TONGLEI LI is Professor in Industrial & Physical Pharmacy at Purdue University, West Lafayette, IN. ALESSANDRA MATTEI is a Senior Scientist in Solid State Chemistry at AbbVie, North Chicago, IL.

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• List of Contributors xiiiPreface xv1 Crystallography 1Susan M. Reutzel-Edens and Peter Müller1.1 Introduction 11.2 History 61.3 Symmetry 71.3.1 Symmetry in Two Dimensions 71.3.2 Symmetry and Translation 111.3.3 Symmetry in Three Dimensions 121.3.4 Metric Symmetry of the Crystal Lattice 131.3.5 Conventions and Symbols 141.3.6 Fractional Coordinates 151.3.7 Symmetry in Reciprocal Space 151.4 Principles of X-ray Diffraction 171.4.1 Bragg’s Law 171.4.2 Diffraction Geometry 191.4.3 Ewald Construction 191.4.4 Structure Factors 211.4.5 Statistical Intensity Distribution 221.4.6 Data Collection 231.5 Structure Determination 241.5.1 Space Group Determination 241.5.2 Phase Problem and Structure Solution 251.5.3 Structure Refinement 281.5.3.1 Resonant Scattering and Absolute Structure 321.6 Powder Methods 331.6.1 Powder Diffraction 341.6.2 NMR Crystallography 351.7 Crystal Structure Prediction 391.8 Crystallographic Databases 411.9 Conclusions 42References 432 Nucleation 47Junbo Gong and Weiwei Tang2.1 Introduction 472.2 Classical Nucleation Theory 482.2.1 Thermodynamics 482.2.2 Kinetics of Nucleation 512.2.3 Metastable Zone 532.2.4 Induction Time 582.2.5 Heterogeneous Nucleation 602.3 Nonclassical Nucleation 632.3.1 Two-Step Mechanism 632.3.2 Prenucleation Cluster Pathway 662.4 Application of Primary Nucleation 662.4.1 Understanding and Control of Polymorphism 662.4.2 Liquid–Liquid Phase Separation 712.5 Secondary Nucleation 732.5.1 Origin from Solution 742.5.2 Origin from Crystals 752.5.3 Kinetics 762.5.4 Application to Continuous Crystallization 762.5.5 Crystal Size Distribution 792.5.6 Seeding 802.6 Summary 81References 823 Solid-state Characterization Techniques 89Ann Newman and Robert Wenslow3.1 Introduction 893.2 Techniques 903.2.1 X-ray Powder Diffraction (XRPD) 903.2.2 Thermal Methods 943.2.2.1 Differential Scanning Calorimetry 943.2.2.2 Thermogravimetric Analysis (TGA) 953.2.3 Spectroscopy 973.2.3.1 Infrared (IR) 973.2.3.2 Raman Spectroscopy 993.2.3.3 Solid-state Nuclear Magnetic Resonance (SSNMR) 1013.2.4 Water Sorption 1053.2.5 Microscopy 1063.3 Case Study LY334370 Hydrochloride (HCl) 1093.4 Summary 114References 1144 Intermolecular Interactions and Computational Modeling 123Alessandra Mattei and Tonglei Li4.1 Introduction 1234.2 Foundation of Intermolecular Interactions 1244.2.1 Electrostatic Interactions 1254.2.2 van der Waals Interactions 1264.2.3 Hydrogen-bonding Interactions 1274.2.4 π–π Interactions 1294.3 Intermolecular Interactions in Organic Crystals 1304.3.1 Approaches to Crystal Packing Description 1304.3.2 Impact of Intermolecular Interactions on Crystal Packing 1364.3.3 Impact of Intermolecular Interactions on Crystal Properties 1384.4 Techniques for Intermolecular Interactions Evaluation 1404.4.1 Crystallography 1404.4.2 Spectroscopy 1414.4.3 Computational Methods 1424.4.3.1 Lattice Energy 1444.4.3.2 Interaction Energy of Molecular Pairs from Crystal Structures 1474.5 Advances in Understanding Intermolecular Interactions 1494.5.1 Crystal Structure Prediction 1504.5.2 Electronic Structural Analysis 152References 1605 Polymorphism and Phase Transitions 169Haichen Nie and Stephen R. Byrn5.1 Concepts and Overview 1695.2 Thermodynamic Principles of Polymorphic Systems 1755.2.1 Monotropy and Enantiotropy 1765.2.2 Phase Rule 1795.2.3 Phase Diagrams 1795.2.4 Phase Stability Rule 1825.2.4.1 Heat of Transition Rule 1825.2.4.2 Heat of Fusion Rule 1825.2.4.3 Entropy of Fusion Rule 1835.2.4.4 Heat Capacity Rule 1835.2.4.5 Density Rule 1835.2.4.6 Infrared Rule 1835.2.5 Crystallization of Polymorphs 1845.2.5.1 Ostwald’s Rule of Stages 1845.2.5.2 Nucleation 1845.3 Stabilities and Phase Transition 1895.3.1 