Crystallization Development of a Pharmaceutical API through Implementation of Real-Time Supersaturation Feedback Control

The powder properties of an Active Pharmaceutical Ingredient (API) often play an important role in drug product formulation and subsequent performance of the formulated product. Generally the physical properties of the drug substance are influenced by the conditions applied to the crystallization during the final isolation step of the API. The established theory of crystallization development indicates that the supersaturation profile throughout the crystallization is a key variable determining the particle size distribution. Thus an established and accepted procedure to increase the robustness of crystallization processes is to ensure a uniform supersaturation profile throughout the crystallization. However, off-line analysis of supersaturation is inconvenient, tedious, and may disturb the system leading to inaccurate data. A more streamlined approach is to monitor solution concentration in-situ through implementation of Process Analytical Technology (PAT). In this work, an automated platform developed to integrate PAT with feedback control software was used for crystallization data collection with minimal manual user input. Coupled with a Matlab-based data analysis and visualization package, a significantly enhanced crystallization data set was obtained for the crystallization of a BMS API. Results from implementation of relative and absolute supersaturation control as well as from imposed antisolvent profiles will be presented and discussed.