A Novel Mechanism of Preferential Enrichment Phenomenon Observed for the Cocrystal of (RS)-2-{4-[(4-Chlorophenoxy)methyl]phenoxy}propionic Acid and Isonicotinamide

A new entry of chiral anti-hyperlipoproteinemia drug is reported, showing an excellent preferential enrichment (PE) phenomenon which is not caused by a polymorphic transition during crystallization, but is proposed to occur by a novel mechanism involving partially irregular stacking of R and S homochiral two-dimensional (2D) sheets with a large dipole moment, followed by selective redissolution of one homochiral 2D sheet into the mother liquor during crystallization. The cocrystal composed of (RS)-2-{4-[(4-chlorophenoxy)methyl]phenoxy}propionic acid (CPPPA) and achiral isonicotinamide exhibited a substantial enrichment in the mother liquor up to 93 % ee by simply repeating recrystallization under nonequilibrium conditions using high supersaturation. Furthermore, the deposited crystals with low ee values obtained at the end of PE experiment were second harmonic generation (SHG)-positive, indicating the formation of homochiral domains in the deposited crystals, which reflects the proposed mechanism of PE.