Crystallization of Cyclosporine in a Multistage Continuous MSMPR Crystallizer

Crystallization processes can be batch or continuous. Potential advantages such as operating at steady state, small equipment size (relative to batch), and ability to recycle are encouraging the pharmaceutical industry to investigate continuous processes. In this work, a continuous cooling crystallization process for the immunosuppressant drug cyclosporine was developed. A multistage mixed suspension mixed product removal (MSMPR) crystallizer was employed which allowed simple analysis of kinetic parameters employing the population balance. Experimentally, the continuous crystallization system was able to operate without any dogging issues for more than four residence times. The experimental yield and purity of the crystals was determined as 71% and 96%, respectively (without recycle) and 87% and 94%, respectively (with recycle). In a batch cooling crystallization experiment, carried out under conditions similar to those of the continuous experiment without recycle, the experimental yield and purity of the crystals were 74% and 95%, respectively. The equilibrium distribution coefficients of cyclosporine impurities were measured experimentally as a function of impurity % of the starting solution. The distribution coefficients increase with a decrease in the purity of the starting solution, indicating a decrease in purification. The MSMPR model was used to estimate the nucleation and crystal growth rate kinetic parameters for cyclosporine crystallization and to evaluate the effect of process conditions on the purity of the crystals and the process yield. Results showed that the temperature of the third stage has a large impact on the final purity of the crystals. As the temperature of the third stage increases, the purity of the crystals also increases while the yield of the process decreases. The effect of recycle ratio on both crystal purity and process yield was also evaluated. A 93% process yield was obtained with a recycle ratio of 0.9. The yield of the process can be significantly improved by increasing the recycle ratio while the crystal purity decreases.