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We recently introduced a thermodynamically based deracemization process, co-crystallization-induced spontaneous deracemization (CoISD). Following the successful development of the CoISD process, we aimed at improving both yield and deracemization and, consequently, the productivity of the process. As the process is based on co-crystallization of the target enantiomer combined with a racemization reaction of the undesired enantiomer, both reaction and crystallization kinetics and thermodynamics need to be considered for optimization. Taking previously published kinetic parameters into account, here we investigate the nature of the solvent, concentration of the racemizing agent, equivalent of the acid co-former, and temperature of the crystallization cell. The evaluation of each parameter allowed for improvement of the yield and/or deracemization, ultimately providing an optimized process with a yield of 73% of pure co-crystals for an overall deracemization of 80%, in parallel, highlighting the viability of recycling the remaining mother liquors.

In this paper, we identified a cocrystal conglomerate of mandelic acid using a drug compound as a coformer. We then developed a chiral resolution process based on preferential cocrystallization. Several versions of such a process were explored and optimized, leading to a successful resolution of mandelic acid, evidencing the efficiency of our system. Excellent enantiopurity (98–99%) was obtained with a process that can run for multiple cycles.