Competitive Chiral Cocrystallization Inspired Enantioseparation: Mechanistic Insights into <i>R</i>/<i>S</i>-Mandelic Acid and <scp>d</scp>/<scp>l</scp>-Prolinamide

To enable efficient separation of chiral drugs and enhance their practical utility, this study investigates cocrystallization as a novel separation and purification strategy. Using R/S-mandelic acid and d/l-prolinamide as model compounds, we screened potential cocrystal/salt coformers and successfully synthesized seven novel chiral salts. The proton transfer was elucidated by analyzing molecular electrostatic potential differences at the hydrogen-bonding sites. Moreover, the formation mechanism of salts was explored through structural analyses, such as Hirshfeld surface calculations, energy framework assessments, and crystal void analysis. Considering the distinct properties of various chiral salts, we conducted competitive cocrystallization experiments, establishing a complementary chiral pairing principle that provides a theoretical foundation for cocrystallization-based chiral resolution. Based on these findings, we developed multiple processes for the separation of R- and S-mandelic acid as well as l- and d-prolinamide, achieving product purities exceeding 80%, which strongly demonstrate the feasibility of cocrystallization separation technology for chiral resolution. This work not only introduces a groundbreaking approach to chiral separation but also highlights the vast potential of cocrystallization technology in pharmaceutical purification and beyond.