Continuous Crystallization of Cyclosporine: Effect of Operating Conditions on Yield and Purity

A continuous crystallization process has potential advantages such as lower cost and improved flexibility in pharmaceutical production when compared to batch crystallization. In this work, multistage continuous cooling crystallization processes for cyclosporine were developed. The approach demonstrated that optimization of stage conditions can be used to improve yield and purity. For a multi-impurity system such as cyclosporine, the segregation of each impurity should be estimated separately due to their different behaviors. The effective distribution coefficients of the impurities were calculated and related to the steady state mother liquor concentrations. A population balance and mass balance model including distribution coefficients for impurities was used to estimate maximum yields and purities that could be obtained at various operating conditions. The results showed the limitation in yield and purity improvement using a mixed-suspension, mixed-product removal cascade. In addition, optimization along with economic analysis can aid in determining operating conditions for a high yield with acceptable equipment and operation cost.