Phase Discrimination Extraction, Foam Fractionation Chiral Separation Of Drug Enantiomers

In this paper, Biphasic recognition chiral extraction was used to separate OFLX through adding different chiral selectors in two phases, and ofloxacin(OFLX) enantiomers was separated by a co-technology—bubble fractionation, with the help of solvent extraction. Meanwhile, inclusion ofβ-Cyclodextrin (β-CD) and L-Mandelic acid (L-MA) based on bubble fractionation was studied. The main contents can be summarized as follows:(1) The distribution behavior of OFLX enantiomers was examined in a two-phase system containing di(2-ethylhexyl) phosphoric acid (D2EHPA) with dibenzoyl-l-tartaric (L-(-)-DBTA) as complex chiral selectors in n-octanol andβ-CD in aqueous phase. Factors affecting the extraction were investigated, including the pH of aqueous phase, volume ratio of aqueous to organicphase, concentration ofβ-CD, concentration of OFLX, concentration of L-(-)-DBTA and the combination of extracting agent. The results showed that the enantiomeric excess value (e.e.%) was 40.4 and the enantioselectivity (a) was 2.48 with the aqueous phase pH 7.0, volume ratio of aqueous to organicphase 5:1, concentration ofβ-CD 0.011g/mL, concentration of OFLX 0.002g/mL, concentration of L-(-)-DBTA 0.055g/mL. Meanwhile, the possible mechanisms of chiral selectors and OFLX in the two phases for reaction in the separation process was discussed. It was found that the formation of mixed complex chiral selectors by mixingβ-CD and L-(-)-DBTA with D2EHPA in different phases can improve the capacity of enantioselective extraction obviously. It may be very helpful to optimize the extraction systems and realize thel arge-scale production of pure enantiomers.(2) A method of bubble fractionation, with the help of solvent extraction, was developed for the resolution of racemic ofloxacin (rac OFLX). In this method, L-(-)-DBTA, D2EHPA and sodium lauryl sulfate (SDS) were used as chiral collector, co-extractant and foamer, respectively. Several important parameters influencing the resolution performances, such as pH in aqueous phase, concentration of OFLX, concentration of L-(-)-DBTA, concentration of SDS and volume ratio of D2EHPA to n-octanol in solution, were investigated. The optimal resolution conditions were obtained with the aqueous phase pH 7, volume ratio of D2EHPA to n-octanol 6/14 in organic phase, concentration of SDS 0.42mg/mL, concentration of OFLX 1.67mg/mL, and concentration of L-(-)-DBTA 0.11g/mL. Under the optimal extraction conditions, the enantiomeric excess value(e.e.%) was 60.08 and the enantioselectivity (a) was 5.58. Meanwhile, the possible mechanism of chiral selectors and OFLX for reaction in the separation process was discussed. It was found that the capacity of enantioselective separation can be greatly improved by the co-technology.(3) A method of fractionation is a new developed technology, which is widely used in industry. Inclusion ofβ-CD and L-MA based on bubble fractionation was studied in this paper. The optimal resolution conditions were obtained with the solution pH 4.0, mass concentration ratio ofβ-CD to L- MA 10:1, reflux equilibration time of 30min, pH of solution of 2.0, gas flow rate of 37.5L/h. It was found that only one kind of compound was formed byβ-CD and L- MA.