A Slug Flow Platform with Multiple Process Analytics Facilitates Flexible Reaction Optimization.

Autor: Wagner F; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, Graz, 8010, Austria.; Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, 8010, Austria., Sagmeister P; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, Graz, 8010, Austria.; Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, 8010, Austria., Jusner CE; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, Graz, 8010, Austria.; Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, 8010, Austria., Tampone TG; Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Manee V; Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Buono FG; Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Williams JD; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, Graz, 8010, Austria.; Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, 8010, Austria., Kappe CO; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, Graz, 8010, Austria.; Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, 8010, Austria.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Apr; Vol. 11 (13), pp. e2308034. Date of Electronic Publication: 2024 Jan 25.
DOI: 10.1002/advs.202308034
Abstrakt: Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low-volume optimization experiments are reported. A Buchwald-Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self-optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using <10% of the material that would be required for standard flow operation. Finally, a chemometric model is built utilizing automated data handling and three subsequent validation experiments demonstrate good agreement between the slug flow reactor and a standard (larger scale) flow reactor.
(© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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