Definitive screening designs for multistep kinetic models in flow

• Published in: Reaction chemistry & engineering Vol. 4; no. 9; pp. 1565 - 157
• Main Authors: Hone, Christopher A, Boyd, Alistair, O'Kearney-McMullan, Anne, Bourne, Richard A, Muller, Frans L
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 01.09.2019
• Subjects: Chemical synthesis; Continuous flow; Data points; Parameter identification; Parameter sensitivity; Rate constants; Screening
• ISSN: 2058-9883; 2058-9883
• DOI: 10.1039/c9re00180h

Currently, rate-based understanding of organic reactions employed in the manufacture of active pharmaceutical ingredients (APIs) is often not obtained. In many cases, the generation of kinetic models is still seen as a specialised and time intensive activity, which can only be justified at certain instances in development. In this Communication, we report the application of a definitive screening design (DSD) in combination with reaction profiling for the efficient collection of kinetic data. The experimental data (10 profiles, 40 experimental data points) were collected within a short time frame (<1 week) within a continuous flow reactor. The data were fitted to a multistep kinetic model consisting of 3 fitted rate constants and 3 fitted activation energies. The approach is demonstrated on a Friedel-Crafts type reaction used in the synthesis of an important API. Our approach enables early identification of the sensitivity of product quality to parameter changes and the early use of process models to identify optimal process-equipment combinations in silico , significantly reducing development time and scale-up risks. A definitive screening design (DSD) combined with reaction profiling was conducted using a flow reactor, in a short time frame, for the accurate estimation of kinetic parameters.