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Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical
journal contributionposted on 2015-05-22, 14:55 authored by Patrick L. Heider, S.C. Born, S. Basak, Brahim BenyahiaBrahim Benyahia, Richard Lakerveld, Haitao Zhang, R. Hogan, L. Buchbinder, Aaron Wolfe, Salvatore Mascia, James M.B. Evans, Timothy F. Jamison, Klavs F. Jensen
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-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. © 2014 American Chemical Society.
Novartis International AG
- Aeronautical, Automotive, Chemical and Materials Engineering
- Chemical Engineering
Published inOrganic Process Research and Development
Pages402 - 409
CitationHEIDER, P.L. et al, 2014. Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical. Organic Process Research and Development, 18(3), pp. 402 - 409
Publisher© American Chemical Society
- AM (Accepted Manuscript)
Publisher statementThis work is made available according to the conditions of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence. Full details of this licence are available at: https://creativecommons.org/licenses/by-nc-nd/4.0/
NotesThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Process Research and Development, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [http://dx.doi.org/10.1021/op400294z].