Spontaneous resolution of RS-fluoxetine through tetrafluoroborate conglomerate salt and racemic kryptoracemate formation via the sulfate ion

Abstract

Obtaining stable conglomerates from racemic mixtures is desirable from the perspective of chiral resolution since they are a prerequisite for feasible and effective preferential crystallization. Here, we have found a conglomerate for racemic fluoxetine (Flx). By forming salts with tetrafluoroborate and sulfate anions, a racemic conglomerate and a kryptoracemate have formed, respectively. Their structures have been determined by single-crystal X-ray diffraction, and the phases have been characterized by thermal (differential calorimetry scanning and thermogravimetric analysis) analysis, powder X-ray diffraction analysis, aqueous solubility, and chiral chromatography. The absolute configuration of the homochiral fluoxetine tetrafluoroborate crystal was established through the Flack parameter method. The sulfate anion recognized the Flx enantiomer, but the ionic units are assembled in a racemic motif. The tetrahedral geometry of BF₄ supports the assembly of a 1D-chain screw arrangement of cations. The resulting 2D-screw arrangement of Flx-BF₄ is driven by NH⋯F and CH⋯F interactions. This feature provides lower thermal stability and water solubility to Flx-BF₄ when compared to the other Flx forms. The discovery of this novel Flx conglomerate salt opens up opportunities for the chiral resolution of Flx, supporting the development of pure enantiomer formulations of this compound.