Thermodynamic Stability 1895.3.2 Chemical Stability 1895.3.3 Polymorphic Interconversions of Pharmaceuticals 1925.3.3.1 Effects of Heat, Compression, and Grinding on Polymorphic Transformation 1925.3.3.2 Solution-mediated Phase Transformation of Drugs 1935.4 Impact on Bioavailability by Polymorphs 1945.5 Regulatory Consideration of Polymorphism 1965.6 Novel Approaches for Preparing Solid State Forms 1995.6.1 High-throughput Crystallization Method 2005.6.2 Capillary Growth Methods 2005.6.3 Laser-induced Nucleation 2015.6.4 Heteronucleation on Single Crystal Substrates 2015.6.5 Polymer Heteronucleation 2015.7 Hydrates and Solvates 2025.7.1 Thermodynamics of Hydrates 2035.7.2 Formation of Hydrates 2045.7.3 Desolvation Reactions 2055.7.4 Phase Transition of Solvates/Hydrates in Formulation and Process Development 2075.8 Summary 209References 2106 Measurement and Mathematical Relationships of Cocrystal Thermodynamic Properties 223Gislaine Kuminek, Katie L. Cavanagh, and Naír Rodríguez-Hornedo6.1 Introduction 2236.2 Structural and Thermodynamic Properties 2246.2.1 Structural Properties 2246.2.2 Thermodynamic Properties 2266.2.2.1 Cocrystal Ksp and Solubility 2266.2.2.2 Transition Points 2296.2.2.3 Supersaturation Index Diagrams 2316.2.3 A Word of Caution About Cmax Obtained from Kinetic Studies 2326.3 Determination of Cocrystal Thermodynamic Stability and Supersaturation Index 2346.3.1 Keu Measurement and Relationships Between Ksp, SCC, and SA 2346.3.2 Cocrystal Solubility and Ksp 2416.3.3 Cocrystal Supersaturation Index and Drug Solubilization 2436.4 What Phase Solubility Diagrams Reveal 2466.5 Cocrystal Discovery and Formation 2496.5.1 Molecular Interactions That Play an Important Role in Cocrystal Discovery 2496.5.2 Thermodynamics of Cocrystal Formation Provide Valuable Insight into the Conditions Where Cocrystals May Form 2516.6 Cocrystal Solubility Dependence on Ionization and Solubilization of Cocrystal Components 2536.6.1 Mathematical Forms of Cocrystal Solubility and Stability 2536.6.2 General Solubility Expressions in Terms of the Sum of Equilibrium Concentrations 2576.6.3 Applications 2586.7 Conclusions and Outlook 265References 2657 Mechanical Properties 273Changquan Calvin Sun7.1 Introduction 2737.1.1 Importance of Mechanical Properties in Pharmaceutical Manufacturing 2737.1.2 Basic Concepts Related to Mechanical Properties 2747.1.2.1 Stress, Strain, and Poisson’s Ratio 2747.1.2.2 Elasticity, Plasticity, and Brittleness 2767.1.2.3 Classification of Mechanical Response 2777.2 Characterization of Mechanical Properties 2787.2.1 Experimental Techniques 2787.2.1.1 Single Crystals 2787.2.1.2 Bulk Powders 2817.2.1.3 Tablet Mechanical Properties 2827.3 Structure–Property Relationship 2847.3.1 Anisotropy of Organic Crystals 2847.3.2 Crystal Plasticity, Elasticity, and Fracture 2867.3.3 Role of Dislocation on Mechanical Properties 2877.3.4 Effects of Crystal Size and Shape on Mechanical Behavior 2897.4 Conclusion and Future Outlook 290References 2918 Primary Processing of Organic Crystals 297Peter L.D. Wildfong, Rahul V. Haware, Ting Xu, and Kenneth R. Morris8.1 Introduction 2978.1.1 Solid Form 2978.1.2 Morphology 2988.2 Primary Manufacturing: Processing Materials to Yield Drug Substance 3008.2.1 Crystallization (Solidification Processing) 3018.2.1.1 Solvent Power 3038.2.1.2 Solvent Classification 3058.2.1.3 Batch Crystallization 3078.2.1.4 Continuous Crystallization 3088.2.2 Filtration and Washing 3098.2.3 Drying (Removal of Crystallization Solvent) 3138.2.4 Preliminary Particle Sizing 3158.3 Challenges During Solidification Processing 3198.3.1 Polymorphism 3208.3.1.1 Cooling Crystallization 3228.3.1.2 Solvent Selection 3258.3.1.3 Antisolvent Crystallization 3288.3.1.4 Selective Crystallization Using Additives 3288.3.2 Hydrate and Organic Solvate Formation 3298.3.2.1 Hydrate Formation 3298.3.2.2 Organic Solvate Formation 3358.3.3 Solvent-mediated