Hsien-Hsin Tung, PhD, is the co-founder of AcrysPharm, LLC. He founded the crystallization lab. at Merck and center of excellence of particle engineering at AbbVie. Edward L. Paul, PhD, (deceased) was retired Director of Chemical Engineering R & D at Merck Research Laboratories. Michael Midler, PhD, (deceased) was retired Senior Investigator, Chemical Engineering R&D at Merck. James A. McCauley, PhD, was a senior investigator in the Analytical R & D at Merck until his retirement, after which he became an adjunct professor in the Department of Chemical and Biochemical Engineering at Rutgers University.

• Preface ix1. Introduction to Crystallization 11.1 Crystal Properties and Polymorphs (Chapters 2 and 3) 31.2 Nucleation and Growth Kinetics (chapter 4) 41.3 Mixing and Scale- Up (Chapter 5) 41.4 Critical Issues and Quality by Design (Chapter 6) 51.5 Crystallization Process Options (Chapters 7–10) 61.6 Downstream Operations (Chapters 11 And 12) 121.7 Special Applications (chapter 13) 132. Properties 152.1 Solubility 152.2 Supersaturation, Metastable Zone, and Induction Time 262.3 Oil, Amorphous, and Crystalline States 302.4 Polymorphism 362.5 Solvate 402.6 Solid Compound, Solid Solution, and Solid Mixture 422.7 Inclusion and Occlusion 452.8 Adsorption, Hygroscopicity, and Deliquesce 472.9 Crystal Morphology 502.10 Partical Size Distribution and Surface Area 533. Polymorphism 573.1 Phase Rule 573.2 Phase Transition 583.3 Prediction of Crystal Structure and its Formation 603.4 Selection and Screening of Crystal Forms 663.5 Examples 75Example 3.1 Indomethacin 76Example 3.2 Sulindac 77Example 3.3 Losartan 79Example 3.4 Finasteride 81Example 3.5 Ibuprofen Lysinate 83Example 3.6 HCl Salt of a Drug Candidate 84Example 3.7 Second HCl Salt of a Drug Candidate 87Example 3.8 Prednisolone t- Butylacetate 91Example 3.9 Phthalylsulfathiazole 934. Kinetics 954.1 Supersaturation and Rate Processes 964.2 Nucleation 974.3 Crystal Growth and Agglomeration 1054.4 Nucleate/Seed Aging and Ostwald Ripening 1164.5 Delivered Product: Purity, Cystal Form, Size and Morphology, and Chemical and Physical Stability 1194.6 Design of Experiment (DOE)— Model- Based Approach 1194.7 Model- Free Feedback Control 1235. Mixing and Crystallization 1255.1 Introduction 1255.2 Mixing Considerations and Factors 1265.3 Mixing Effects on Nucleation 1305.4 Mixing Effects on Crystal Growth 1355.5 Mixing Distribution and Scale- Up 1395.6 Crystallization Equipment 1415.7 Process Design and Examples 150Example 5.1 Mixing Impact on Crystallization Kinetics 150Example 5.2 Mixing Scale- Up Impact on Particle Size 1516. Critical Issues and Quality by Design 1556.1 Quality By Design 1556.2 Basic Properties 1566.3 Seed 1586.4 Supersaturation 1626.5 Mixing and Scale— Selection of Equipment and Operating Procedures 1726.6 Strategic Considerations for Crystallization Process Development 1746.7 Summary of Critical Issues 1767. Cooling Crystallization 1777.1 Batch Operation 1777.2 Continuous Operations 1837.3 Process Design— Examples 187Example 7.1 Intermediate in a Multistep Synthesis 187Example 7.2 Pure Crystallization of an API 191Example 7.3 Crystallization Using the Heel from the Previous Batch as Seed 194Example 7.4 Resolution of Ibuprofen Via Stereospecific Crystallization 195Example 7.5 Crystallization of Pure Bulk with Polymorphism 199Example 7.6 Continuous Separation of Stereoisomers 