The Construction Of Theromosensitive Aqueous Two-phase System And Its Application In The Enantioseparation Of Chiral Drug

ABSTRACT:Aqueous two-phase system(ATPS) was applicated in many aspects owing to its advantages of mild operating conditions, strong processing capacity and easy-industrialization. However, traditional ATPS, such as polyethylene glycol(PEG)-Dextran, was expensive and lack of recoverability, which limited the applications to a large degree. In current study, Poly(MAH-β-CD-co-NIPAAm), a novel synthesized themosentive polymer, was used to form ATPS with dextrin40000. The ability of phase forming was researched, and the chiral separation of the mandelic acid’s racemates was studied by using the new ATPS. After enantioseparation procedure was accomplished, the polymer could be recycled by heating and centrifugation. It can overcome the difficulties of recycling phase compositions and chiral selector that existed in other liquid-liquid extraction technique. The theromosensitive ATPS is a green and economical approach for the chiral separation of mandelic acid.Firstly, the novel polymer was synthesized by copolymerization of N-isopropylazylamide with the monomer of madeic andydride modified (3-cyclodextrin. Its structure was characterized by DSC-TG and IR spectrum analysis. The polymer exhibits both chiral selectivity based on molecular recognition of (3-cyclodextrin and thermosensitivity due to the phase transition of Poly(N-isopropylazylamide). The yield of the product was46.7%under the optimal reaction condition:copolymerization time(24h), reaction temperature(70℃), molar ratio of NIPAAm and MAH-β-CD (14:1), the amount of initiator used (1.5%). Compared with Poly(N-isopropylazylamide), lower critical solution temperature(LCST) of Poly(MAH-(3-CD-NIPAAm) was higher and increased with the ratio of MAH-β-CD, which means the hydrophily of polymer increased after copolymerization. The polymer’s LCST could decrease under the condition of lower pH vaule and stronger ionic strength.Secondly, the ATPS formation ability of various polymers and salts with themosensive polymer were tested. The results showed that Poly(MAH-β-CD-NIPAAm) was easy to form ATPS with dextran40000. And the equilibrium curve, the tie line length and the slope of tie line were studied. The top phase and bottom phase ratio range from0.8-2.5indicated that this system has great ability to form ATPS. The phase ratio would change with the different environment temperature and ionic strength. The results showed that the top phase ratio decrease and the phase separation speed increase at the high temperature and ionic strength condition. Furthermore, the themosensitive ATPS phase separation achieved easily under the condition of high temperature and moderate pH value.Thirdly, the distribution behavior of mandelic acid was investigated in this novel ATPS mentioned above. The influencing parameters on the distribution behavior were studied respectively. The chiral separation factor a=1.27under the optimal separate condition:the mass fraction of Poly(MAH-β-CD-NIPAAm)(15.0wt%), pH(2.0), operational temperat-ure(℃5) and the initial concentration of mandelic acid enantiomers (10.0mmol/L). The results showed that this thermosensitive ATPS has chiral recognition ability for mandelic acid enantiomers and preferentially recognizes the (S)-enantiomer rather than the (R)-enantiomer.