Transformations (SMTs) 3378.3.4 Morphology/Habit Control 3428.3.4.1 Predicting Solvent Effects on Crystal Habit 3438.3.4.2 Influence of Morphology on Surface Wetting 3468.3.5 Crystallization Process Control 3498.4 Summary and Concluding Remarks 350References 3519 Secondary Processing of Organic Crystals 361Peter L.D. Wildfong, Rahul V. Haware, Ting Xu, and Kenneth R. Morris9.1 Introduction 3619.1.1 Structure and Symmetry 3619.1.2 Process-induced Transformations (PITs) in 2 Manufacturing 3629.2 Secondary Manufacturing–Processing Materials to Yield Drug Products 3659.2.1 Milling of Organic Crystals 3669.2.1.1 Materials Properties Influencing Milling 3669.2.1.2 Physical Transformations Associated with Milling 3719.2.1.3 Chemical Transformations Associated with Milling 3759.2.2 Pharmaceutical Blending 3789.2.3 Granulation of Pharmaceutical Materials 3829.2.3.1 Wet Granulation 3849.2.3.2 Potential Transformations During Wet Granulation 3859.2.3.3 Hydration and Dehydration 3859.2.3.4 Solvent-mediated Transformations (SMT) 3889.2.3.5 Polymorphic Transitions During Granulation 3909.2.3.6 Salt Breaking 3929.2.3.7 Formulation Considerations in Wet Granulation 3929.2.3.8 Risk Assessment and Summary 3949.2.4 Consolidation of Organic Crystals 3959.2.4.1 Materials Properties Contributing to Effective Consolidation 3979.2.4.2 Structural and Molecular Properties Contributing to Effective Consolidation 4029.2.4.3 Macroscopic Properties Affecting Effective Consolidation 4039.2.4.4 Compaction-induced Material Transformations 4049.2.4.5 Compression Temperature and Material Transformation 4079.2.5 Data Management Approaches 4089.3 Summary and Concluding Remarks 4119.3.1 Development History 4119.3.2 Risk Assessment 412References 41210 Chemical Stability and Reaction 427Alessandra Mattei and Tonglei Li10.1 Introduction 42710.2 Overview of Organic Solid-state Reactions 42910.2.1 Photochemical Reactions 43110.2.2 Thermal Reactions 43210.2.3 Mechanochemical Reactions 43310.2.4 Hydrolysis Reactions 43410.2.5 Oxidative Reactions 43410.3 Mechanisms of Organic Solid-state Reactions 43610.3.1 General Theoretical Concepts 43610.3.2 Crystal Packing Effects on the Course of Organic Solid-state Reactions 43810.3.2.1 Perfect Crystals and Topochemical Control of Organic Solid-state Reactions 43810.3.2.2 Crystal Defects and Nontopochemical Control of Organic Solid-state Reactions 44010.4 Kinetics of Chemical Reactions: From Homogeneous to Heterogeneous Systems 44510.4.1 Fundamental Principles of Chemical Kinetics 44510.4.2 Solid-state Reaction Kinetics 44610.5 Factors Affecting Chemical Stability 44810.5.1 Moisture 44810.5.2 Temperature 44810.5.3 Pharmaceutical Processing 45010.6 Strategies to Prevent Chemical Reactions 45210.6.1 Formulation-related Approaches 45310.6.2 Prodrugs 454References 45511 Crystalline Nanoparticles 463Yi Lu, Wei Wu, and Tonglei Li11.1 Introduction 46311.2 Top-down Technology 46711.2.1 Media Milling (MM) 46711.2.2 High-pressure Homogenization (HPH) 46811.3 Bottom-up Technology 47111.3.1 Precipitation by Solvent–Antisolvent Mixing 47111.3.1.1 Sonoprecipitation 47311.3.1.2 CIJP 47311.3.1.3 HGCP 47611.3.2 Supercritical Fluid Techniques 47611.3.2.1 RESS 47811.3.2.2 SAS 47911.3.3 Precipitation by Removal of Solvent 47911.3.3.1 SFL 47911.3.3.2 CCDF 47911.4 Nanoparticle Stabilization 48011.5 Applications 48211.5.1 Oral Drug Delivery 48211.5.2 Parenteral Drug Delivery 48411.5.3 Pulmonary Drug Delivery 48511.5.4 Ocular Drug Delivery 48611.5.5 Dermal Drug Delivery 48611.6 Characterization of Crystalline Nanoparticles 48711.6.1 Particle Size and Size Distribution 48711.6.2 Surface Charge 48711.6.3 Morphology 49111.6.4 Crystallinity 49111.6.5 Dissolution 491References 492Index 503

TONGLEI LI is Professor in Industrial & Physical Pharmacy at Purdue University, West Lafayette, IN. ALESSANDRA MATTEI is a Senior Scientist in Solid State Chemistry at AbbVie, North Chicago, IL.

