(606e) A Novel Computational Approach to Guide Impurities Rejection By Crystallization

Process organic impurities arise from many sources throughout the synthesis and storage of active pharmaceutical ingredients (APIs). These impurities may include the starting materials, intermediates, byproducts, reagents, and degradation products. Regulatory expectations for control of impurities in new drugs have been established through ICH guidelines, which outline requirements for the registration of new drugs. The most efficient approach to impurity rejection and control is provided by API (re)crystallization. Until recently, molecular modeling support was focused predominantly on rational solvent selection for impurity rejection, considering one impurity at a time in one solid form of API.¹ Here we present a new model that allows assessment and comparison of multiple impurities in parallel, and describes the effects of initial impurity concentration (or doping), as well as API solid form and impurity-lattice interaction on impurity rejection. The model was successfully tested on multiple public domain examples. In addition, a special validation study was designed for impurities rejection of an investigational drug candidate.

1. Abramov, Y.A. Rational Solvent Selection for Pharmaceutical Impurity Purge. Cryst. Growth Des. 2018, 18, 1208−1214.