Separation Of Formoterol Enantiomers By Simulated Moving Bed Process

Formoterol (FMT) is an important drug for the treatment of asthma symptoms. Racemic formoterol has two enantiomers, RR-FMT and SS-FMT. It is reported that the treatment effect of RR-FMT is 1000 times that of SS-FMT, while SS-FMT has little drug’s effect and sometimes increases the level of the inflammatory cytokine. Therefore, the preparation of single enantiomer RR-FMT with high optical purity has becoming an important research direction in modern medication. The objective of this work is to investigate experimentally and theoretically the separation of racemic formoterol using simulated moving bed (SMB) process, that will lay a solid engineering foundation for the large-scale separation. The main contents and results are described as follows:Firstly, the chromatographic separation of racemic formoterol is carried out using four kinds of commercial chiral stationary phases, respectively, and it is found that Chiralcel OJ chiral stationary phase has a good resolution performance, being a promising chiral stationary phase. According to the solubility of formoterol in mobile phase and chromatographic separation efficiency of racemic formoterol on Chiralcel OJ column (150×4.6 mm,5μm), mobile phase is selected as ethanol/n-hexane/diethylamine (40/60/0.1, v/v/v). And then, the effects of operation conditions on resolution performance, including flowrate, feed concentration, feed injection amount and column temperature, et.al, are investigated, and the optimal operation conditions are determined for the chromatographic separation of racemic formoterolSecondly, binary competitive adsorption equilibrium isotherms of formoterol enantiomers on Chiralcel OJ stationary phase are measured using HPLC, and the experimental data are fitted with the isotherm model. Dynamic adsorption mathematic model is developed for the separation of formoterol enantiomers on Chiralcel OJ packed column. The model parameters are measured using pulse and adsorption-desorption experiments, and the dynamic adsorption mathematic model is verified by elution curves of formoterol enantiomers from Chiralcel OJ packed column. It provides basic information for the optimization of multi-column SMB process for the separation of formoterol enantiomers.Thirdly, the mathematic model of multi-column SMB process is developed, and the stable numerical solution is obtained using the orthogonal collocation method in finite element embodied in gPROMS software. According to Trangle theory, separation region of formoterol enantiomers is designed, and the effect of mass transfer resistance of particle, column number and configuration on separation region are discussed. Depending on the optimal operation conditions selected in separation region, it is found that formoterol enantiomers are separated by SMB process with the 98.0% purity of RR-FMT and SS-FMT.