2018. Evaporative Crystallization 2078.1 Introduction 2078.2 Solubility Diagrams 2078.3 Factors Affecting Nucleation and Growth 2108.4 Scale- Up 2118.5 Equipment 2128.6 Process Design and Examples 215Example 8.1 Crystallization of a Pharmaceutical Intermediate Salt 215Example 8.2 Crystallization of the Sodium Salt of a Drug Candidate 217Example 8.3 API Hydrate with Low Water Solubility 2199. Anti- solvent Crystallization 2239.1 Operation 2239.2 In- Line Mixing Crystallization 2289.3 Process Design and Examples 229Example 9.1 Crystallization of an Intermediate 229Example 9.2 Rejection of Isomeric Impurities of Final Bulk Active Product 231Example 9.3 Crystallization of a Pharmaceutical Product with Strong Nucleation and Poor Growth Characteristics 234Example 9.4 Impact of Solvent and Supersaturation on Particle Size and Crystal Form 238Example 9.5 Crystallization of an API Using Impinging Jets 241Example 9.6 Crystallization of a Pharmaceutical Product Candidate Using an Impinging Jet with Recycle 245Example 9.7 In Situ Wet Seed and Particle Generation Using In- line Mixer 24910. Reactive Crystallization 25310.1 Introduction 25310.2 Control of Particle Size 25510.3 Key Issues in Organic Reactive Crystallization 25610.4 Creation of Fine Particles— In- Line Reactive Crystallization 26410.5 Process Design and Scale- Up 267Example 10.1 Reactive Crystallization of an API 267Example 10.2 Reactive Crystallization of an Intermediate 270Example 10.3 Reactive Crystallization of a Sodium Salt of an API 272Example 10.4 Reactive Crystallization of an API 27511. Filtration 27711.1 Introduction 27711.2 Basic Properties 27811.3 Kinetics 28011.4 Process Design and Scale- Up 290Example 11.1 Design of Cake Wash Composition and Wash Mode 29312. Drying 29712.1 Introduction 29712.2 Basic Properties 29812.3 Kinetics 30512.4 Process Design and Scale- Up 309Example 12.1 Scale- Up— Residual Solvent 311Example 12.2 Scale- Up— Particle Agglomeration and Fracturing 31413. Special Applications 31713.1 Introduction 31713.2 Crystallization with Supercritical Fluids 31813.3 Resolution of Stereo- Isomers 31913.4 Wet Mills in Crystallization 32013.5 Computational Fluid Dynamics in Crystallization 32113.6 Solid Dispersion— Crystalline and/or Amorphous Drugs 32113.7 Process Design and Examples 322Example 13.1 Sterile Crystallization of Imipenem 322Example 13.2 Enhanced Selectivity of a Consecutive–Competitive Reaction by Crystallization of the Desired Product During the Reaction 327Example 13.3 Applying Solubility to Improve Reaction Selectivity 330Example 13.4 Melt Crystallization of Dimethyl Sulfoxide 335Example 13.5 Freeze Crystallization of Imipenem 338Example 13.6 Continuous Separation of Stereoisomers 342Example 13.7 Hybrid Solid Dispersion 349References 355Index 363

Hsien-Hsin Tung, PhD, is the co-founder of AcrysPharm, LLC. He founded the crystallization lab. at Merck and center of excellence of particle engineering at AbbVie. Edward L. Paul, PhD, (deceased) was retired Director of Chemical Engineering R & D at Merck Research Laboratories. Michael Midler, PhD, (deceased) was retired Senior Investigator, Chemical Engineering R&D at Merck. James A. McCauley, PhD, was a senior investigator in the Analytical R & D at Merck until his retirement, after which he became an adjunct professor in the Department of Chemical and Biochemical Engineering at Rutgers University.

