Operating Strategy to Produce Consistent CSD in Combined Antisolvent-Cooling Crystallization Using FBRM

In this study, an operating strategy which uses focused beam reflectance measurement (FBRM) to achieve consistent product quality in a combined antisolvent-cooling crystallization process is developed. The proposed operating strategy involves rapid generation of seed crystals by antisolvent addition, which is followed by a seed conditioning process through gentle heating. Subsequently, the conditioned seed crystals are grown by combined antisolvent addition and cooling. FBRM statistics were used as indications for switching from one operating region to the subsequent one. The operating strategy is demonstrated for the crystallization of paracetamol in acetone water solution and glycine in water ethanol solution. The crystal size distribution (CSD) produced by this operating strategy is significantly more consistent than that produced by the unseeded antisolvent crystallization and slightly more consistent than that produced by seeded antisolvent crystallization. The proposed operating strategy also reduces agglomerations in product crystals substantially and is robust in the presence of initial concentration disturbances. Furthermore, a new implementation of a distance measure is proposed for quantitative assessment of product CSD consistency.