Streamlining Process Research Via Reaction Progress Kinetic Analysis

Reaction progress kinetic analysis streamlines pharmaceutical process development by exploiting the extensive data sets available from accurate in-situ monitoring of global reaction progress under practical operating conditions. This methodology involves the graphical manipulation of a critical minimum set of carefully designed experiments that permits rapid extraction of key information about the reaction’s driving forces and its robustness. While classical kinetic analysis can provide concrentration dependences, RPKA provides the only in-situ method readily available for probing catalyst deactivation. RPKA may be used even before a mechanistic framework has been established, which is a requirement for use of tools such as Dynochem for kinetic analysis.  An advantage of the RPKA approach is that information may be rapidly obtained even in earliest process research studies and requires little mathematical prowess and no specialized computer programs. These studies may also help inform the direction of further reaction optimization to finalize the synthetic route and prepare for efficient scale-up. Examples from catalytic reactions ranging from Pd-catalyzed Buchwald-Hartwig amination and C-H functionalization to asymmetric organocatalytic Michael additions illustrate the use of the methodology.