• Preface ix1. Introduction to Crystallization 11.1 Crystal Properties and Polymorphs (Chapters 2 and 3) 31.2 Nucleation and Growth Kinetics (chapter 4) 41.3 Mixing and Scale- Up (Chapter 5) 41.4 Critical Issues and Quality by Design (Chapter 6) 51.5 Crystallization Process Options (Chapters 7–10) 61.6 Downstream Operations (Chapters 11 And 12) 121.7 Special Applications (chapter 13) 132. Properties 152.1 Solubility 152.2 Supersaturation, Metastable Zone, and Induction Time 262.3 Oil, Amorphous, and Crystalline States 302.4 Polymorphism 362.5 Solvate 402.6 Solid Compound, Solid Solution, and Solid Mixture 422.7 Inclusion and Occlusion 452.8 Adsorption, Hygroscopicity, and Deliquesce 472.9 Crystal Morphology 502.10 Partical Size Distribution and Surface Area 533. Polymorphism 573.1 Phase Rule 573.2 Phase Transition 583.3 Prediction of Crystal Structure and its Formation 603.4 Selection and Screening of Crystal Forms 663.5 Examples 75Example 3.1 Indomethacin 76Example 3.2 Sulindac 77Example 3.3 Losartan 79Example 3.4 Finasteride 81Example 3.5 Ibuprofen Lysinate 83Example 3.6 HCl Salt of a Drug Candidate 84Example 3.7 Second HCl Salt of a Drug Candidate 87Example 3.8 Prednisolone t- Butylacetate 91Example 3.9 Phthalylsulfathiazole 934. Kinetics 954.1 Supersaturation and Rate Processes 964.2 Nucleation 974.3 Crystal Growth and Agglomeration 1054.4 Nucleate/Seed Aging and Ostwald Ripening 1164.5 Delivered Product: Purity, Cystal Form, Size and Morphology, and Chemical and Physical Stability 1194.6 Design of Experiment (DOE)— Model- Based Approach 1194.7 Model- Free Feedback Control 1235. Mixing and Crystallization 1255.1 Introduction 1255.2 Mixing Considerations and Factors 1265.3 Mixing Effects on Nucleation 1305.4 Mixing Effects on Crystal Growth 1355.5 Mixing Distribution and Scale- Up 1395.6 Crystallization Equipment 1415.7 Process Design and Examples 150Example 5.1 Mixing Impact on Crystallization Kinetics 150Example 5.2 Mixing Scale- Up Impact on Particle Size 1516. Critical Issues and Quality by Design 1556.1 Quality By Design 1556.2 Basic Properties 1566.3 Seed 1586.4 Supersaturation 1626.5 Mixing and Scale— Selection of Equipment and Operating Procedures 1726.6 Strategic Considerations for Crystallization Process Development 1746.7 Summary of Critical Issues 1767. Cooling Crystallization 1777.1 Batch Operation 1777.2 Continuous Operations 1837.3 Process Design— Examples 187Example 7.1 Intermediate in a Multistep Synthesis 187Example 7.2 Pure Crystallization of an API 191Example 7.3 Crystallization Using the Heel from the Previous Batch as Seed 194Example 7.4 Resolution of Ibuprofen Via Stereospecific Crystallization 195Example 7.5 Crystallization of Pure Bulk with Polymorphism 199Example 7.6 Continuous Separation of Stereoisomers 2018. Evaporative Crystallization 2078.1 Introduction 2078.2 Solubility Diagrams 2078.3 Factors Affecting Nucleation and Growth 2108.4 Scale- Up 2118.5 Equipment 2128.6 Process Design and Examples 215Example 8.1 Crystallization of a Pharmaceutical Intermediate Salt 215Example 8.2 Crystallization of the Sodium Salt of a Drug Candidate 217Example 8.3 API Hydrate with Low Water Solubility 2199. Anti- solvent Crystallization 2239.1 Operation 2239.2 In- Line Mixing Crystallization 2289.3 Process Design and Examples 229Example 9.1 Crystallization of an Intermediate 229Example 9.2 Rejection of Isomeric Impurities of Final Bulk Active Product 231Example 9.3 Crystallization of a Pharmaceutical Product with Strong Nucleation and Poor Growth Characteristics 234Example 9.4 Impact of Solvent and Supersaturation on Particle Size and Crystal Form 238Example 9.5 Crystallization of an API Using Impinging Jets 241Example 9.6 Crystallization of a Pharmaceutical Product Candidate Using an Impinging Jet with Recycle 245Example 9.7 In Situ Wet Seed and Particle Generation Using In- line Mixer 24910. Reactive Crystallization 25310.1 