Development of Continuous Crystallization Processes Using a Single-Stage Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle

An ideal pharmaceutical crystallization process produces a pure product at a high yield while minimizing energy input, the process equipment footprint, and its complexity. A good candidate for such a process is a single-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer with recycle (SMR) system, where the characteristics of the refined crystal are controlled by the crystallization conditions of the MSMPR and the yield is manipulated by the recycle ratio. In this study, two continuous SMR systems, for the cooling crystallization of cyclosporine and the antisolvent-cooling crystallization of deferasirox, were developed. Both systems were designed to maintain the desired operating conditions inside the MSMPR crystallizer. For cooling crystallization, the recycle stream was concentrated via vacuum evaporation. For antisolvent-cooling crystallization, the desired solvent to antisolvent ratio was maintained by controlling the flow rates of feed, antisolvent, and recycle streams. The maximum experimental yield and purity of the crystals were determined as 91.8% and 94.3%, respectively (for cyclosporine) and 89.1% with 0.2 ppm impurity A, respectively (for deferasirox). For cyclosporine, this yield is 5.5% higher than that of a multistage MSMPR with a recycle system. Additionally, the SMR system is relatively simple, having a lower operational demand, in terms of space and number of unit operations required.