(89b) Reaction Kinetics Modeling of a Challenging Amide Coupling Step: Quantitative Process Understanding and Enhanced Robustness

This talk will describe the development and application of a reaction kinetics model of an amide coupling step, which, due to the convergent nature of the synthesis and limited impurity rejection downstream, proved challenging. Incorporating the dissolution/desupersaturation kinetics of the poorly soluble starting materials, as well as a competitive hydrolysis side reaction, the model (1) identified the reactants’ stoichiometric ratio as a critical parameter and pinpointed the most reliable process center point, (2) evaluated in silico the process robustness improvement from proposed in-process control changes, (3) corrected prior assumptions of the phase equilibria, and lastly, (4) confirmed the causality between atypical experimental observations and poor moisture control, helping to establish KF specifications of the reagents. Throughout the process development, the modeling and experimental efforts guided, refined, and validated each other synergistically. In summary, the reaction kinetics modeling enabled quantitative process understanding and enhanced the process robustness of a challenging step.