Spherical Crystallization for Pharmaceutical Continuous Manufacturing System

Abstract

Spherical crystallization enables the fusion of pharmaceutical downstream manufacturing process by direct preparation of crystal agglomerates of active pharmaceutical ingredients (APIs) with improved crystal handling properties, the concept of which is suitable for effective pharmaceutical manufacturing. However, batch operation for spherical crystallization would be difficult to optimize the scale-up for large scale production because the phenomenon of spherical crystallization is complicated compared with conventional crystallization. The continuous spherical crystallization of salbutamol sulfate and fenofibrate as a model API was developed using a mixed-suspension, mixed-product removal (MSMPR) crystallizer. We demonstrated the continuous spherical crystallization of salbutamol sulfate and fenofibrate using MSMPR and the continuous production over 24 h. The controlling process conditions such as residence time during crystallization affected the characterization of spherical agglomeration of APIs. In the case of water soluble APIs such as salbutamol sulfate, the use of a large amount of organic solvent (antisolvent) would be issue for commercial production. The application of a solvent recycling system for reuse of the antisolvent in the single-stage MSMPR crystallizer was also demonstrated. In the MSMPR crystallizer, 90% of the mother liquor was recycled during the continuous spherical crystallization of salbutamol sulfate by optimizing the rate of each stream.