(355d) Automated Crystallization Platform: Integrating Hardware, Software, and PAT to Expedite the Process of Crystallization Development

In the absence of in situ monitoring techniques, crystallization development can prove labor intensive, requiring frequent sampling to monitor process variables such as solution concentration, crystal size distribution, etc. Frequent sampling for off-line analysis is inconvenient and may disturb the system, affecting the accuracy and limiting the completeness of the data collected. To this end, platforms have been developed that integrate process analytical technology (PAT) with hardware and software to enhance the efficiency and accuracy of data collection during crystallization studies [e.g., see Refs. 1 and 2]. This technology has been implemented at BMS for the study of both antisolvent and cooling crystallizations. Real-time readings from Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) spectroscopy and Focused Beam Reflectance Measurement (FBRM) are used to control solvent composition and temperature profiles for the crystallization process. In addition, automated experiments have been conducted to determine the solubility and metastable zone width, and monitor supersaturation throughout a recipe-driven antisolvent addition or cooling profile. This presentation will discuss results from the study of several pharmaceutical crystallizations, including those for late-stage active pharmaceutical ingredients (APIs). The productivity enhancements realized through the use of PAT, computer-driven hardware, and automated data analysis and visualization will also be described.

1. G. X. Zhou, M. Fujiwara, X. Y. Woo, E. Rusli, H.-H. Tung, C. Starbuck, O. Davidson, Z. Ge, and R. D. Braatz. Direct design of pharmaceutical antisolvent crystallization through concentration control. Crystal Growth & Design, 6, 892-898, 2006.

2. A. Cote, G. Zhou, and M. A. Stanik, Novel crystallization methodology to ensure isolation of the most stable crystal form, Organic Process Research & Development, 13, 1277-1283, 2009.