Practical Process Research and Development
A guide for Organic Chemists
- 2nd Edition - April 9, 2012
- Author: Neal G. Anderson
- Language: English
- Paperback ISBN:9 7 8 - 1 - 4 9 3 3 - 0 1 2 5 - 6
- Hardback ISBN:9 7 8 - 0 - 1 2 - 3 8 6 5 3 7 - 3
- eBook ISBN:9 7 8 - 0 - 1 2 - 3 8 6 5 3 8 - 0
Designed to provide a comprehensive, step-by-step approach to organic process research and development in the pharmaceutical, fine chemical, and agricultural chemical in… Read more
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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
- 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
- Edition: 2
- Published: April 9, 2012
- Language: English
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Neal G. Anderson
Neal G. Anderson is a synthetic organic chemist with over 40 years of experience in chemical process R&D in the pharmaceutical industry. He earned a B.S. degree in biology from the University of Illinois and a Ph.D. in medicinal chemistry from the University of Michigan, followed by industrial post-doctoral studies at McNeil Laboratories. He has extensive hands-on experience in the laboratory, pilot plant, and in manufacturing facilities. At Squibb / Bristol-Myers Squibb he made key contributions to processes for the manufacture of four major drug substances, including captopril, and has participated in 12 manufacturing start-ups and introductions of many processes to pilot plants. He received a BMS President's Award and spot awards, and his final position was Principal Scientist. In 1997, Anderson established Anderson’s Process Solutions L.L.C., a consulting firm based in the USA to offer 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. He is experienced in laboratory research, scale-up, and technology transfer to ensure reproducibility and optimal product quality.
Affiliations and expertise
Neal G. Anderson, Anderson's Process Solutions LLC, USARead Practical Process Research and Development on ScienceDirect