Use of a Polymer Additive To Enhance Impurity Rejection in the Crystallization of a Pharmaceutical Compound

The control of impurity content in active pharmaceutical ingredients is of utmost importance for the pharmaceutical industry. While crystallization is oftentimes used as an efficient and cost-effective means of achieving this purification, structurally similar impurities can be very difficult to separate via crystallization. The impact of nonadsorbing polymers on the crystallization of the compound of interest can be leveraged to enhance the purification of pharmaceutical molecules. Here we discuss a case study in which an impurity formed in a pilot plant batch at a level of 3% could not be adequately rejected using conventional crystallization processes. We used a polymer additive to modify the crystallization to enhance impurity rejection. The process was implemented on scale to successfully deliver the product with less than 0.1% of the impurity. We explain the observed influence of the polymer additive on the crystallization of the product by carrying out additional investigations and considering the effect of the additive on the energy barrier to nucleation and growth kinetics of the impurity crystals. This work demonstrates the utility of polymer additives in the crystallization process development of pharmaceutical compounds.