Introduction 25310.2 Control of Particle Size 25510.3 Key Issues in Organic Reactive Crystallization 25610.4 Creation of Fine Particles— In- Line Reactive Crystallization 26410.5 Process Design and Scale- Up 267Example 10.1 Reactive Crystallization of an API 267Example 10.2 Reactive Crystallization of an Intermediate 270Example 10.3 Reactive Crystallization of a Sodium Salt of an API 272Example 10.4 Reactive Crystallization of an API 27511. Filtration 27711.1 Introduction 27711.2 Basic Properties 27811.3 Kinetics 28011.4 Process Design and Scale- Up 290Example 11.1 Design of Cake Wash Composition and Wash Mode 29312. Drying 29712.1 Introduction 29712.2 Basic Properties 29812.3 Kinetics 30512.4 Process Design and Scale- Up 309Example 12.1 Scale- Up— Residual Solvent 311Example 12.2 Scale- Up— Particle Agglomeration and Fracturing 31413. Special Applications 31713.1 Introduction 31713.2 Crystallization with Supercritical Fluids 31813.3 Resolution of Stereo- Isomers 31913.4 Wet Mills in Crystallization 32013.5 Computational Fluid Dynamics in Crystallization 32113.6 Solid Dispersion— Crystalline and/or Amorphous Drugs 32113.7 Process Design and Examples 322Example 13.1 Sterile Crystallization of Imipenem 322Example 13.2 Enhanced Selectivity of a Consecutive–Competitive Reaction by Crystallization of the Desired Product During the Reaction 327Example 13.3 Applying Solubility to Improve Reaction Selectivity 330Example 13.4 Melt Crystallization of Dimethyl Sulfoxide 335Example 13.5 Freeze Crystallization of Imipenem 338Example 13.6 Continuous Separation of Stereoisomers 342Example 13.7 Hybrid Solid Dispersion 349References 355Index 363

Hsien-Hsin Tung, PhD, is the co-founder of AcrysPharm, LLC. He founded the crystallization lab. at Merck and center of excellence of particle engineering at AbbVie. Edward L. Paul, PhD, (deceased) was retired Director of Chemical Engineering R & D at Merck Research Laboratories. Michael Midler, PhD, (deceased) was retired Senior Investigator, Chemical Engineering R&D at Merck. James A. McCauley, PhD, was a senior investigator in the Analytical R & D at Merck until his retirement, after which he became an adjunct professor in the Department of Chemical and Biochemical Engineering at Rutgers University.

• Preface ix1. Introduction to Crystallization 11.1 Crystal Properties and Polymorphs (Chapters 2 and 3) 31.2 Nucleation and Growth Kinetics (chapter 4) 41.3 Mixing and Scale- Up (Chapter 5) 41.4 Critical Issues and Quality by Design (Chapter 6) 51.5 Crystallization Process Options (Chapters 7–10) 61.6 Downstream Operations (Chapters 11 And 12) 121.7 Special Applications (chapter 13) 132. Properties 152.1 Solubility 152.2 Supersaturation, Metastable Zone, and Induction Time 262.3 Oil, Amorphous, and Crystalline States 302.4 Polymorphism 362.5 Solvate 402.6 Solid Compound, Solid Solution, and Solid Mixture 422.7 Inclusion and Occlusion 452.8 Adsorption, Hygroscopicity, and Deliquesce 472.9 Crystal Morphology 502.10 Partical Size Distribution and Surface Area 533. Polymorphism 573.1 Phase Rule 573.2 Phase Transition 583.3 Prediction of Crystal Structure and its Formation 603.4 Selection and Screening of Crystal Forms 663.5 Examples 75Example 3.1 Indomethacin 76Example 3.2 Sulindac 77Example 3.3 Losartan 79Example 3.4 Finasteride 81Example 3.5 Ibuprofen Lysinate 83Example 3.6 HCl Salt of a Drug Candidate 84Example 3.7 Second HCl Salt of a Drug Candidate 87Example 3.8 Prednisolone t- Butylacetate 91Example 3.9 Phthalylsulfathiazole 934. Kinetics 954.1 Supersaturation and Rate Processes 964.2 Nucleation 974.3 Crystal Growth and Agglomeration 1054.4 Nucleate/Seed Aging and Ostwald Ripening 1164.5 Delivered Product: Purity, Cystal Form, Size and Morphology, and Chemical and Physical Stability 1194.6 Design of Experiment (DOE)— Model- Based Approach 1194.7 Model- Free Feedback Control 1235. Mixing and Crystallization 1255.1 Introduction 