Practical Process Research and Development

Designed to provide a comprehensive, step-by-step approach to organic process research and development in the pharmaceutical, fine chemical, and agricultural chemical industries, this book describes the steps taken, following synthesis and evaluation, to bring key compounds to market in a cost-effective manner. It describes hands-on, step-by-step, approaches to solving process development problems, including route, reagent, and solvent selection; optimising catalytic reactions; chiral syntheses; and "green chemistry."

Second Edition highlights:
• Reflects the current thinking in chemical process R&D for small molecules
• Retains similar structure and orientation to the first edition.
• Contains approx. 85% new material
• Primarily new examples (work-up and prospective considerations for pilot plant and manufacturing scale-up)
• Some new/expanded topics (e.g. green chemistry, genotoxins, enzymatic processes)
• Replaces the first edition, although the first edition contains useful older examples that readers may refer to

• Provides insights into generating rugged, practical, cost-effective processes for the chemical preparation of "small molecules"
• Breaks down process optimization into route, reagent and solvent selection, development of reaction conditions, workup, crystallizations and more
• Presents guidelines for implementing and troubleshooting processes

Industrial (primarily organic) chemists, and academicians (particularly those involved in a growing number of start-up companies) and students who need insight into industrial process R&D.

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