Crystallization of Organic Compounds An

This book summarizes crystallization methodologies that have been developed and/or observed by the authors during their employment as Process Engineers in the Chemical Engineering Research & Development Department of the Merck Research Laboratories Division. Analysis covers the four major methods of carrying out crystallization operations, their strengths and potential issues, as well as numerous examples of crystallization processes from development through manufacturing scale. A key resource for chemical engineers, the book focuses primarily on the authors' experiences with various crystallization operations through examples as well as a summary experiences in guiding development and scale-up.

Hsien-Hsin Tung, PhD, was a senior investigator in Pharmaceutical Research & Development for Merck Research Laboratories until his retirement. Dr. Tung founded the Crystallization Laboratory in Chemical Engineering Research & Development, Merck Research Laboratories.

Edward L. Paul, PhD, is retired director of Chemical Engineering Research & Development at Merck Research Laboratories. In addition to numerous patents and publications, Dr. Paul was coauthor of several chapters in, and senior editor of, the Handbook of Industrial Mixing: Science and Practice (Wiley).

Michael Midler, PhD, is retired senior investigator, Chemical Engineering, with Merck Research Laboratories. His more recent patents and publications are primarily in processes for crystallization and the mixing of liquids. Dr. Midler coauthored, with Dr. Paul, "Mixing in the Fine Chemicals and Pharmaceutical Industries," in the Handbook of Industrial Mixing: Science and Practice.

James A. Mccauley, PhD, was a senior investigator in the Analytical Research Department for Merck Research Laboratories until his retirement. After that, he served as an adjunct professor for the Pharmaceutical Engineering Training Program in the Department of Chemical and Biochemical Engineering at Rutgers University.

Preface	p. ix
Introduction to Crystallization Issues	p. 1
Crystal Properties and Polymorphism (Chapters 2 and 3)	p. 2
Nucleation and Growth Kinetics (Chapter 4)	p. 3
Critical Issues (Chapter 5)	p. 3
Mixing and Crystallization (Chapter 6)	p. 4
Crystallization Process Options (Chapters 7-10)	p. 4
Special Applications (Chapter 11)	p. 9
Regulatory Issues	p. 10
Properties	p. 13
Solubility	p. 13
Supersaturation, Metastable Zone, and Induction Time	p. 21
Oil, Amorphous, and Crystalline States	p. 25
Polymorphism	p. 29
Solvate	p. 32
Solid Compound, Solid Solution, and Solid Mixture	p. 34
Inclusion and Occlusion	p. 37
Adsorption, Hygroscopicity, and Deliquescence	p. 39
Crystal Morphology	p. 42
Particle Size Distribution and Surface Area	p. 44
Polymorphism	p. 49
Phase Rule	p. 49
Phase Transition	p. 50
Examples	p. 52
Indomethacin	p. 53
Sulindac	p. 55
Losartan	p. 57
Finasteride	p. 58
Ibuprofen Lysinate	p. 61
HCI Salt of a Drug Candidate	p. 62
Second HCI Salt of a Drug Candidate	p. 66
Prednisolone t-Butylacetate	p. 70
Phthalylsulfathiazole	p. 74
Future Direction	p. 76
Kinetics	p. 77
Supersaturation and Rate Processes	p. 77
Nucleation	p. 79
Crystal Growth	p. 87
Nucleate/Seed Aging and Ostwald Ripening	p. 98
Delivered Product: Size Distribution and Morphology	p. 99
Critical Issues in Crystallization Practice	p. 101
Introduction	p. 101
Nucleation	p. 101
Growth	p. 104
Oiling Out, Agglomeration / Aggregation	p. 106
Seeding	p. 110
Rate of Generation of Supersaturation	p. 115
Summary of Critical Issues	p. 116
Mixing and Crystallization	p. 117
Introduction	p. 117
Mixing Considerations	p. 118
Mixing Effects on Nucleation	p. 119
Mixing Effects on Crystal Growth	p. 123
Mixing Scale-up	p. 126
Crystallization Equipment	p. 127
	p. 135
Cooling Crystallization	p. 137
Batch Operation	p. 137
Continuous Operations	p. 143
Process Design-Examples	p. 147
Intermediate in a Multistep Synthesis	p. 147
Pure Crystallization of an API	p. 150
Crystallization Using the Heel from the Previous Batch as Seed	p. 154
Resolution of Ibuprofen Via Stereospecific Crystallization	p. 155
Crystallization of Pure Bulk with Polymorphism	p. 160
Continuous Separation of Stereoisomers	p. 161
Evaporative Crystallization	p. 167
Introduction	p. 167
Solubility Diagrams	p. 167
Factors Affecting Nucleation and Growth	p. 170
Scale-up	p. 171
Equipment	p. 171
Crystallization of a Pharmaceutical Intermediate Salt	p. 175
Crystallization of the Sodium Salt of a Drug Candidate	p. 177
Antisolvent Crystallization	p. 179
Semibatch Operation	p. 179
Crystallization of an Intermediate	p. 184
Rejection of Isomeric Impurities of Final Bulk Active Product	p. 185
Crystallization of a Pharmaceutical Product with Poor Nucleation and Growth Characteristics	p. 188
Impact of Solvent and Supersaturation on Particle Size and Crystal Form	p. 192
In-Line Mixing Crystallization	p. 196
Crystallization of an API Using Impinging Jets	p. 197
Crystallization of a Pharmaceutical Product Candidate Using an Impinging Jet with Recycle	p. 204
Reactive Crystallization	p. 207
Introduction	p. 207
Control of Particle Size	p. 209
Key Issues in Organic Reactive Crystallization	p. 210
Scale-up	p. 218
Reactive Crystallization of an API	p. 218
Reactive Crystallization of an Intermediate	p. 223
Reactive Crystallization of a Sodium Salt of an API	p. 225
Reactive Crystallization of an API	p. 228
Creation of Fine Particles-In-Line Reactive Crystallization	p. 231
Special Applications	p. 235
Introduction	p. 235
Crystallization with Supercritical Fluids	p. 236
Ultrasound in Crystallization	p. 237
Computational Fluid Dynamics in Crystallization	p. 238
Sterile Crystallization of Imipenem	p. 238
Enhanced Selectivity of a Consecutive-Competitive Reaction by Crystallization of the Desired Product During the Reaction	p. 243
Applying Solubility to Improve Reaction Selectivity	p. 246
Melt Crystallization of Dimethyl Sulfoxide	p. 251
Freeze Crystallization of Imipenem	p. 255
Continuous Separation of Stereoisomers	p. 259
Strategic Considerations for Development of a New Crystallization Process	p. 272
References	p. 279
Index	p. 285
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Crystallization of Organic Compounds An Industrial Perspective

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