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A Flow Reactor with Inline Analytics: Design and Implementation



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A Flow Reactor with Inline Analytics: Design and Implementation

Org. Process Res. Dev., 2014, 18 (11), pp 1315–1320
DOI: 10.1021/op5002512
pp 1315–1320
Publication Date (Web): October 13, 2014 (Article)
DOI: 10.1021/op5002512
A continuous flow system complete with inline analytics is described. Sampling from a high pressure reactor and automated delivery mechanisms are detailed. The ability of the system to maintain critical process parameters (CPP) throughout a reaction process is demonstrated. Setup performance was evaluated using the Claisen rearrangement of allyl phenyl ether (1).
Flow synthesis has garnered industrial interest from the promise of reducing wasteful and inefficient batch-manufacturing process development(1) by replacing the conventional “scale up” approach with “scale out” continuous production.(2) The development of synthetic protocols to supply material for early phase discovery (medicinal chemistry), formulation, and clinical trials consumes significant time and resources and carries a high cost.(3) Further, the effort put into developing a robust and compliant batch scale-up methodology goes for naught if the active pharmaceutical ingredient (API) ultimately fails later stage trials. By developing a flow process early on, any amount of product required may be obtained by running the flow system with the same conditions for the appropriate length of time. The promise of flow technology is that, once optimized, a process remains viable through the entire drug development process. Furthermore, quality by design (QbD) can be facilitated by flow synthesis because of the ability to closely monitor and control CPPs (those parameters “whose variability has an impact on a critical quality attribute (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality,” e.g., temperature, flow rate, stoichiometry; “where a CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality,”(4) e.g., yield, impurity) during a run.(5) Ultimately, flow-reactor technology will be employed for full-scale commercial API production.(6)
  • 1.

    Wu, H., Dong, Z., Haitao, L., and Khan, M. Org. Process Res. Dev. 2014, 18, 10.1021/op500056a.

  • 2.

    (a) Razzaq, T.; Kappe, C. O. Chem.—Asian J. 2010, 5, 12741289

    (b) Wiles, C.; Watts, P. Green Chem. 2014, 16, 5562

    (c) Moseley, J. D.; Woodman, E. K. Org. Process Res. Dev. 2008, 12, 967981

  • 3.

    Ullah, F.; Samarakoon, T.; Rolfe, A.; Kurtz, R. D.; Hanson, P. R.; Organ, M. G. Chem.—Eur. J. 2010, 16, 1095910962

    and references cited therein

  • 4.

    Guidance for Industry, Q8(R2) Pharmaceutical Development; U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research: Silver Springs, MD, 2009; p 18.

  • 5.

    Calibrese, G. S.; Pissavini, S. AIChE J. 2011, 54, 828834

  • 6.

    (a) Alsten, J. G.; Reeder, L. M.; Stanchina, C. L.; Knoechel, D. J. Org. Process Res. Dev. 2008, 12, 989994

    (b) Roberge, D. M.; Zimmermann, B.; Rainonee, F.; Gottsponer, M.; Eyholzer, M.; Kockmann, N. Org. Process Res. Dev. 2008, 12, 905910

Vijay Kirpalani

Vijay Kirpalani


Pi-inc (Process Intensification Experts LLP)


Toronto, canada

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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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