Development of a Mixing Model in the Scale-up of An API Crystallization

The conversion to product in a reactive-mixing system is governed in part by the scale and intensity of feed component segregation. During fed-batch anti-solvent crystallization, segregation drives the local-scale supersaturation, the magnitude of which influences nucleation and subsequent growth of crystals. Furthermore, the solvating ability of the anti-solvent system controls the nucleation order and dictates the required mixing intensity. This case study examines an approach to understanding and characterizing the role mixing plays during the development and scale-up of a drowning-out crystallization for a biopharmaceutical enzyme. Lasentec FBRM provided real-time feedback during ranging and scale-up studies, while a model competitive-parallel reaction system was adopted to gain insight into the feed-mixing process. These tools provided for a successful scale-up from the 20g bench scale to 30kg engineering runs.