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• List of Contributors xiiiPreface xv1 Crystallography 1Susan M. Reutzel-Edens and Peter Müller1.1 Introduction 11.2 History 61.3 Symmetry 71.3.1 Symmetry in Two Dimensions 71.3.2 Symmetry and Translation 111.3.3 Symmetry in Three Dimensions 121.3.4 Metric Symmetry of the Crystal Lattice 131.3.5 Conventions and Symbols 141.3.6 Fractional Coordinates 151.3.7 Symmetry in Reciprocal Space 151.4 Principles of X-ray Diffraction 171.4.1 Bragg’s Law 171.4.2 Diffraction Geometry 191.4.3 Ewald Construction 191.4.4 Structure Factors 211.4.5 Statistical Intensity Distribution 221.4.6 Data Collection 231.5 Structure Determination 241.5.1 Space Group Determination 241.5.2 Phase Problem and Structure Solution 251.5.3 Structure Refinement 281.5.3.1 Resonant Scattering and Absolute Structure 321.6 Powder Methods 331.6.1 Powder Diffraction 341.6.2 NMR Crystallography 351.7 Crystal Structure Prediction 391.8 Crystallographic Databases 411.9 Conclusions 42References 432 Nucleation 47Junbo Gong and Weiwei Tang2.1 Introduction 472.2 Classical Nucleation Theory 482.2.1 Thermodynamics 482.2.2 Kinetics of Nucleation 512.2.3 Metastable Zone 532.2.4 Induction Time 582.2.5 Heterogeneous Nucleation 602.3 Nonclassical Nucleation 632.3.1 Two-Step Mechanism 632.3.2 Prenucleation Cluster Pathway 662.4 Application of Primary Nucleation 662.4.1 Understanding and Control of Polymorphism 662.4.2 Liquid–Liquid Phase Separation 712.5 Secondary Nucleation 732.5.1 Origin from Solution 742.5.2 Origin from Crystals 752.5.3 Kinetics 762.5.4 Application to Continuous Crystallization 762.5.5 Crystal Size Distribution 792.5.6 Seeding 802.6 Summary 81References 823 Solid-state Characterization Techniques 89Ann Newman and Robert Wenslow3.1 Introduction 893.2 Techniques 903.2.1 X-ray Powder Diffraction (XRPD) 903.2.2 Thermal Methods 943.2.2.1 Differential Scanning Calorimetry 943.2.2.2 Thermogravimetric Analysis (TGA) 953.2.3 Spectroscopy 973.2.3.1 Infrared (IR) 973.2.3.2 Raman Spectroscopy 993.2.3.3 Solid-state Nuclear Magnetic Resonance (SSNMR) 1013.2.4 Water Sorption 1053.2.5 Microscopy 1063.3 Case Study LY334370 Hydrochloride (HCl) 1093.4 Summary 114References 1144 Intermolecular Interactions and Computational Modeling 123Alessandra Mattei and Tonglei Li4.1 Introduction 1234.2 Foundation of Intermolecular Interactions 1244.2.1 Electrostatic Interactions 1254.2.2 van der Waals Interactions 1264.2.3 Hydrogen-bonding Interactions 1274.2.4 π–π Interactions 1294.3 Intermolecular Interactions in Organic Crystals 1304.3.1 Approaches to Crystal Packing Description 1304.3.2 Impact of Intermolecular Interactions on Crystal Packing 1364.3.3 Impact of Intermolecular Interactions on Crystal Properties 1384.4 Techniques for Intermolecular Interactions Evaluation 1404.4.1 Crystallography 1404.4.2 Spectroscopy 1414.4.3 Computational Methods 1424.4.3.1 Lattice Energy 1444.4.3.2 Interaction Energy of Molecular Pairs from Crystal Structures 1474.5 Advances in Understanding Intermolecular Interactions 1494.5.1 Crystal Structure Prediction 1504.5.2 Electronic Structural Analysis 152References 1605 Polymorphism and Phase Transitions 169Haichen Nie and Stephen R. Byrn5.1 Concepts and Overview 1695.2 Thermodynamic Principles of Polymorphic Systems 1755.2.1 Monotropy and Enantiotropy 1765.2.2 Phase Rule 1795.2.3 Phase Diagrams 1795.2.4 Phase Stability Rule 1825.2.4.1 Heat of Transition Rule 1825.2.4.2 Heat of Fusion Rule 1825.2.4.3 Entropy of Fusion Rule 1835.2.4.4 Heat Capacity Rule 1835.2.4.5 Density Rule 1835.2.4.6 Infrared Rule 1835.2.5 Crystallization of Polymorphs 1845.2.5.1 Ostwald’s Rule of Stages 1845.2.5.2 Nucleation 1845.3 Stabilities and Phase Transition 1895.3.1 Thermodynamic Stability 1895.3.2 Chemical Stability 1895.3.3 Polymorphic Interconversions of Pharmaceuticals 1925.3.3.1 Effects of Heat, Compression, and Grinding on Polymorphic Transformation 1925.3.3.2 Solution-mediated Phase Transformation of Drugs 1935.4 Impact on Bioavailability by Polymorphs 1945.5 Regulatory Consideration of Polymorphism 1965.6 Novel Approaches for Preparing Solid State Forms 1995.6.1 High-throughput Crystallization Method 2005.6.2 Capillary Growth Methods 2005.6.3 Laser-induced Nucleation 2015.6.4 Heteronucleation on Single Crystal Substrates 2015.6.5 Polymer Heteronucleation 2015.7 Hydrates and Solvates 2025.7.1 Thermodynamics of Hydrates 2035.7.2 Formation of Hydrates 2045.7.3 Desolvation Reactions 2055.7.4 Phase Transition of Solvates/Hydrates in Formulation and Process Development 2075.8 Summary 209References 2106 