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|Title: ||Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical|
|Authors: ||Heider, Patrick L.|
Evans, James M.B.
Jamison, Timothy F.
Jensen, Klavs F.
|Issue Date: ||2014|
|Publisher: ||© American Chemical Society|
|Citation: ||HEIDER, 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|
|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-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.|
|Description: ||This 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].|
|Sponsor: ||Novartis International AG|
|Version: ||Accepted for publication|
|Publisher Link: ||http://dx.doi.org/10.1021/op400294z|
|Appears in Collections:||Published Articles (Chemical Engineering)|
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