Crystallization of Organic Compounds: An Industrial Perspective

1. Introduction to Crystallization Issues.

1.1 Crystal Properties and Polymorphism (Chapters 2 and 3).

1.2 Nucleation and Growth Kinetics (Chapter 4).

1.3 Critical Issues (Chapter 5).

1.4 Mixing and Crystallization (Chapter 6).

1.5 Crystallization Process Options (Chapters 7–10).

1.6 Special Applications (Chapter 11).

1.7 Regulatory Issues.

2. Properties.

2.1 Solubility.

2.2 Supersaturation, Metastable Zone, and Induction Time.

2.3 Oil, Amorphous, and Crystalline States.

2.4 Polymorphism.

2.5 Solvate.

2.6 Solid Compound, Solid Solution, and Solid Mixture.

2.7 Inclusion and Occlusion.

2.8 Adsorption, Hygroscopicity, and Deliquescence.

2.9 Crystal Morphology.

2.10 Particle Size Distribution and Surface Area.

3. Polymorphism.

3.1 Phase Rule.

3.2 Phase Transition.

3.3 Examples.

Example 3-1 Indomethacin.

Example 3-2 Sulindac.

Example 3-3 Losartan.

Example 3-4 Finasteride.

Example 3-5 Ibuprofen Lysinate.

Example 3-6 HCl Salt of a Drug Candidate.

Example 3-7 Second HCl Salt of a Drug Candidate.

Example 3-8 Prednisolone t-Butylacetate.

Example 3-9 Phthalylsulfathiazole.

3.4 Future Direction.

4. Kinetics.

4.1 Supersaturation and Rate Processes.

4.2 Nucleation.

4.3 Crystal Growth.

4.4 Nucleate/Seed Aging and Ostwald Ripening.

4.5 Delivered Product: Size Distribution and Morphology.

5. Critical Issues in Crystallization Practice.

5.1 Introduction.

5.2 Nucleation.

5.3 Growth.

5.4 Oiling Out, Agglomeration/Aggregation.

5.5 Seeding.

5.6 Rate of Generation of Supersaturation.

5.7 Summary of Critical Issues.

6. Mixing and Crystallization.

6.1 Introduction.

6.2 Mixing Considerations.

6.3 Mixing Effects on Nucleation.

6.4 Mixing Effects on Crystal Growth.

6.5 Mixing Scale-up.

6.6 Crystallization Equipment.

Example 6-1.

7. Cooling Crystallization.

7.1 Batch Operation.

7.2 Continuous Operations.

7.3 Process Design—Examples.

Example 7-1 Intermediate in a Multistep Synthesis.

Example 7-2 Pure Crystallization of an API.

Example 7-3 Crystallization Using the Heel from the Previous Batch as Seed.

Example 7-4 Resolution of Ibuprofen Via Stereospecific Crystallization.

Example 7-5 Crystallization of Pure Bulk with Polymorphism.

Example 7-6 Continuous Separation of Stereoisomers.

8. Evaporative Crystallization.

8.1 Introduction.

8.2 Solubility Diagrams.

8.3 Factors Affecting Nucleation and Growth.

8.4 Scale-up 171

8.5 Equipment.

Example 8-1 Crystallization of a Pharmaceutical Intermediate Salt.

Example 8-2 Crystallization of the Sodium Salt of a Drug Candidate.

9. Antisolvent Crystallization.

9.1 Semibatch Operation.

Example 9-1 Crystallization of an Intermediate.

Example 9-2 Rejection of Isomeric Impurities of Final Bulk Active Product.

Example 9-3 Crystallization of a Pharmaceutical Product with Poor Nucleation and Growth Characteristics.

Example 9-4 Impact of Solvent and Supersaturation on Particle Size and Crystal Form.

9.2 In-Line Mixing Crystallization.

Example 9-5 Crystallization of an API Using Impinging Jets.

Example 9-6 Crystallization of a Pharmaceutical Product Candidate Using an Impinging Jet with Recycle.

10. Reactive Crystallization.

10.1 Introduction.

10.2 Control of Particle Size.

10.3 Key Issues in Organic Reactive Crystallization.

10.4 Scale-up.

Example 10-1 Reactive Crystallization of an API.

Example 10-2 Reactive Crystallization of an Intermediate.

Example 10-3 Reactive Crystallization of a Sodium Salt of an API.

Example 10-4 Reactive Crystallization of an API.

10.5 Creation of Fine Particles—In-Line Reactive Crystallization.

11. Special Applications.

11.1 Introduction.

11.2 Crystallization with Supercritical Fluids.

11.3 Ultrasound in Crystallization.

11.4 Computational Fluid Dynamics in Crystallization.

Example 11-1 Sterile Crystallization of Imipenem.

Example 11-2 Enhanced Selectivity of a Consecutive-Competitive Reaction by Crystallization of the Desired Product During the Reaction.

Example 11-3 Applying Solubility to Improve Reaction Selectivity.

Example 11-4 Melt Crystallization of Dimethyl Sulfoxide.

Example 11-5 Freeze Crystallization of Imipenem.

Example 11-6 Continuous Separation of Stereoisomers.

11.5 Strategic Considerations for Development of a New Crystallization Process.

References.

Index.