1255.2 Mixing Considerations and Factors 1265.3 Mixing Effects on Nucleation 1305.4 Mixing Effects on Crystal Growth 1355.5 Mixing Distribution and Scale- Up 1395.6 Crystallization Equipment 1415.7 Process Design and Examples 150Example 5.1 Mixing Impact on Crystallization Kinetics 150Example 5.2 Mixing Scale- Up Impact on Particle Size 1516. Critical Issues and Quality by Design 1556.1 Quality By Design 1556.2 Basic Properties 1566.3 Seed 1586.4 Supersaturation 1626.5 Mixing and Scale— Selection of Equipment and Operating Procedures 1726.6 Strategic Considerations for Crystallization Process Development 1746.7 Summary of Critical Issues 1767. Cooling Crystallization 1777.1 Batch Operation 1777.2 Continuous Operations 1837.3 Process Design— Examples 187Example 7.1 Intermediate in a Multistep Synthesis 187Example 7.2 Pure Crystallization of an API 191Example 7.3 Crystallization Using the Heel from the Previous Batch as Seed 194Example 7.4 Resolution of Ibuprofen Via Stereospecific Crystallization 195Example 7.5 Crystallization of Pure Bulk with Polymorphism 199Example 7.6 Continuous Separation of Stereoisomers 2018. Evaporative Crystallization 2078.1 Introduction 2078.2 Solubility Diagrams 2078.3 Factors Affecting Nucleation and Growth 2108.4 Scale- Up 2118.5 Equipment 2128.6 Process Design and Examples 215Example 8.1 Crystallization of a Pharmaceutical Intermediate Salt 215Example 8.2 Crystallization of the Sodium Salt of a Drug Candidate 217Example 8.3 API Hydrate with Low Water Solubility 2199. Anti- solvent Crystallization 2239.1 Operation 2239.2 In- Line Mixing Crystallization 2289.3 Process Design and Examples 229Example 9.1 Crystallization of an Intermediate 229Example 9.2 Rejection of Isomeric Impurities of Final Bulk Active Product 231Example 9.3 Crystallization of a Pharmaceutical Product with Strong Nucleation and Poor Growth Characteristics 234Example 9.4 Impact of Solvent and Supersaturation on Particle Size and Crystal Form 238Example 9.5 Crystallization of an API Using Impinging Jets 241Example 9.6 Crystallization of a Pharmaceutical Product Candidate Using an Impinging Jet with Recycle 245Example 9.7 In Situ Wet Seed and Particle Generation Using In- line Mixer 24910. Reactive Crystallization 25310.1 Introduction 25310.2 Control of Particle Size 25510.3 Key Issues in Organic Reactive Crystallization 25610.4 Creation of Fine Particles— In- Line Reactive Crystallization 26410.5 Process Design and Scale- Up 267Example 10.1 Reactive Crystallization of an API 267Example 10.2 Reactive Crystallization of an Intermediate 270Example 10.3 Reactive Crystallization of a Sodium Salt of an API 272Example 10.4 Reactive Crystallization of an API 27511. Filtration 27711.1 Introduction 27711.2 Basic Properties 27811.3 Kinetics 28011.4 Process Design and Scale- Up 290Example 11.1 Design of Cake Wash Composition and Wash Mode 29312. Drying 29712.1 Introduction 29712.2 Basic Properties 29812.3 Kinetics 30512.4 Process Design and Scale- Up 309Example 12.1 Scale- Up— Residual Solvent 311Example 12.2 Scale- Up— Particle Agglomeration and Fracturing 31413. Special Applications 31713.1 Introduction 31713.2 Crystallization with Supercritical Fluids 31813.3 Resolution of Stereo- Isomers 31913.4 Wet Mills in Crystallization 32013.5 Computational Fluid Dynamics in Crystallization 32113.6 Solid Dispersion— Crystalline and/or Amorphous Drugs 32113.7 Process Design and Examples 322Example 13.1 Sterile Crystallization of Imipenem 322Example 13.2 Enhanced Selectivity of a Consecutive–Competitive Reaction by Crystallization of the Desired Product During the Reaction 327Example 13.3 Applying Solubility to Improve Reaction Selectivity 330Example 13.4 Melt Crystallization of Dimethyl Sulfoxide 335Example 13.5 Freeze Crystallization of Imipenem 338Example 13.6 Continuous Separation of Stereoisomers 342Example 13.7 Hybrid Solid Dispersion 349References 355Index 363