Multistage Continuous Mixed-Suspension, Mixed-Product Removal (MSMPR) Crystallization with Solids Recycle

Continuous crystallization process has potential advantages such as lower cost and improved flexibility in pharmaceutical production when compared to batch crystallization. A good continuous crystallization process should achieve a high product yield and purity comparable to current batch crystallization processes. For compounds that have low growth rates, a high yield is difficult to achieve without long residence times. Solids recycle is a potential solution for this problem as it can increase the surface area of crystals in the crystallizer thus increasing the mass deposition rate. In this study, solids recycle was used in a two-stage continuous mixed-suspension, mixed-product removal (MSMPR) cooling crystallization. Manual solids recycle and the use of a designed column for automatic slurry concentration were employed. The crystallization of cyclosporine, which has very low growth rate (about 0.1 μm/min) at low temperatures in acetone, showed only 65.0% yield in a two-stage MSMPR without solids recycle. With solids recycle to the second stage and both stages, 75.3% and 79.8% in yield were achieved, respectively. The product purity remained the same, while the yield was enhanced. A population balance model was developed to estimate the final yield of continuous process with solids recycle. The simulation results showed that optimization in stage number, stage temperatures, and solids recycle ratios could improve the yield to 83.9% in four-stage MSMPR crystallization with solids recycle. This yield was close to the batch yield at equilibrium, i.e., 86.0%.