Spontaneous Resolution of RS-Fluoxetine to a Racemic Conglomerate upon Salt Formation with Oxalic Acid

Fluoxetine (Flx), an important active pharmaceutical ingredient (API) for the treatment of depression, is commercially available as a racemic hydrochloride salt. Interestingly, the spontaneous resolution of RS-Flx occurred upon salt formation with oxalic acid (H(2)Oxa). Single crystals of Flx hydrogen-oxalate salt (Flx HOxa) have been obtained by slow evaporation from solution. They have been examined by single-crystal and powder X-ray diffraction, chiral chromatography, thermal analysis, and equilibrium solubility, revealing that Flx HOxa salt crystallizes as a racemic conglomerate. In the salt structure, the Flx+... HOxa- ionic pairs assemble in 21-helical chains in the Sohncke space group P21 and Z' = 1, through N+H...O- H-bonds. Additional cationic homochiral chains are formed in the crystals through noncovalent interactions between helicoidal motifs. It was shown that Flx HOxa conglomerates are as thermally stable as the hydrochloride salt of Flx, confirmed by thermal analysis. The identification of Flx HOxa salt conglomerates is a crucial step for the further chiral resolution process for the API and is also a novel multicomponent crystal with promising properties for a new drug formulation.