Measurement and Mathematical Relationships of Cocrystal Thermodynamic Properties 223Gislaine Kuminek, Katie L. Cavanagh, and Naír Rodríguez-Hornedo6.1 Introduction 2236.2 Structural and Thermodynamic Properties 2246.2.1 Structural Properties 2246.2.2 Thermodynamic Properties 2266.2.2.1 Cocrystal Ksp and Solubility 2266.2.2.2 Transition Points 2296.2.2.3 Supersaturation Index Diagrams 2316.2.3 A Word of Caution About Cmax Obtained from Kinetic Studies 2326.3 Determination of Cocrystal Thermodynamic Stability and Supersaturation Index 2346.3.1 Keu Measurement and Relationships Between Ksp, SCC, and SA 2346.3.2 Cocrystal Solubility and Ksp 2416.3.3 Cocrystal Supersaturation Index and Drug Solubilization 2436.4 What Phase Solubility Diagrams Reveal 2466.5 Cocrystal Discovery and Formation 2496.5.1 Molecular Interactions That Play an Important Role in Cocrystal Discovery 2496.5.2 Thermodynamics of Cocrystal Formation Provide Valuable Insight into the Conditions Where Cocrystals May Form 2516.6 Cocrystal Solubility Dependence on Ionization and Solubilization of Cocrystal Components 2536.6.1 Mathematical Forms of Cocrystal Solubility and Stability 2536.6.2 General Solubility Expressions in Terms of the Sum of Equilibrium Concentrations 2576.6.3 Applications 2586.7 Conclusions and Outlook 265References 2657 Mechanical Properties 273Changquan Calvin Sun7.1 Introduction 2737.1.1 Importance of Mechanical Properties in Pharmaceutical Manufacturing 2737.1.2 Basic Concepts Related to Mechanical Properties 2747.1.2.1 Stress, Strain, and Poisson’s Ratio 2747.1.2.2 Elasticity, Plasticity, and Brittleness 2767.1.2.3 Classification of Mechanical Response 2777.2 Characterization of Mechanical Properties 2787.2.1 Experimental Techniques 2787.2.1.1 Single Crystals 2787.2.1.2 Bulk Powders 2817.2.1.3 Tablet Mechanical Properties 2827.3 Structure–Property Relationship 2847.3.1 Anisotropy of Organic Crystals 2847.3.2 Crystal Plasticity, Elasticity, and Fracture 2867.3.3 Role of Dislocation on Mechanical Properties 2877.3.4 Effects of Crystal Size and Shape on Mechanical Behavior 2897.4 Conclusion and Future Outlook 290References 2918 Primary Processing of Organic Crystals 297Peter L.D. Wildfong, Rahul V. Haware, Ting Xu, and Kenneth R. Morris8.1 Introduction 2978.1.1 Solid Form 2978.1.2 Morphology 2988.2 Primary Manufacturing: Processing Materials to Yield Drug Substance 3008.2.1 Crystallization (Solidification Processing) 3018.2.1.1 Solvent Power 3038.2.1.2 Solvent Classification 3058.2.1.3 Batch Crystallization 3078.2.1.4 Continuous Crystallization 3088.2.2 Filtration and Washing 3098.2.3 Drying (Removal of Crystallization Solvent) 3138.2.4 Preliminary Particle Sizing 3158.3 Challenges During Solidification Processing 3198.3.1 Polymorphism 3208.3.1.1 Cooling Crystallization 3228.3.1.2 Solvent Selection 3258.3.1.3 Antisolvent Crystallization 3288.3.1.4 Selective Crystallization Using Additives 3288.3.2 Hydrate and Organic Solvate Formation 3298.3.2.1 Hydrate Formation 3298.3.2.2 Organic Solvate Formation 3358.3.3 Solvent-mediated Transformations (SMTs) 3378.3.4 Morphology/Habit Control 3428.3.4.1 Predicting Solvent Effects on Crystal Habit 3438.3.4.2 Influence of Morphology on Surface Wetting 3468.3.5 Crystallization Process Control 3498.4 Summary and Concluding Remarks 350References 3519 Secondary Processing of Organic Crystals 361Peter L.D. Wildfong, Rahul V. Haware, Ting Xu, and Kenneth R. Morris9.1 Introduction 3619.1.1 Structure and Symmetry 3619.1.2 Process-induced Transformations (PITs) in 2 Manufacturing 3629.2 Secondary Manufacturing–Processing Materials to Yield Drug Products 3659.2.1 Milling of Organic Crystals 3669.2.1.1 Materials Properties Influencing Milling 3669.2.1.2 Physical Transformations Associated with Milling 3719.2.1.3 Chemical Transformations Associated with Milling 3759.2.2 Pharmaceutical Blending 3789.2.3 Granulation of Pharmaceutical Materials 3829.2.3.1 Wet Granulation 3849.2.3.2 Potential Transformations During Wet Granulation 3859.2.3.3 Hydration and Dehydration 3859.2.3.4 Solvent-mediated Transformations (SMT) 3889.2.3.5 Polymorphic Transitions During Granulation 3909.2.3.6 Salt Breaking 3929.2.3.7 Formulation Considerations in Wet Granulation 3929.2.3.8 Risk Assessment and Summary 3949.2.4 Consolidation of Organic Crystals 3959.2.4.1 Materials Properties Contributing to Effective Consolidation 3979.2.4.2 Structural and Molecular Properties Contributing to Effective Consolidation 4029.2.4.3 Macroscopic Properties Affecting Effective Consolidation 4039.2.4.4 Compaction-induced Material Transformations 