Chiral Resolution of Raloxifene Mandelate Conglomerate: Investigating the Impact of Chirality on In Vitro Cytotoxic Potency against Breast Cancer Cell Lines

Chiral resolution of racemic mixtures stems from the stereospecific interaction between chiral counterparts of the interacting species. Unlike diastereomeric resolution, resolution achieved by an achiral agent depends on the spontaneity introduced by nucleation free energy barriers of the enantiopure and racemic crystals. The spontaneous resolution during crystallization via conglomeration of racemic salts of Raloxifene Mandelate is the first instance of a salt-based resolution of (±)mandelic acid with Raloxifene free base as the achiral resolving agent. Various analytical techniques are employed to substantiate the formation of the racemate and the conglomerate. Comparative Hirshfeld surface analysis and solubility studies are reported to correlate the structure–property relationships of the solid phases obtained. The chiral resolution of the racemic mandelate salt is achieved through seeded isothermal preferential crystallization, resulting in an enantiopurity of 86% under ambient conditions. The in vitro cytotoxic activity of Raloxifene Mandelate salts is evaluated across a dual panel of phenotypically distinct breast cancer cell lines under different stereochemical compositions, indicating a relatively better stereospecific competence for Raloxifene-(R)-Mandelate compared to -(S)- form and the marketed hydrochloride salt formulation.