Crystallization Improvements of a Diastereomeric Kinetic Resolution through Understanding of Secondary Nucleation

The crystallization of a diastereomeric kinetic resolution was studied as part of a continuous process improvement initiative. The isolated intermediate was failing optical purity specifications at a contract manufacturing site. These failed batches also exhibited longer filtration and drying times. Experimentation studied the significant secondary nucleation event observed during the process. By using the secondary nucleation induction temperature as the response variable, the shear rate introduced by the impeller and seed surface area were identified as the critical process parameters that significantly influence this significant secondary nucleation event. Scale-up implementation of the laboratory findings led to a more robust resolution process with no optical purity failure reported with well over 50 commercial batches executed. The results from the experimental studies are compared to those from various mechanistic models available in the literature.