4049.2.4.5 Compression Temperature and Material Transformation 4079.2.5 Data Management Approaches 4089.3 Summary and Concluding Remarks 4119.3.1 Development History 4119.3.2 Risk Assessment 412References 41210 Chemical Stability and Reaction 427Alessandra Mattei and Tonglei Li10.1 Introduction 42710.2 Overview of Organic Solid-state Reactions 42910.2.1 Photochemical Reactions 43110.2.2 Thermal Reactions 43210.2.3 Mechanochemical Reactions 43310.2.4 Hydrolysis Reactions 43410.2.5 Oxidative Reactions 43410.3 Mechanisms of Organic Solid-state Reactions 43610.3.1 General Theoretical Concepts 43610.3.2 Crystal Packing Effects on the Course of Organic Solid-state Reactions 43810.3.2.1 Perfect Crystals and Topochemical Control of Organic Solid-state Reactions 43810.3.2.2 Crystal Defects and Nontopochemical Control of Organic Solid-state Reactions 44010.4 Kinetics of Chemical Reactions: From Homogeneous to Heterogeneous Systems 44510.4.1 Fundamental Principles of Chemical Kinetics 44510.4.2 Solid-state Reaction Kinetics 44610.5 Factors Affecting Chemical Stability 44810.5.1 Moisture 44810.5.2 Temperature 44810.5.3 Pharmaceutical Processing 45010.6 Strategies to Prevent Chemical Reactions 45210.6.1 Formulation-related Approaches 45310.6.2 Prodrugs 454References 45511 Crystalline Nanoparticles 463Yi Lu, Wei Wu, and Tonglei Li11.1 Introduction 46311.2 Top-down Technology 46711.2.1 Media Milling (MM) 46711.2.2 High-pressure Homogenization (HPH) 46811.3 Bottom-up Technology 47111.3.1 Precipitation by Solvent–Antisolvent Mixing 47111.3.1.1 Sonoprecipitation 47311.3.1.2 CIJP 47311.3.1.3 HGCP 47611.3.2 Supercritical Fluid Techniques 47611.3.2.1 RESS 47811.3.2.2 SAS 47911.3.3 Precipitation by Removal of Solvent 47911.3.3.1 SFL 47911.3.3.2 CCDF 47911.4 Nanoparticle Stabilization 48011.5 Applications 48211.5.1 Oral Drug Delivery 48211.5.2 Parenteral Drug Delivery 48411.5.3 Pulmonary Drug Delivery 48511.5.4 Ocular Drug Delivery 48611.5.5 Dermal Drug Delivery 48611.6 Characterization of Crystalline Nanoparticles 48711.6.1 Particle Size and Size Distribution 48711.6.2 Surface Charge 48711.6.3 Morphology 49111.6.4 Crystallinity 49111.6.5 Dissolution 491References 492Index 503

TONGLEI LI is Professor in Industrial & Physical Pharmacy at Purdue University, West Lafayette, IN. ALESSANDRA MATTEI is a Senior Scientist in Solid State Chemistry at AbbVie, North Chicago, IL.

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• List of Contributors xiiiPreface xv1 Crystallography 1Susan M. Reutzel-Edens and Peter Müller1.1 Introduction 11.2 History 61.3 Symmetry 71.3.1 Symmetry in Two Dimensions 71.3.2 Symmetry and Translation 111.3.3 Symmetry in Three Dimensions 121.3.4 Metric Symmetry of the Crystal Lattice 131.3.5 Conventions and Symbols 141.3.6 Fractional Coordinates 151.3.7 Symmetry in Reciprocal Space 151.4 Principles of X-ray Diffraction 171.4.1 Bragg’s Law 171.4.2 Diffraction Geometry 191.4.3 Ewald Construction 191.4.4 Structure Factors 211.4.5 Statistical Intensity Distribution 221.4.6 Data Collection 231.5 Structure Determination 241.5.1 Space Group Determination 241.5.2 Phase Problem and Structure Solution 251.5.3 Structure Refinement 281.5.3.1 Resonant Scattering and Absolute Structure 321.6 Powder Methods 331.6.1 Powder Diffraction 341.6.2 NMR Crystallography 351.7 Crystal Structure Prediction 391.8 Crystallographic Databases 411.9 Conclusions 42References 432 Nucleation 47Junbo Gong and Weiwei Tang2.1 Introduction 472.2 Classical Nucleation Theory 482.2.1 Thermodynamics 482.2.2 Kinetics of Nucleation 512.2.3 Metastable Zone 532.2.4 Induction Time 582.2.5 Heterogeneous Nucleation 602.3 Nonclassical Nucleation 632.3.1 Two-Step Mechanism 632.3.2 Prenucleation Cluster Pathway 662.4 Application of Primary Nucleation 662.4.1 Understanding and Control of Polymorphism 662.4.2 Liquid–Liquid Phase Separation 712.5 Secondary Nucleation 732.5.1 Origin from Solution 742.5.2 Origin from Crystals 752.5.3 Kinetics 762.5.4 Application to Continuous Crystallization 762.5.5 Crystal Size Distribution 792.5.6 Seeding 802.6 Summary 81References 823 Solid-state Characterization Techniques 89Ann Newman and Robert Wenslow3.1 Introduction 893.2 Techniques 903.2.1 X-ray Powder Diffraction (XRPD) 903.2.2 Thermal Methods 943.2.2.1 Differential Scanning Calorimetry 943.2.2.2 Thermogravimetric Analysis (TGA) 953.2.3 Spectroscopy 973.2.3.1 Infrared (IR) 973.2.3.2 Raman Spectroscopy 993.2.3.3 Solid-state Nuclear Magnetic Resonance (SSNMR) 1013.2.4 Water Sorption 1053.2.5 Microscopy 1063.3 Case Study LY334370 Hydrochloride (HCl) 1093.4 Summary 