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.

Abstract:We report the mechanism and scope of "preferential enrichment", which is an unusual symmetry-breaking enantiomeric resolution phenomenon that is initiated by the solvent-assisted solid-to-solid transformation of a metastable polymorphic form into a thermodynamically stable one during crystallization from the supersaturated solution of certain kinds of racemic mixed crystals (i.e., solid solutions or pseudoracemates) composed of two enantiomers. The mechanism can well be interpreted in terms of a symmetrybreaking complexity phenomenon involving multistage processes that affect each other.

The preferential enrichment phenomenon has been observed for two neutral R-amino acids, leucine and alanine, by applying kinetic crystallization conditions using high concentrations and appropriate solvents. The mechanism of preferential enrichment of leucine and alanine is proposed on the basis of (i) the difference in solubility between the racemic and enantiomerically pure samples, (ii) the observation of polymorphic transition during crystallization by in situ attenuated total reflection infrared spectroscopy, (iii) the characterization of deposited crystals by X-ray crystallographic analysis, and (iv) the optical microscopic or atomic force microscopy observation of the crystal shape or surface, respectively.

Preferential enrichment is an unusual symmetry-breaking enantiomeric resolution phenomenon that is initiated by the solvent-assisted solid-to-solid transformation of a metastable polymorphic form into a thermodynamically stable one during crystallization from the supersaturated solution of a certain kind of racemic crystals. On the basis of the proposed mechanism of preferential enrichment, both induction and inhibition of preferential enrichment were successfully achieved by controlling the mode of the polymorphic transition during crystallization either by minor molecular modification or with appropriate seed crystals. Furthermore, by inducing a desired polymorphic transition during crystallization of several -amino acids or their cocrystals with dicarboxylic acids, which were classified as a racemic compound, preferential enrichment could also be accomplished.

An excellent chiral symmetry-breaking spontaneous enantiomeric resolution phenomenon, denoted preferential enrichment, was observed on recrystallization of the 1:1 cocrystal of dl-arginine and fumaric acid, which is classified as a racemic compound crystal with a high eutectic ee value (>95 %), under non-equilibrium crystallization conditions. On the basis of temperature-controlled video microscopy and in situ time-resolved solid-state (13) C NMR spectroscopic studies on the crystallization process, a new mechanism of phase transition that can induce preferential enrichment is proposed.