(277a) Chiral Control of Enantiomers through Crystallization: Moving from Ternary Phase Diagrams to Design Spaces

Although chiral purity is a critical quality attribute for the majority of synthetic drugs being developed, the understanding of process design for chiral purity in terms of conventional batch crystallization processes is limited. The industrial implementation within this area has relied heavily on the construction of ternary phase diagrams, system classification, and the use of subject matter experts to determine thermodynamic operating policies. These operating policies have been developed to yield resulting solids with 100% ee; regardless of the product specification/target and the potential upgrades to ee remaining between the molecule being isolated and the drug substance. In the present work (which for simplicity is limited to the case of a single chiral center in the absence of salts, polymorphs, and solvates/hydrates), a new policy is proposed for obtaining resulting solids with ee < 100% but passing specifications for arbitrary systems. This operating policy can provide significant isolation yield improvements when compared to the conventional policy. Additionally, this work demonstrates an approach for the creation of design spaces for arbitrary ternary systems based on the collection of limited small (<10 g total) scale solubility data. This approach has been extended to processes with sequential re-crystallizations and can be used to determine “global” optimal policies for an entire synthetic route.