.7.1 Overview 1146.7.2 Thermodynamics of Molecular Mixing in Amorphous Solids 1156.7.3 The Glass Transition Temperature and Molecular Mobility of Miscible Amorphous Mixtures 1167 Crystal Mesophases and Nanocrystals 1217.1 Introduction 1217.2 Overview of Crystal Mesophases 1217.3 Liquid Crystals 1227.4 Conformationally Disordered (Condis) Crystals 1277.5 Plastic Crystals 1277.6 Nanocrystals 1288 X-Ray Crystallography and Crystal-Packing Analysis 1318.1 Introduction 1318.2 Crystals 1318.3 Miller Indices and Crystal Faces 1318.4 Determination of the Miller Indices of the Faces of a Crystal 1338.5 Determination of Crystal Structure 1348.5.1 Diffraction of X-Rays 1348.5.2 Experimental Measurements 1358.5.3 Determination of Space Group Symmetry 1368.5.4 Calculation of the Density of the Crystal 1368.5.5 Structure Determination 1368.5.6 Crystal-packing Drawings 1378.5.7 Atomic Displacement Parameters and Molecular Mobility 1378.6 Variable-Temperature X-ray Studies 1389 X-Ray Powder Diffraction 1399.1 Introduction 1399.2 XRPD of Crystalline Materials 1399.3 Qualitative Analysis of Crystalline Materials 1419.4 Phase Transformations 1439.5 Quantitative Phase Analysis Using XRPD 1439.6 Solving Crystal Structures Using XRPD 1479.7 X-ray Diffraction of Amorphous and Crystal Mesophase Forms 1499.8 Pair Distribution Function 1499.9 X-ray Diffractometers 1529.10 Variable Temperature XRPD 15610 Differential Scanning Calorimetry and Thermogravimetric Analysis 15910.1 Introduction 15910.2 The Basics of DSC 15910.3 Thermal Transitions of Pharmaceutical Materials 16010.3.1 Melting 16010.3.2 Glass Transition in Amorphous Solids 16110.3.3 Enthalpy Relaxation for Amorphous Solids 16110.3.4 Crystallization 16210.3.5 Crystal Form Transitions 16210.3.6 Desolvation/Dehydration 16310.3.7 Chemical Degradation 16310.4 DSC Instrumentation 16310.4.1 Heat-flux DSC 16310.4.2 Power-compensated DSC 16410.4.3 Modulated DSC 16410.4.4 Fast-scan DSC 16510.4.5 Operation of DSC Instrumentation 16510.5 Thermogravimetric Analysis 16810.6 Operating a TGA Instrument 16910.7 Evolved Gas Analysis 16910.8 Applications of DSC and TGA 16910.8.1 The Study of Polymorphs, Solvates, and Hydrates 16910.8.2 Polymer Characterization 17110.8.3 Characterization of Amorphous Forms and Amorphous Solid Dispersions 17210.8.4 Dehydration and Desolvation Kinetics 17210.8.5 Optimization of the Freezing–Drying Cycle in Lyophilization 17310.8.6 Melting-point Depression Method for Purity Analysis and Drug–Polymer Miscibility Assessment 17410.8.7 Study of Solid-state Chemical Stability 17610.8.8 Characterization of Macromolecules and Their Interactions 17610.9 Summary of Using DSC and TGA 17811 Microscopy 18111.1 Introduction 18111.2 Light Microscopy 18111.3 Polarized Light Microscopy 18311.4 Thermal Microscopy 18311.5 Functionality of Light Microscopy 18411.6 Digital Microscope 18511.7 Application of Light Microscopy to Pharmaceutical Materials 18611.7.1 Differentiation of Amorphous and Crystalline Materials 18611.7.2 Characterization of Polymorphs, Hydrates, and Solvates 18611.7.3 Polymorph Conversion 18911.7.4 Control of Crystallization 19011.7.5 Screening for Cocrystals 19111.7.6 Analysis of Particle Size 19211.7.7 Contaminant Analysis 19211.8 Scanning Electron Microscope 19311.9 Environmental SEM 19511.10 TEM and ED 19611.11 Atomic Force Microscopy 19812 Vibrational Spectroscopy 20312.1 Introduction 20312.2 The Nature of Molecular Vibrations 20412.3 FT-IR Spectroscopy 20512.4 Material Characterization by FT-IR Spectroscopy 20612.5 FT-IR Instrumentation 20812.6 Diffuse Reflectance FT-IR 20912.7 Atr Ft-ir 21112.8 FT-IR Microscopy 21212.9 NIR Spectroscopy 21312.10 Raman Spectroscopy 21512.11 Raman Instrumentation and Sampling 21712.12 Raman Microscopy 21912.13 Terahertz Spectroscopy 22012.14 Comparison of FT-IR, NIR, Raman, and Terahertz Spectroscopy 22212.14.1 Spectral Information 22212.14.2 Spectral Resolution 22312.14.3 Sampling 22312.14.4 Environmental Control 22312.14.5 Microscopy 22312.14.6 Fluorescence and Photodamage 22413 Solid-State NMR Spectroscopy 22713.1 