Crystallization of Organic Compounds

Preface ix 1. Introduction to Crystallization 1 1.1 Crystal Properties and Polymorphs (Chapters 2 and 3) 3 1.2 Nucleation and Growth Kinetics (chapter 4) 4 1.3 Mixing and Scale- Up (Chapter 5) 4 1.4 Critical Issues and Quality by Design (Chapter 6) 5 1.5 Crystallization Process Options (Chapters 7–10) 6 1.6 Downstream Operations (Chapters 11 And 12) 12 1.7 Special Applications (chapter 13) 13 2. Properties 15 2.1 Solubility 15 2.2 Supersaturation, Metastable Zone, and Induction Time 26 2.3 Oil, Amorphous, and Crystalline States 30 2.4 Polymorphism 36 2.5 Solvate 40 2.6 Solid Compound, Solid Solution, and Solid Mixture 42 2.7 Inclusion and Occlusion 45 2.8 Adsorption, Hygroscopicity, and Deliquesce 47 2.9 Crystal Morphology 50 2.10 Partical Size Distribution and Surface Area 53 3. Polymorphism 57 3.1 Phase Rule 57 3.2 Phase Transition 58 3.3 Prediction of Crystal Structure and its Formation 60 3.4 Selection and Screening of Crystal Forms 66 3.5 Examples 75 Example 3.1 Indomethacin 76 Example 3.2 Sulindac 77 Example 3.3 Losartan 79 Example 3.4 Finasteride 81 Example 3.5 Ibuprofen Lysinate 83 Example 3.6 HCl Salt of a Drug Candidate 84 Example 3.7 Second HCl Salt of a Drug Candidate 87 Example 3.8 Prednisolone t- Butylacetate 91 Example 3.9 Phthalylsulfathiazole 93 4. Kinetics 95 4.1 Supersaturation and Rate Processes 96 4.2 Nucleation 97 4.3 Crystal Growth and Agglomeration 105 4.4 Nucleate/Seed Aging and Ostwald Ripening 116 4.5 Delivered Product: Purity, Cystal Form, Size and Morphology, and Chemical and Physical Stability 119 4.6 Design of Experiment (DOE)— Model- Based Approach 119 4.7 Model- Free Feedback Control 123 5. Mixing and Crystallization 125 5.1 Introduction 125 5.2 Mixing Considerations and Factors 126 5.3 Mixing Effects on Nucleation 130 5.4 Mixing Effects on Crystal Growth 135 5.5 Mixing Distribution and Scale- Up 139 5.6 Crystallization Equipment 141 5.7 Process Design and Examples 150 Example 5.1 Mixing Impact on Crystallization Kinetics 150 Example 5.2 Mixing Scale- Up Impact on Particle Size 151 6. Critical Issues and Quality by Design 155 6.1 Quality By Design 155 6.2 Basic Properties 156 6.3 Seed 158 6.4 Supersaturation 162 6.5 Mixing and Scale— Selection of Equipment and Operating Procedures 172 6.6 Strategic Considerations for Crystallization Process Development 174 6.7 Summary of Critical Issues 176 7. Cooling Crystallization 177 7.1 Batch Operation 177 7.2 Continuous Operations 183 7.3 Process Design— Examples 187 Example 7.1 Intermediate in a Multistep Synthesis 187 Example 7.2 Pure Crystallization of an API 191 Example 7.3 Crystallization Using the Heel from the Previous Batch as Seed 194 Example 7.4 Resolution of Ibuprofen Via Stereospecific Crystallization 195 Example 7.5 Crystallization of Pure Bulk with Polymorphism 199 Example 7.6 Continuous Separation of Stereoisomers 201 8. Evaporative Crystallization 207 8.1 Introduction 207 8.2 Solubility Diagrams 207 8.3 Factors Affecting Nucleation and Growth 210 8.4 Scale- Up 211 8.5 Equipment 212 8.6 Process Design and Examples 215 Example 8.1 Crystallization of a Pharmaceutical Intermediate Salt 215 Example 8.2 Crystallization of the Sodium Salt of a Drug Candidate 217 Example 8.3 API Hydrate with Low Water Solubility 219 9. Anti- solvent Crystallization 223 9.1 Operation 223 9.2 In- Line Mixing Crystallization 228 9.3 Process Design and Examples 229 Example 9.1 Crystallization of an Intermediate 229 Example 9.2 Rejection of Isomeric Impurities of Final Bulk Active Product 231 Example 9.3 Crystallization of a Pharmaceutical Product with Strong Nucleation and Poor Growth Characteristics 234 Example 9.4 Impact of Solvent and Supersaturation on Particle Size and Crystal Form 238 Example 9.5 Crystallization of an API Using Impinging Jets 241 Example 9.6 Crystallization of a Pharmaceutical Product Candidate Using an Impinging Jet with Recycle 245 Example 9.7 In Situ Wet Seed and Particle Generation Using In- line Mixer 249 10. Reactive Crystallization 253 10.1 Introduction 253 10.2 Control of Particle Size 255 10.3 Key Issues in Organic Reactive Crystallization 256 10.4 Creation of Fine Particles— In- Line Reactive Crystallization 264 10.5 Process Design and Scale- Up 267 Example 10.1 Reactive Crystallization of an API 267 Example 10.2 Reactive Crystallization of an Intermediate 270 Example 10.3 Reactive Crystallization of a Sodium Salt of an API 272 Example 10.4 Reactive Crystallization of an API 275 11. Filtration 277 11.1 Introduction 277 11.2 Basic Properties 278 11.3 Kinetics 280 11.4 Process Design and Scale- Up 290 Example 11.1 Design of Cake Wash Composition and Wash Mode 293 12. Drying 297 12.1 Introduction 297 12.2 Basic Properties 298 12.3 Kinetics 305 12.4 Process Design and Scale- Up 309 Example 12.1 Scale- Up— Residual Solvent 311 Example 12.2 Scale- Up— Particle Agglomeration and Fracturing 314 13. Special Applications 317 13.1 Introduction 317 13.2 Crystallization with Supercritical Fluids 318 13.3 Resolution of Stereo- Isomers 319 13.4 Wet Mills in Crystallization 320 13.5 Computational Fluid Dynamics in Crystallization 321 13.6 Solid Dispersion— Crystalline and/or Amorphous Drugs 321 13.7 Process Design and Examples 322 Example 13.1 Sterile Crystallization of Imipenem 322 Example 13.2 Enhanced Selectivity of a Consecutive–Competitive Reaction by Crystallization of the Desired Product During the Reaction 327 Example 13.3 Applying Solubility to Improve Reaction Selectivity 330 Example 13.4 Melt Crystallization of Dimethyl Sulfoxide 335 Example 13.5 Freeze Crystallization of Imipenem 338 Example 13.6 Continuous Separation of Stereoisomers 342 Example 13.7 Hybrid Solid Dispersion 349 References 355 Index 363