Practical Process Research and Development

Chapter 1. Introduction

I Introduction

II Equipment Considerations on Scale

III Operations Preferred on Scale

IV Patent Considerations

V Summary and Perspective

Chapter 2. Process Safety

I Introduction

II Repercussions of Using Compounds Regarded as Environmental Hazards

III Toxicological Hazards of Compounds

IV Controlling Chemical Reaction Hazards

V Perspective on SAFETY

Chapter 3. Route Selection

I Introduction

II Green Chemistry Considerations

III Biotransformations

IV Sleuthing to Determine Routes used to Make Drugs

V COG Estimates

VI Summary and Perspective

Chapter 4. Reagent Selection

I Introduction

II Biocatalysis

III Strong Bases

IV Phase-Transfer Catalysis

V Peptide Coupling

VI Oxidations

VII Reductions

VIII Treatments to Remove a Boc Group

Chapter 5. Solvent Selection

I Introduction

II Using Azeotropes to Select Solvents

III Choosing Solvents to Increase Reaction Rates and Minimize Impurities

IV Impurities in Solvents and Reactions of Solvents

V Water as Solvent

VI Solvent Substitutions

VII Solvent-Free Processes

VIII Summary and Perspective

Chapter 6. Effects of Water

I Introduction

II Detecting and Quantitating Water

III Removing Water from Routine Organic Processing

IV Where to Monitor and Control Water

V Operations to Remove or Consume Water

VI Operations Where Water can be Crucial

VII Perspective

Chapter 7. In-Process Assays, In-Process Controls, and Specifications

I Introduction

II Understanding Critical Details Behind In-Process Assays

III Benefits of In-Process Assays In Optimizing Processes

IV In-Process Controls

V Specifications

VI Process Analytical Technology

VII Summary and Perspective

Chapter 8. Practical Considerations for Scale-Up

I Introduction

II SAFETY: Inert Atmospheres Reduce Risks

III Temperature Control

IV Heterogeneous Processing and Considerations for Agitation

V Additions and Mixing Considerations

VI Solvent Considerations

VII Simple Procedures

VIII Impact of IPCs on Processing

IX Consider the Volatility of Reaction Components, and Use of Pressure

X Practical Considerations for Efficient Workups and Isolations

XI Additional Considerations for Kilo Lab Operations

XII Summary and Perspective

Chapter 9. Optimizing Processes by Minimizing Impurities

I Introduction

II Benefits and Limitations of Heterogeneous Processing

III Decrease Side Products by Decreasing Degradation of Starting Materials

IV Controlling pH

V Addition Sequence, Duration of Addition, and Time Between Additions

VI Temperature Control

VII Minimizing Impurities Formed During Workup

VIII Factors Affecting Hydrogenations

IX Statistical Design of Experiments

X Reaction Kinetics

XI Alternative Addition Protocols, or Continuous Processing

XII Perspective

Chapter 10. Optimizing Organometallic Reactions

I Introduction

II Chemical Activation to Improve Reaction Conditions

III Operations to Minimize Side Reactions

IV Impact of Impurities

V Some Considerations for Heterogeneous Reactions

VI Perspective and Summary

Chapter 11. Workup

I Introduction

II Quenching Reactions

III Extractions

IV Treatment With Activated Carbon and Other Absorbents

V Filtration to Remove Impurities

VI Removing Metal Salts and Metals

VII Quenching and Working Up Biocatalytic Reactions

VIII Chromatography

IX Perspective on Workup

Chapter 12. Crystallization and Purification

I Introduction

II Slow Application of Crystallization Pressure, and Seeding

III Crystallization by Cooling

IV Crystallization by Concentrating

V Crystallization by Adding an Antisolvent

VI Reactive Crystallization

VII Handling and Isolating Water-Soluble Products

VIII Polymorphs

IX Processing Enantiomeric Crystals

X Guidelines for a Practical Crystallization

XI Perspective

Chapter 13. Final Product Form and Impurities

I Introduction

II Physicochemical Considerations in APIs and Final Form Selection

III Impurity Considerations in APIs

IV Genotoxic Impurities

V Stability of Drug Substance

VI Perspective and Summary

Chapter 14. Continuous Operations

I Introduction

II Microreactors and Small-Diameter Tubing for Scale-Up

III Continuous Operations using Tubing or Reactors of Larger Diameter

IV Summary and Perspective

Chapter 15. Refining the Process for Simplicity and Ruggedness

I Introduction

II The Importance of Mass Balances

III Documenting a Process for Technology Transfer

IV Case Studies on Refined Processes

V Summary and Perspective

Chapter 16. Process Validation and Implementation

I Introduction

II Laboratory Investigations Focused on Process Implementation

III Activities Prior to Introducing a Process to the Pilot Plant or Manufacturing Plant

IV Actions During Process Implementation

V Cleaning and Removing Water from Processing Equipment

VI Follow-Up After Process Introduction

VII Managing Outsourcing

VIII Summary and Perspective

Chapter 17. Troubleshooting

I Introduction

II Perspective