Introduction 22713.2 An Overview of Solid-state 13C CP/MAS NMR Spectroscopy 22713.2.1 Dipolar Decoupling 22813.2.2 Magic-Angle Spinning 23113.2.3 Cross Polarization 23213.3 Solid-state NMR Studies of Pharmaceuticals 23213.4 Phase Identification in Dosage Forms 23313.5 Other Basic Solid-state NMR Experiments Useful for Pharmaceutical Analysis 23713.5.1 Interrupted Decoupling for Protonated Carbon Atoms 23713.5.2 Block-Decay Experiments for Screening Submolecular Mobility 23913.6 Determination of the Domain Structure of Amorphous Dispersions Using Solid-state NMR 24113.7 Solid-state NMR of Amorphous Materials 24213.8 Summary 24414 Particle and Powder Analysis 24714.1 Introduction 24714.2 Particles in Pharmaceutical Systems 24714.2.1 Micelles 24714.2.2 Protein Aggregates 24814.2.3 Liposomes 24814.2.4 Microemulsions 24814.2.5 Nanoemulsions 24814.2.6 Nanosuspensions 24914.2.7 Nanoparticles 24914.2.8 Aerosols 24914.2.9 Emulsions 24914.2.10 Suspensions 24914.2.11 Powders 24914.2.12 Granules 25014.2.13 Pellets 25014.3 Particle Size and Shape 25014.4 Particle Size Distribution 25114.5 Dynamic Light Scattering 25214.6 Zeta Potential 25414.7 Laser Diffraction 25614.8 Acoustic Spectroscopy 25814.9 Dynamic Image Analysis 25914.10 Sieve Analysis 26014.11 Bulk Properties of Pharmaceutical Particulates and Powder 26014.12 Surface Area Measurement 26215 Hygroscopic Properties of Solids 26715.1 Introduction 26715.2 Water Vapor Sorption–Desorption 26815.3 Water Vapor Sorption Isotherms, Relative Humidity, and Water Activity 26815.4 Measurement of Water Content and Water Vapor Sorption–Desorption Isotherms 27015.4.1 Measurement of Water Content 27015.4.2 Measurement of Water Vapor Sorption–Desorption Isotherms 27115.5 Modes of Water Vapor Sorption 27215.5.1 Introduction 27215.5.2 Adsorption 27315.5.3 Deliquescence 27715.5.4 Capillary Condensation 27815.5.5 Absorption by Amorphous Solids 28016 Mechanical Properties of Pharmaceutical Materials 28716.1 Introduction 28716.2 Stress and Strain 28716.3 Elasticity 28816.4 Plasticity 28916.5 Viscoelasticity 29016.6 Brittleness 29116.7 Hardness 29316.8 Powder Compression 29416.9 Powder Compression Models and Compressibility 29516.10 Compactibility and Tensile Strength 29616.11 Effect of Solid Form on Mechanical Properties 29716.12 Effect of Moisture on Mechanical Properties 29916.13 Methods for Testing Mechanical Properties 30116.13.1 Beam Bending 30116.13.2 Thermomechanical Analyzer 30216.13.3 Dynamic Mechanical Analyzer 30316.13.4 Nanoindentation 30417 Solubility and Dissolution 30717.1 Introduction 30717.2 Principal Concepts Associated with Solubility 30717.3 Prediction of Aqueous Drug Solubility 30817.4 Solubility of Pharmaceutical Solid Forms 31017.5 Solubility Determination Using the Shake-Flask Method 31117.6 High-throughput Screening of Solubility 31217.7 Solubility Measurement of Metastable Forms 31317.8 Kinetic Solubility Measurement 31417.9 Solubility Determination of Drugs in Polymer Matrices 31517.10 Dissolution Testing 31617.11 Nonsink Dissolution Test 32017.12 Biorelevant Dissolution Test 32117.13 Intrinsic Dissolution Studies 32417.14 Summary 32518 Physical Stability of Solids 32918.1 Introduction 32918.2 Underlying Basis for Physical Instability in Pharmaceutical Systems 33018.3 Disorder in Crystals 33118.4 Quantitative Determination of Partially Amorphous Material in Crystals 33318.5 Phase Transformation 33518.5.1 Solid-state Crystallization 33518.5.2 Solvent-mediated Phase Transformations 33818.6 Examples of the Role of Process-induced Disorder in Solid-state Physical Instability in Pharmaceutical Systems 33918.7 Poor Wettability of Solids During Dosage Form Processing and Administration 34118.8 Considerations in Evaluating Solid-state Physical Stability 34519 Chemical Stability of Solids 34919.1 Introduction 34919.2 Examples of Chemical Reactivity in the Solid State 34919.3 Some General Principles That Establish the Rate of Chemical Reactions in Solution 35219.4 Some General Principles Governing the Rates of Solid-state Reactions 35519.5 The Role of Crystal Defects