Population Balance Modeling to Predict Particle Size Distribution Upon Scale-up of a Combined Antisolvent and Cooling Crystallization of an Active Pharmaceutical Ingredient

Herein a population balance model (PBM) for a combined cooling and antisolvent crystallization process for an active pharmaceutical ingredient (API) has been developed, and utilized to predict the product PSD for two sets of four ~35 kg scale plant batches, with good agreement to data. The PBM was constructed from lab scale (~10 g) crystallization runs using seed and product particle size distribution (PSD) measurements along with concentration measurements of the API during batch desupersaturation experiments. The PBM model was then used to predict the product PSD for two sets of four plant batches, run using different reactors equipped with different agitator types operated at different agitation rates. Analysis of the crystallization kinetics reveals that secondary nucleation due to attrition has a strong influence on the PSD in the crystallization process of the API, thus mixing conditions (agitator type, agitator speed, pumping and power numbers) have a strong effect on PSD. The model provides a more...