Continuous spherical crystallization of albuterol sulfate with solvent recycle system

Spherical crystallization enables the direct preparation of crystal agglomerates of active pharmaceutical ingredients (APIs) with improved crystal handling properties. The continuous spherical crystallization of albuterol sulfate as a model API was developed using a mixed-suspension, mixed-product removal (MSMPR) crystallizer. The application of a solvent recycling system for reuse of the antisolvent in the single-stage MSMPR crystallizer was also demonstrated. Spherical agglomerates of albuterol sulfate were obtained via antisolvent crystallization using the MSMPR crystallizer with water as the solvent and an ethyl acetate/emulsifier (Pluronic L-121) mixture as the antisolvent. Steady-state continuous spherical crystallization was rapidly achieved after 30 min, and a yield of >95% was obtained. The influence of process parameters such as the solvent/antisolvent ratio, emulsifier concentration, residence time, and reactor scale on the properties of the agglomerates formed during the crystallization process was examined. In the MSMPR crystallizer, the desired solvent to antisolvent ratio was maintained by controlling the flow rates of the feed, antisolvent, and recycle stream, and 90% of the mother liquor was recycled during the continuous spherical crystallization of albuterol sulfate by optimizing the rate of each stream.