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Practical Process Research and Development - 2nd Edition - ISBN: 9780123865373, 9780123865380

Practical Process Research and Development

2nd Edition

A guide for Organic Chemists

Author: Neal Anderson
Hardcover ISBN: 9780123865373
Paperback ISBN: 9781493301256
eBook ISBN: 9780123865380
Imprint: Academic Press
Published Date: 9th April 2012
Page Count: 488
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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

Key Features

  • 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.

Table of Contents

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


No. of pages:
© Academic Press 2012
9th April 2012
Academic Press
Hardcover ISBN:
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About the Author

Neal Anderson

Neal G. Anderson, Ph.D., has worked for over 20 years in chemical process R&D in the pharmaceutical industry. He earned a B.S. degree from the University of Illinois and a Ph.D. in medicinal chemistry from the University of Michigan and completed post-doctoral studies at McNeil Laboratories. With almost 18 years in process R&D at Bristol-Myers Squibb Co. in New Brunswick, New Jersey, Dr. Anderson has extensive hands-on experience in the laboratory, pilot plant, and manufacturing facilities. He has made key contributions to processes for the manufacture of four major drug substances, including captopril, and has participated in 12 manufacturing start-ups and successfully introduced many processes to pilot plants. He received the Bristol-Myers Squibb President's Award and spot awards, and his final position was Principal Scientist.In 1997, Dr. Anderson established Process Solutions L.L.C., a consulting firm offering practical guidance on developing and implementing processes for bulk pharmaceuticals and fine chemicals. As part of these consulting services, he presents courses on selected aspects of practical process R&D.

Affiliations and Expertise

Neal G. Anderson, Anderson's Process Solutions LLC, Jacksonville, Oregon, USA


"This second edition text is at a more advanced level than the original, reflecting the abundant sources of information that have become available in the last ten years and the author’s reconsideration of this presentation. Anderson has worked for 30-plus years in the pharmaceutical industry. His text offers a step-by-step approach, beginning with discussion of how and why operations are carried out and then illustrating principles with examples. Coverage encompasses process safety; route, reagent, and solvent selection; effect of water; in-process assays, controls, and specifications; practical considerations for scale-up; refining the process for simplicity and ruggedness; and troubleshooting, among other topics." --Reference and Research Book News, August 2012

"I would hope that most readers of this journal are very familiar with the first edition of Neal Anderson’s excellent book on Chemical Process Research and Development and are as keen to see the second edition as I was. The good news is that the new edition is bigger (by over 100 pages), better than the original, and cheaper… The big improvement in the new edition is the layout so that the schemes are now much closer to the relevant text than before which makes reading that much easier…Overall this book is highly recommended even if you already have a copy of the original edition." --Organic Process Research and Development

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