Compressing Experiences of Optical Resolution Trials, Based on Diastereomeric Salt or Co-Crystal Formation, into Ternary Equilibrium Melting Phase Diagrams of Two Chiral Enantiomers and a Resolving Agent Molecule with the Help of DSC and Powder XRD

This study contains a combination of a review and a related individual case study, which discusses the possibility of predicting the success of enantiomers’ optical separation using fractional crystallization of diastereomeric salts. The key idea is to use relatively simple and rapid experimental methods, such as differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD), to construct ternary melting diagrams. These diagrams can be used for visualization and predicting compositional conditions favorable for successful separation. The main limitations are also mentioned, such as the ideal eutectic behavior of components and the need to identify all crystalline phases in the system. For demonstration, three novel studies, attempts in ternary resolution systems of racemic o- and p-chloromandelic acids with chiral 1-cyclohexylethylamine or pregabalin, resulting in either declined or promising aspects for a successful resolution, were completed, and the corresponding individual ternary phase diagrams have been compiled and presented, as well. In addition, indexing and modeling of one of the diastereomeric salts’ unit cells have been successfully carried out by means of powder X-ray diffraction, using the DASH software package.