Evaluation on Cocrystal Screening Methods and Synthesis of Multicomponent Crystals: A Case Study

Abstract

Screening of suitable coformers is a major challenge during the development of cocrystals. To guide and simplify the cocrystal synthesis process, we evaluated three different predictive methods as well as their combinations during the cocrystallization of 2-amino-4,6-dimethoxypyrimidine (MOP) with 63 components. The conductor-like screening model for the real solvents (COSMO-RS) approach offered the best predictive results among three methods with an overall success rate of 84.1%. When combined with molecular complementarity (MC) analysis, the success rate was up to 85.7%. The Hansen solubility parameters (HSP) method did not deliver a satisfying outcome no matter if used individually or in combination for the MOP system. In addition, based on the screened results, 21 new solid phases of MOP were experimentally observed. Among them, the crystal structures of 10 multicomponent crystals (cocrystals and salts) were revealed by single crystal X-ray diffraction analysis (SCXRD), and their thermodynamic and spectroscopy properties were also characterized. The Hirshfeld surface analysis and the molecular electrostatic potential (MEP) surface analysis were conducted to explore the interactions in multicomponent crystals and the origin for salts and cocrystals. The cases in this study not only enriched the solid forms of MOP, evidenced the feasibility of the combined screening method, but also set an effective example for choosing potential coformers to prepare multicomponent crystals.