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Practical Process Research and development; Development..Optimizing the Reaction by Minimizing Impurities



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Chapter 8 – Optimizing the Reaction by Minimizing Impurities

  • Process Solutions L.L.C., Nicasio, California

The goals of process optimization change with the successful development of a project from early process research through scale-up into dedicated manufacturing. This general order of optimization may differ according to the nature of the process being considered; for instance, a process generating an inordinate amount of waste may be optimized to decrease waste before scaling up to the pilot plant. The initial goal of all process research and development is to maximize the amount of product generated under the reaction conditions. This is done by driving the reaction to completion, that is, by consuming any starting material that is charged in limiting amounts and by generating product with a minimal amount of by-products. Once the in-process yield has been optimized, the maximum yield of isolated product is expected. Rapid optimization is possible by judiciously changing solvents, reagents, catalysts, and ligands; investigations in this area allow the chemist considerable room for creativity and simplifying a process. Such changes may generate different impurities in the isolated intermediates, and it may be necessary to examine the tolerance of subsequent processes for the new impurities.

I consult to the pharmaceutical and fine chemical industries on developing and trouble-shooting processes to efficiently prepare drug substances and intermediates on large scale.  Anticipating and avoiding problems are key for effective and efficient scale-up.  For 17 years I have been consulting and presenting short courses internationally on process chemistry R & D for “small molecules” (over 1400 participants from more than 160 companies).  Prior to consulting I worked at Bristol-Myers Squibb for 17 years.  During that time I had extensive hands-on experience with chemical process development in the lab, pilot plant, and manufacturing sites, including 12 manufacturing start-ups and process development for four major drugs and many new drug candidates.  I wrote Practical Process Research & Development (Academic Press, 2000; 2nd edition 2012).

Practical Process Research & Development describes the development of chemical processes for the pharmaceutical and fine chemicals industries.  It provides a comprehensive, step-by-step approach to process R & D, and it is designed for those who want insights into generating rugged, practical, cost-effective processes.  Guidelines for industrial process R & D are rarely taught in academia, although this book has been used as a textbook.  It is primarily used by those in industry.

The second edition updates the first edition and includes topics not covered in the first editionPPR&D 2nd ed Japanese cover, such as genotoxins, biocatalysis, green solvents, predicting effective solvent combinations, and process validation.  Almost 85% of the references cited were published after the first edition was published, and virtually all examples in the Figures are new.  Trevor Laird kindly wrote a forward for this edition.

The second edition has been translated into Japanese and graced with a handsome cover.  Noriaki Murase was the translation supervisor, and the translators were Shohei Imachi, Koreaki Imura, Dai Tatsuta, Taro Tsukude, Toyoharu Numata, Yujiro Furuya, Akira Manaka, and Noriaki Murase. Sayaka Nukatsuka was the editor. I am very grateful to these people for their hard work to translate my book.

I am grateful to Barry Sharpless and Jerry Moniot for writing forwards to the first edition  I am also grateful to the following people for their translations of the first edition of my book.  Noriaki Murase, Yoshinori Murata, Toyoharu Numata, Mio Sakai, and Tatsuo Ueki translated Practical Process Research & Development into Japanese.  Kwang-Hyun Ahn, Yeung-Ho Park, and Sung-Kwan Hwang  translated Practical Process Research & Development into Korean.  Zhinong Gao and Wenhao Hu translated Practical Process Research & Development into Chinese.


In the foreword to Neal Anderson’s second edition of Practical process research and development, Trevor Laird states that, in his opinion, this is the best book on process chemistry. Having just co-edited a book with similar subject matter, I agree that this is one of the best available, and would add that it is an exceptionally clear, well written and researched book. This edition is also special for its chronological flow from discovery to production. The author achieves this by having a good understanding of the subject from the process chemist perspective, though consequently the complementary area of process engineering is less well covered.
The book communicates the excitement of this highly creative subject, but also the responsibility that lies with every process development job. This is a timely update with discussions covering contemporary issues such as product safety, process waste, catalysis, continuous operations, optimisation and validation. The updated introduction has a fascinating discussion of recent events that are shaping the direction of the pharma industry. And new chapters on Process safety, Effects of water, Organometallic reactions and Work-up are highly pertinent and will be recognised by all those involved in process development day-to-day. I like the fact that green chemistry and chirality are woven into chapters, reflecting their status within the field.
The book is packed with useful facts and information making it very dense, yet its structure makes it easy to read and find them. Many of the figures and schemes provide contemporary illustrative examples, and the use of text boxes to highlight key facts facilitates browsing. I already recommend the first edition as essential reading to process chemistry and engineering students and academic staff, and am certain this second edition will rapidly establish itself with this audience and those in the wider process chemical industry. Congratulations to Anderson, and thank you; the hard work that has clearly gone into this book has been very worthwhile.
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Below my own thoughts of process chemist
  • Evaluate the existing synthesis and identify steps, or sequences in the route that may pose a problem for large scale synthesis
  • Propose alternatives to any problematic steps or sequences and then implement these alternatives bases upon laboratory experimentation using Ph.D. level chemists with process research expertise
  • Ensure the synthesis is suitable for the immediate needs of the project, which maybe for only a few kilograms of API
  • Ensure the synthesis is suitable for long term, large scale manufacturing
  • Optimize reagent charges, operating temperatures, concentrations, work-up conditions and volumes, and solvent use in general
  • Identify which steps can be combined to result in a “through process” and implement the through process
  • Optimize purification schemes by identifying key crystalline intermediates and remove chromatographies from the synthesis
  • Optimize recrystallization parameters to ensure consistently high purity with similar impurity profiles from batch to batch, with low mother liquor losses
  • Institute appropriate analytical controls for in-process assays, end of reaction specifications, and acceptable intermediate or API purity
  • The process research team works closely with the analytical team to integrate the chemistry and analytical controls into the process at an early stage of the development cycle. The process research is then documented into a JACS style development report that outlines the chemistry and synthetic approaches that were tried as part of the synthetic development effort. This development report also includes a detailed experimental with supporting analytical data for the successful chemistry that results from our effort.The experimental that is part of these development reports is much more detailed than any journal publication. When coupled with our analytical and cGMP capabilities, the process research we provide is an essential groundwork for any compound that is just advancing from nomination at the discovery phase into clinical trial development. The process we develop provides the foundation of the ultimate manufacturing process, and should not need any changes (at a later date), to the synthetic strategy or bond forming steps used to prepare the API.

1 Comment

  1. MK says:

    thanks it was really helpful

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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