Practical Process Research and Development

Practical Process Research and Development

A guide for Organic Chemists

2nd Edition - August 9, 1973

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  • Author: Neal Anderson
  • Paperback ISBN: 9781493301256
  • eBook ISBN: 9780123865380

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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

Product details

  • No. of pages: 488
  • Language: English
  • Copyright: © Academic Press 2012
  • Published: August 9, 1973
  • Imprint: Academic Press
  • Paperback ISBN: 9781493301256
  • eBook ISBN: 9780123865380

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

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