Implementation of Supersaturation Control In Large Scale Crystallization

Monday, October 17, 2011: 4:55 PM
202 B (Minneapolis Convention Center)
Brenda Remy1, Jose E. Tabora1, Amanda Rogers1, Jacob Albrecht1, Nathan Domagalski1, Hamm Jason2, Daniel Wasser2 and George Armenante2, (1)Chemical Development, Bristol-Myers Squibb Co., New Brunswick, NJ, (2)Chemical Development Operations, Bristol-Myers Squibb Co., New Brunswick, NJ

Development of robust and reliable crystallization processes is required to obtaine predictable and controlled physical properties of the crystallized material, particularly API’s.  Crystallization robustness requires control of mechanisms such as growth, secondary nucleation, agglomeration etc.  These mechanisms are generally dictated, in large part, by the supersaturation profile of the crystallization.  Crystallizations which control supersaturation to a uniformly low value are expected to provide maximum robustness of the final API quality and physical attributes.  Previous work reported laboratory scale implementations of supersaturation control during crystallizations [1-3].  In this work we describe the development of a supersaturation control methodology in a 50 L scale by connecting the PAT (ATR-FFTIRS)directly to the pilot plant’s process control system thus enabling constant supersaturation control of a temperature driven crystallization.  The workflow incorporated automatic diagnostic of a standard crystallization, calibration of the IR spectra, and crystallization control at different levels of constant relative super saturation.  This work also discusses the effect of different constant supersaturation crystallizations and seed protocols on the resulting crystal habit and size.

[1] Fujiwara, M.; Nagy, Z. K.; Chew, J. W.; Braatz, R. D. J. Process Contr.2005, 15, 493-504

[2] Cote el al., Org. Process Res. Dev.200913 (6), pp 1276–1283

[3] Yu, Z. Q.; Chow, P. S.; Tan, R. B. H. Ind. Eng. Chem. Res. 2006, 45,438-444

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