in Solid-state Reactions 35619.6 Chemical Reactivity in the Amorphous Solid State 36019.7 Chemical Reactivity and Processed-induced Disorder 36319.8 The Effects of Residual Water on Solid-state Chemical Reactivity 36419.9 Drug–Excipient Interactions 36919.10 Summary 37120 Solid-State Properties of Proteins 37520.1 Introduction 37520.2 Solution Properties of Proteins 37520.3 Amorphous Properties of Proteins 37920.4 Crystalline Properties of Proteins 38120.5 Local Molecular Motions and the Dynamical Transitional Temperature, T d 38220.6 Solid-state Physical and Chemical Stability of Proteins 38420.7 Cryoprotection and Lyoprotection 38521 Physical and Chemical Properties of RNA Therapeutics 38921.1 Introduction 38921.2 Mode of Action 38921.2.1 Antisense RNA 39021.2.2 Small Interference RNA 39021.2.3 Messenger RNA 39121.2.4 Crispr 39221.3 Building Blocks and Primary Structure 39221.4 RNA Structure in Solution 39421.4.1 Hydrogen Bonding 39521.4.2 Stacking Interaction 39521.4.3 Ionic Interaction 39521.4.4 RNA Secondary and Tertiary Structure 39621.5 RNA Stability in Solution 39821.6 Solid-state Properties 40021.7 Pharmaceutical Development 40221.7.1 Drug Delivery Challenges and Current Platforms 40221.7.2 How to Make RNA Therapeutics 40321.7.3 Characterization of mRNA LNPs 40421.7.4 Stability of mRNA LNPs 40621.7.5 Lyophilization of mRNA LNPs 40721.8 Summary 40822 Solid Form Selection of Active Pharmaceutical Ingredients 41122.1 Introduction 41122.2 Solid Form Selection 41122.3 Amorphous Form Screening 41322.4 Salt Selection 41422.5 Cocrystal Screening 41722.6 Polymorph Screening 41922.7 Slurrying 42022.8 High-Throughput Screening 42122.9 Crystallization in Confined Space 42222.10 Nonsolvent-based Polymorph Screening 42322.11 Polymer-induced Heteronucleation 42422.12 Physical Characterization 42522.13 Thermodynamic Stability and Solid Form Selection 42622.14 Summary 42723 Final Stage Drug Substance Manufacturing and Control 43123.1 Introduction 43123.2 Crystallization and Impurity Purge 43123.3 Removal of Residual Solvents 43423.4 Control of Genotoxic Impurities 43623.5 Control of N-Nitrosamines 43723.6 Chiral Separation Through Salt and Cocrystal Formation 43823.7 Preparation of the Final Solid Form 44123.8 Particle Size and Shape Control During Crystallization 44423.9 Powder Agglomeration and Caking 44723.10 Milling and Micronization 44823.11 Impact of Process Impurities on Crystallization 44923.12 Summary 45024 Solid-State Mixture Analysis 45524.1 Introduction 45524.2 Limitations of Wet Chemistry 45524.3 Pharmaceutical Analysis in the Solid State 45624.3.1 Sample Preparation 45624.3.2 Data Collection 45624.3.3 Data Transformation 45724.3.4 Calibration Model Development and Validation 45724.4 Measurement of Amorphous Content 45924.5 Detection of Crystallinity 46224.6 Quantification of Mixtures of Polymorphs 46424.7 Salt and Free Form Composition 46624.8 Analysis of Particulate Contaminants in Drug Products 46724.9 Process Analytical Technology 47024.9.1 Physical and Chemical Attributes of a Process 47124.9.2 Selection of Process Analyzers 47124.9.3 Location of the Process Analyzer 47324.9.4 Development of Analytical Models for Process Monitoring 47424.9.5 Validation 47524.10 Summary 47625 Drug Product Development 47925.1 Chemistry, Manufacture, and Control 47925.2 Preformulation 48125.3 Drug–Excipient Compatibility 48225.4 Solid Dispersions 48425.5 Abuse-Deterrent Dosage Forms 48925.6 Drug-Eluting Stents 49125.7 Dry Powder Inhalers 49425.8 Lyophilization of Biopharmaceutical Products 49725.9 Oral Delivery of Peptides 50025.10 Injectable Drug–Device Combination Products 50225.11 Control of N-Nitrosamine in Drug Product 50425.12 Summary 50626 Quality by Design 51126.1 Introduction 51126.2 QbD Wheel 51126.3 Learning Before Doing 51426.4 Risk-based Orientation 51626.5 API Attributes and Process Design 51726.6 Development and Design Space 51726.7 Process Design – Crystallization 52026.8 Phase Transformations During Wet Granulation 52126.9 Dissolution Tests with an IVIVC for QbD 52226.10 Summary 525Index 527