Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical
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Author(s)
Heider, Patrick L.
Basak, Soubir
Benyahia, Brahim
Lakerveld, Richard
Zhang, Haitao
Hogan, Rachael
Buchbinder, Louis
Wolfe, Aaron
Mascia, Salvatore
Evans, James M. B.
Date Issued
February 2014
Journal
Organic Process Research & Development
Publisher
American Chemical Society (ACS)
Citation
Heider, Patrick L., Stephen C. Born, Soubir Basak, Brahim Benyahia, Richard Lakerveld, Haitao Zhang, Rachael Hogan, et al. “Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical.” Org. Process Res. Dev. 18, no. 3 (March 21, 2014): 402–409.
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Author's final manuscript
Abstract
The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h[superscript –1] of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid–liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90–95%) under closed-loop control despite process disturbances.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/op400294z
