Green and Efficient Resolution of Racemic Ofloxacin Using Tartaric Acid Derivatives via Forming Cocrystal in Aqueous Solution

The separation of chiral compounds into their enantiomers is widely used in the pharmaceutical industry. Two types of environmentally benign tartaric acid derivatives, O,O′-dibenzoyl-(2S,3S)-tartaric acid (d-DBTA) and O,O′-dibenzoyl-(2R,3R)-tartaric acid (l-DBTA), were selected as efficient chiral selectors for the separation of racemic ofloxacin by forming diastereomeric cocrystal pairs in the aqueous phase. Effects of the type of chiral selectors, resolution time, the amounts of racemic ofloxacin, and temperature on the resolution performance of ofloxacin were investigated. The results indicated that d-DBTA selectively cocrystallized with the R-enantiomer (R-OFLX), while l-DBTA selectively cocrystallized with the S-enantiomer (S-OFLX) in the aqueous phase. Under the optimal conditions, the enantiomer excesses (% ee) reached up to 81.8% ee and 82.3% ee for S-OFLX and R-OFLX at 278.2 K, respectively. The stoichiometric ratio of d-DBTA or l-DBTA to R-ofloxacin or S-ofloxacin in cocrystals was 1:1. Various characterization and calculation methods, such as powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and density functional theory (DFT), were performed for the study of the resolution mechanism, the results of which demonstrated that the cocrystals were formed by hydrogen bonding between d-DBTA or l-DBTA and ofloxacin. Compared with previous studies, the proposed separation process was not only environmentally benign but also beneficial to increasing % ee. The proposed method has explored a new path for green and efficient separation of racemic compounds that cannot form salts.