114References 1144 Intermolecular Interactions and Computational Modeling 123Alessandra Mattei and Tonglei Li4.1 Introduction 1234.2 Foundation of Intermolecular Interactions 1244.2.1 Electrostatic Interactions 1254.2.2 van der Waals Interactions 1264.2.3 Hydrogen-bonding Interactions 1274.2.4 π–π Interactions 1294.3 Intermolecular Interactions in Organic Crystals 1304.3.1 Approaches to Crystal Packing Description 1304.3.2 Impact of Intermolecular Interactions on Crystal Packing 1364.3.3 Impact of Intermolecular Interactions on Crystal Properties 1384.4 Techniques for Intermolecular Interactions Evaluation 1404.4.1 Crystallography 1404.4.2 Spectroscopy 1414.4.3 Computational Methods 1424.4.3.1 Lattice Energy 1444.4.3.2 Interaction Energy of Molecular Pairs from Crystal Structures 1474.5 Advances in Understanding Intermolecular Interactions 1494.5.1 Crystal Structure Prediction 1504.5.2 Electronic Structural Analysis 152References 1605 Polymorphism and Phase Transitions 169Haichen Nie and Stephen R. Byrn5.1 Concepts and Overview 1695.2 Thermodynamic Principles of Polymorphic Systems 1755.2.1 Monotropy and Enantiotropy 1765.2.2 Phase Rule 1795.2.3 Phase Diagrams 1795.2.4 Phase Stability Rule 1825.2.4.1 Heat of Transition Rule 1825.2.4.2 Heat of Fusion Rule 1825.2.4.3 Entropy of Fusion Rule 1835.2.4.4 Heat Capacity Rule 1835.2.4.5 Density Rule 1835.2.4.6 Infrared Rule 1835.2.5 Crystallization of Polymorphs 1845.2.5.1 Ostwald’s Rule of Stages 1845.2.5.2 Nucleation 1845.3 Stabilities and Phase Transition 1895.3.1 Thermodynamic Stability 1895.3.2 Chemical Stability 1895.3.3 Polymorphic Interconversions of Pharmaceuticals 1925.3.3.1 Effects of Heat, Compression, and Grinding on Polymorphic Transformation 1925.3.3.2 Solution-mediated Phase Transformation of Drugs 1935.4 Impact on Bioavailability by Polymorphs 1945.5 Regulatory Consideration of Polymorphism 1965.6 Novel Approaches for Preparing Solid State Forms 1995.6.1 High-throughput Crystallization Method 2005.6.2 Capillary Growth Methods 2005.6.3 Laser-induced Nucleation 2015.6.4 Heteronucleation on Single Crystal Substrates 2015.6.5 Polymer Heteronucleation 2015.7 Hydrates and Solvates 2025.7.1 Thermodynamics of Hydrates 2035.7.2 Formation of Hydrates 2045.7.3 Desolvation Reactions 2055.7.4 Phase Transition of Solvates/Hydrates in Formulation and Process Development 2075.8 Summary 209References 2106 Measurement and Mathematical Relationships of Cocrystal Thermodynamic Properties 223Gislaine Kuminek, Katie L. Cavanagh, and Naír Rodríguez-Hornedo6.1 Introduction 2236.2 Structural and Thermodynamic Properties 2246.2.1 Structural Properties 2246.2.2 Thermodynamic Properties 2266.2.2.1 Cocrystal Ksp and Solubility 2266.2.2.2 Transition Points 2296.2.2.3 Supersaturation Index Diagrams 2316.2.3 A Word of Caution About Cmax Obtained from Kinetic Studies 2326.3 Determination of Cocrystal Thermodynamic Stability and Supersaturation Index 2346.3.1 Keu Measurement and Relationships Between Ksp, SCC, and SA 2346.3.2 Cocrystal Solubility and Ksp 2416.3.3 Cocrystal Supersaturation Index and Drug Solubilization 2436.4 What Phase Solubility Diagrams Reveal 2466.5 Cocrystal Discovery and Formation 2496.5.1 Molecular Interactions That Play an Important Role in Cocrystal Discovery 2496.5.2 Thermodynamics of Cocrystal Formation Provide Valuable Insight into the Conditions Where Cocrystals May Form 2516.6 Cocrystal Solubility Dependence on Ionization and Solubilization of Cocrystal Components 2536.6.1 Mathematical Forms of Cocrystal Solubility and Stability 2536.6.2 General Solubility Expressions in Terms of the Sum of Equilibrium Concentrations 2576.6.3 Applications 2586.7 Conclusions and Outlook 265References 2657 Mechanical Properties 273Changquan Calvin Sun7.1 Introduction 2737.1.1 Importance of Mechanical Properties in Pharmaceutical Manufacturing 2737.1.2 Basic Concepts Related to Mechanical Properties 2747.1.2.1 Stress, Strain, and Poisson’s Ratio 2747.1.2.2 Elasticity, Plasticity, and Brittleness 2767.1.2.3 Classification of Mechanical Response 2777.2 Characterization of Mechanical Properties 2787.2.1 Experimental Techniques 2787.2.1.1 Single Crystals 2787.2.1.2 Bulk Powders 2817.2.1.3 Tablet Mechanical Properties 2827.3 Structure–Property Relationship 2847.3.1 Anisotropy of Organic Crystals 2847.3.2 Crystal Plasticity, Elasticity, and Fracture 2867.3.3 Role of Dislocation on Mechanical Properties 2877.3.4 Effects of Crystal Size and Shape on Mechanical Behavior 2897.4 Conclusion and Future Outlook 290References 2918 Primary Processing of Organic Crystals 297Peter