(665a) Impurity Rejection in Crystallization –Quantification and Mechanisms

Other than isolating the product as a solid, the perhaps most important objective in crystallization of pharmaceuticals is purification. Nevertheless, most of the engineering research in academia and industry has been focused on particle size and polymorph control. Notwithstanding their importance, crystallization as a unit operation is relied on not just in the API step but across the entire synthetic scheme to reject a number of different impurities. These can be reagents, reaction by-products, process impurities, degradants, chiral impurities, inorganic impurities and even genotoxic impurities. Purification via crystallizations is thus critical in producing a drug substance that is suitable for pre-clinical and clinical trials and eventually for market demands. A stringent regulatory oversight is also in place to ensure that the API meets all purity and quality attributes prior to administration to humans.

In Pharma industry, most of the impurity control in crystallization has traditionally been carried out by synthetic chemists who mainly rely on a before and after approach that is highly empirical in nature. Presented herein is the use of engineering principles to accurately quantify rejection of impurities throughout the crystallization. Various mechanisms of impurity rejection are identified and linked to thermodynamic and/or kinetic effects. Case studies from pharmaceutical development are presented that provide a clear understanding on the impurity purge mechanisms and how they are affected by process conditions. This work thus enables simple control measures to be introduced in the crystallization process that are capable of producing materials with targeted purity profile, whether that is for toxicity studies or for clinical trials.