Observation of Efficient Preferential Enrichment Phenomenon for a Cocrystal of (dl)-Phenylalanine and Fumaric Acid under Nonequilibrium Crystallization Conditions

Described is a new strategy using cocrystallization, one of the crystal engineering techniques, to convert a racemic compound crystal into a racemic mixed crystal which can show preferential enrichment, a symmetry-breaking spontaneous enantiomeric resolution phenomenon observed upon recrystallization of a certain kind of racemic mixed crystal with a fairly ordered arrangement of the two enantiomers under nonequilibrium conditions. The 1:1 cocrystal ( 2 ) of ( dl )-phenylalanine (Phe) and fumaric acid satisfied the requirements proposed for the occurrence of preferential enrichment, such as (i) a sufficient solubility difference (racemic crystal ≪ enantiomeric crystal), (ii) the occurrence of polymorphic transition during crystallization, and (iii) the deposition of nonracemic mixed crystals with a unique crystal structure, and thus successfully showed preferential enrichment. In contrast, a racemic compound ( dl )-Phe itself failed to show a polymorphic transition during crystallization and thereby preferential enrichment. These results indicate that (a) crystal engineering principles based on a high potential of two-component crystals to show a polymorphism and induce a polymorphic transition during crystallization can significantly contribute to the occurrence of preferential enrichment and (b) the proposed requirements described above for the occurrence of preferential enrichment are mandatory.