L.D. Wildfong, Rahul V. Haware, Ting Xu, and Kenneth R. Morris8.1 Introduction 2978.1.1 Solid Form 2978.1.2 Morphology 2988.2 Primary Manufacturing: Processing Materials to Yield Drug Substance 3008.2.1 Crystallization (Solidification Processing) 3018.2.1.1 Solvent Power 3038.2.1.2 Solvent Classification 3058.2.1.3 Batch Crystallization 3078.2.1.4 Continuous Crystallization 3088.2.2 Filtration and Washing 3098.2.3 Drying (Removal of Crystallization Solvent) 3138.2.4 Preliminary Particle Sizing 3158.3 Challenges During Solidification Processing 3198.3.1 Polymorphism 3208.3.1.1 Cooling Crystallization 3228.3.1.2 Solvent Selection 3258.3.1.3 Antisolvent Crystallization 3288.3.1.4 Selective Crystallization Using Additives 3288.3.2 Hydrate and Organic Solvate Formation 3298.3.2.1 Hydrate Formation 3298.3.2.2 Organic Solvate Formation 3358.3.3 Solvent-mediated Transformations (SMTs) 3378.3.4 Morphology/Habit Control 3428.3.4.1 Predicting Solvent Effects on Crystal Habit 3438.3.4.2 Influence of Morphology on Surface Wetting 3468.3.5 Crystallization Process Control 3498.4 Summary and Concluding Remarks 350References 3519 Secondary Processing of Organic Crystals 361Peter L.D. Wildfong, Rahul V. Haware, Ting Xu, and Kenneth R. Morris9.1 Introduction 3619.1.1 Structure and Symmetry 3619.1.2 Process-induced Transformations (PITs) in 2 Manufacturing 3629.2 Secondary Manufacturing–Processing Materials to Yield Drug Products 3659.2.1 Milling of Organic Crystals 3669.2.1.1 Materials Properties Influencing Milling 3669.2.1.2 Physical Transformations Associated with Milling 3719.2.1.3 Chemical Transformations Associated with Milling 3759.2.2 Pharmaceutical Blending 3789.2.3 Granulation of Pharmaceutical Materials 3829.2.3.1 Wet Granulation 3849.2.3.2 Potential Transformations During Wet Granulation 3859.2.3.3 Hydration and Dehydration 3859.2.3.4 Solvent-mediated Transformations (SMT) 3889.2.3.5 Polymorphic Transitions During Granulation 3909.2.3.6 Salt Breaking 3929.2.3.7 Formulation Considerations in Wet Granulation 3929.2.3.8 Risk Assessment and Summary 3949.2.4 Consolidation of Organic Crystals 3959.2.4.1 Materials Properties Contributing to Effective Consolidation 3979.2.4.2 Structural and Molecular Properties Contributing to Effective Consolidation 4029.2.4.3 Macroscopic Properties Affecting Effective Consolidation 4039.2.4.4 Compaction-induced Material Transformations 4049.2.4.5 Compression Temperature and Material Transformation 4079.2.5 Data Management Approaches 4089.3 Summary and Concluding Remarks 4119.3.1 Development History 4119.3.2 Risk Assessment 412References 41210 Chemical Stability and Reaction 427Alessandra Mattei and Tonglei Li10.1 Introduction 42710.2 Overview of Organic Solid-state Reactions 42910.2.1 Photochemical Reactions 43110.2.2 Thermal Reactions 43210.2.3 Mechanochemical Reactions 43310.2.4 Hydrolysis Reactions 43410.2.5 Oxidative Reactions 43410.3 Mechanisms of Organic Solid-state Reactions 43610.3.1 General Theoretical Concepts 43610.3.2 Crystal Packing Effects on the Course of Organic Solid-state Reactions 43810.3.2.1 Perfect Crystals and Topochemical Control of Organic Solid-state Reactions 43810.3.2.2 Crystal Defects and Nontopochemical Control of Organic Solid-state Reactions 44010.4 Kinetics of Chemical Reactions: From Homogeneous to Heterogeneous Systems 44510.4.1 Fundamental Principles of Chemical Kinetics 44510.4.2 Solid-state Reaction Kinetics 44610.5 Factors Affecting Chemical Stability 44810.5.1 Moisture 44810.5.2 Temperature 44810.5.3 Pharmaceutical Processing 45010.6 Strategies to Prevent Chemical Reactions 45210.6.1 Formulation-related Approaches 45310.6.2 Prodrugs 454References 45511 Crystalline Nanoparticles 463Yi Lu, Wei Wu, and Tonglei Li11.1 Introduction 46311.2 Top-down Technology 46711.2.1 Media Milling (MM) 46711.2.2 High-pressure Homogenization (HPH) 46811.3 Bottom-up Technology 47111.3.1 Precipitation by Solvent–Antisolvent Mixing 47111.3.1.1 Sonoprecipitation 47311.3.1.2 CIJP 47311.3.1.3 HGCP 47611.3.2 Supercritical Fluid Techniques 47611.3.2.1 RESS 47811.3.2.2 SAS 47911.3.3 Precipitation by Removal of Solvent 47911.3.3.1 SFL 47911.3.3.2 CCDF 47911.4 Nanoparticle Stabilization 48011.5 Applications 48211.5.1 Oral Drug Delivery 48211.5.2 Parenteral Drug Delivery 48411.5.3 Pulmonary Drug Delivery 48511.5.4 Ocular Drug Delivery 48611.5.5 Dermal Drug Delivery 48611.6 Characterization of Crystalline Nanoparticles 48711.6.1 Particle Size and Size Distribution 48711.6.2 Surface Charge 48711.6.3 Morphology 49111.6.4 Crystallinity 49111.6.5 Dissolution 491References 492Index 503