Development of Continuous Anti-Solvent/Cooling Crystallization Process using Cascaded Mixed Suspension, Mixed Product Removal Crystallizers

Abstract

This paper describes a two-stage mixed-suspension, mixed-product removal (MSMPR) continuous crystallization developed for a pharmaceutical intermediate which uses anti-solvent and cooling to generate supersaturation. The results indicate that the stage in which anti-solvent is added has a significant influence on the final crystal properties, while purity and yield were nearly identical. The population balance model was employed to determine growth and nucleation kinetics through parameter estimation. With the incorporation of measured equilibrium distribution coefficients, the model was used to optimize crystal purity and yield of the product with respect to operating temperature and residence time.

Design and optimization of a multistage continuous cooling mixed suspension, mixed product removal crystallizer

“…Considering that current crystallizers in industry are of the stirred tank type, the MSMPR perhaps affords the most convenient route of transition from batch to continuous operation (Chen et al, 2011). Much of the research into MSMPR crystallizers has focused on the development and characterization of the process itself and extraction of the kinetic data for various combinations of MSMPRs in series (Alvarez et al, 2011;Quon et al, 2012;Zhang et al, 2012). Few studies have focused on the utilization of the estimated parameters to develop design strategies to optimize the process.…”

Advanced control approaches for combined cooling/antisolvent crystallization in continuous mixed suspension mixed product removal cascade crystallizers

“…high yield) of having recycle loop in a single stage MSMPR crystallizer. A continuous CCAC process using two stage MSMPR cascade crystallizer was implemented by Zhang et al (2012), and was experimentally proved to be able to well control CSD, yield and purity. In these continuous MSMPR crystallization systems, process analytical technology (PAT) tools like focused beam reflectance measurement (FBRM) and high performance liquid chromatography (HPLC) were successfully implemented.…”

End‐to‐End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation

“…[20] The solution is cooled to 5 8C and mixed with the antisolvent heptane. The slurry is then fed into an in-house-built continuous filter (W 1).…”