Digital Determination of Pars for the Synthesis of a Pharmaceutical Intermediate

This work describes the development of a first principles mathematical model for the digital determination of proven acceptable ranges (PARs) prior to the validation campaign of a pharmaceutical intermediate. The proposed model is capable of predicting the effect of catalyst, solvent composition,  and temperature on the reaction kinetics (i.e., it predicts yield, reaction time, and reaction selectivity). Semi-batch addition of the limiting reactant was the preferred approach to minimize the instantaneous excess of the other starting material (genotoxic impurity) needed to maintain the generation of polymeric impurities below a desired limit. In preparation for an upcoming validation campaign, the model will not only be used for digital PAR determination but also will be used to guide the identification of the  robust process center point, to describe the overall design space, and to perform the failure modes and effects analysis (FMEA).