(406b) Continuous Processing As a Process Development Tool for Fast Reactions

Continuous processing is rarely seen as an investigational tool in the early development of chemical reactions in the pharmaceutical industry although it is sometimes most fit to provide needed kinetics and impurity profile related information. This is particularly the case for fast reactions that are sensitive to water and/or oxygen for which sampling may be challenging.

Our approach to reaction process development using a continuous process is showcased through a loop formation reaction in the presence of NaHMDS. The aim of the investigation is to optimize the reaction operating conditions by varying temperature and base composition. Process optimization has been achieved through a design of experiment approach encompassing eight operating conditions. The DOE was concluded in half a day and utilized only four grams of substrate. A statistical analysis of the experimental data allowed establishing correlations between the operating conditions and the impurity generation as well as obtaining reaction kinetics related information, thus leading to identifying optimal operating conditions. Conclusions drawn from this work have allowed a speedy and successful scale up to pilot plant scale.