Chiral Separation Of Aminoglutethimide Enantiomers By Simulated Moving Bed Chromatography

Aminoglutethimide(AG) has been used clinically as a chiral drug in the treatment of hormone-dependent metastatic breast cancer. Each enantiomer of racemic aminoglutethimide presents different pharmacological activities, R-aminoglutethimide (R-AG) is proved to has a better treatment effect than S-aminoglutethimide (S-AG) and also to reduce the side effect compared with racemic aminoglutethimide. The objective of this work is to separate racemic aminoglutethimide by both simulated moving bed (SMB) and Varicol process in order to obtain high purity R-AG, and the separation performance of SMB and Varicol process are evaluated based on the theoretical and experimental researches. The main contents and results are described as follows:According to the solubility of aminogluththimide in mobile phase and the chromatographic separation efficiency of aminoglutethimide enantiomers in Chiralcel OD packed column, n-hexane-ethanol (30:70, v/v) with 0.1% menonethanolamine additive is selected as the mobile phase. Binary competitive adsorption equilibrium isotherms of aminoglutethimide enantiomers on Chiralcel OD stationary phase are measured using HPLC, and the experimental data are fitted with Modified Langmuir isotherm model with an acceptable accuracy. Dynamic adsorption mathematic model is developed for the separation of aminoglutethimide enantiomers on Chiralcel OD packed column, a stable numerical solution is obtained using the orthogonal collocation method in finite element embodied in gPROMS software, and the model parameters including column porosity, axial dispersion coefficient and mass transfer resistance coefficient are measured and estimated. The elution curves of aminoglutethimide enantiomers from Chiralcel OD packed column are investigated experimentally and theoretically to verify the developed model.Mathematic models for both SMB and Varicol processes are developed, respectively, and the stable numerical solutions are obtained using the orthogonal collocation method in finite element embodied in gPROMS software. According to "Trangle theory", the separation zones of aminoglutethimide enantiomers are calculated using the developed mathematic models, and the experimental separation conditions are determined from the separation zone. With the designed operation conditions, the enantioseparation of racemic aminogutethimide by SMB and Varicol processes are carried out in VARICOL-Micro unit, products of R-AG and S-AG with more than 99.0% purity are continuously obtained from the experiments. Comparing the separation performance of 5-column Varicol process with that of 6-column SMB process, a 20% increase in productivity is founded for Varicol process, which demonstrates that Varicol process could significantly improve the separation performance of traditional SMB process. Moreover, Varicol process with a lower column number will save the usage of the expensive chiral stationary phase, reduce the system pressure, decrease the separation cost.