The Preparative Separation Of Two Kind Of Drugs By Simulated Moving Bed Chromatography

The separation and purification of natural medicines and synthetic drugs from complex mixtures is a major step in drug production. Liquid chromatography is the main approach for the separation of difficult systems such as chiral drugs and natural product containing homologues. However, liquid chromatography is an expensive preparative technique and its application is limited to small scale. In order to solve this problem, researchers have invented some continuous chromatography techniques in the last few decades. Among them, simulated moving bed (SMB) is the most promising technique in industrial application. In the new century, SMB is more improved in terms of theories and equipments and is getting increasing attention in the pharmaceutical industry. SMB is a powerful method and is particularly useful for mixtures which have similarities in chemical structures and physical properties, such as enantiomers, isomers, and homologues. Compared with liquid chromatography, it has advantages in solvent consumption and productivity. In this work, some fundamental issues on the preparative separation of polyunsaturated fatty acid ethyl esters and citalopram racemates by SMB or supercritical fluid SMB (SF-SMB) were investigated. The main contents and results are described as follows:Ethyl esters of eicosapentaenoic acid (EPA-EE) and docosahexaenoic acid (DHA-EE) were separated based on C18 and poly(styrene-divinylbenzene) resin as stationary phases. The performance of different mobile phases on retention and resolution were investigated for the selection of a suitable desorbent for SMB. It was found that EPA-EE and DHA-EE were well separated on C18 and PSDVB resin semi-preparative columns. EPA-EE is the less retained component and DHA-EE is the more retained component for both stationary phases. The optimal mobile phase is pure methanol for C18 column with a resolution of 1.53, and the recommended mobile phase for PSDVB resin is a mixture of methanol and ethanol in a volume ratio of 70:30 with a resolution of 0.97.Adsorption equilibrium isotherms of EPA-EE and DHA-EE were measured on C18 and PSDVB resin using adsorption-desorption method. The experimental data were fitted by Langmuir isotherm model with an acceptable accuracy. The adsorption equilibrium constants were calculated and extended to binary competitive adsorption equilibrium isotherms. The maximum adsorbing capacity of EPA-EE and DHA-EE are 422 g/L and 612 g/L on C18, respectively. For PSDVB resin, the maximum adsorbing capacity of solutes are 106 g/L and 130 g/L which are much smaller than those on C18, leading to a more severely nonlinear behavior.The Henry constants, axial dispersion coefficients, and mass transfer coefficients of EPA-EE and DHA-EE were determined by moment analysis, which are key parameters of lumped pore kinetic model. In the case of C18, the axial dispersion coefficients for EPA-EE and DHA-EE are 1.87×10-3 cm2/min and 1.85×10-3 cm2/min, and the mass transfer coefficients are 0.339 cm/min and 0.348 cm/min. While in the case of PSDVB resin, the contribution of molecular diffusion is negligibly small and the height of an equivalent theoretical plate (HETP) is approximately becoming a linear function of the interstitial velocity:8.78×10-3×uint. The mass transfer coefficients are 0.227 cm/min and 0.221 cm/min. The model parameters obtained were used to simulate the adsorption-desorption profiles and the results matched well.The complete separation regions depicted according to "triangle theory", and the effect of feed concentration on separation region was investigated. The separation region area becomes smaller with the increase of feed concentration. Consequently, the selection of operating point is more difficult. SMB experiments were carried out at different feed concentrations, and the performance of SMB processes were analyzed according to separation indicators. The maximum feed concentration was about 100 g/L for C18 SMB with a purity of 99.82% in extract, a purity of 99.91% in raffinate, a productivity of 13.1 g/L adsorbent/h, and a solvent consumption of 0.46 L/g. In the case of PSDVB resin SMB, the purities for both outlet streams were above 99%, the productivity was 6.09 g/L adsorbent/h, and the solvent consumption of 3.33 L/g was achieved at the maximum feed concentration of 10 g/L. Based on lumped pore model and node balance, a mathematic model for SMB was developed, where axial dispersion and mass transfer resistance are taken into account. The simulated results demonstrated that the SMB model could predict separation performance with accepted accuracy, and the C18 SMB process is superior to the PSDVB resin SMB process. More work is needed to boost the PSDVB resin SMB process, making this process economically viable.The enantioseparation of citalopram by supercritical fluid chromatography (SFC) with Chiralpak AD stationary phase was studied. Citalopram enantiomers were strongly retained on the chiral stationary phase, and no product was eluted by pure supercritical CO2. An appropriate modifier and additive could improve the separation significantly. The elution order was unchanged under all the experimental conditions, as R-citalopram was the less retained component. The effect of type and percentage of modifier in mobile phase on the retention time and resolution was investigated. It was found that the complete separation was achieved only when 10% 2-propanol was used as modifier in the place of methanol and ethanol, the resolution was 2.15. The effect of temperature on retention is intrinsic under constant pressures, and no clear trends were observed for the relationship of retention factor and temperature. The plot of Inα versus 1/T were straight lines but the linear relationship between Ink and 1/T is nonexistent according to the van’t Hoff equation. It was found the enantioselectivity decreased as the temperature increased. Based on thermodynamics calculation, the isoelution temperatures (Tiso) for both enantiomers were larger than 100℃, and the separation was "enthalpy driven". The densities of mobile phase at various temperature and pressure were calculated by the Peng-Robinson equation of state with Mathias-Klotz-Prausnitz mixing rule. The simplified lattice-fluid model could correlate the retention factor with the density and temperature.The density dependency of adsorption equilibrium constant was investigated. At a given density, the decline of the retention factor with increasing temperature was observed, which is consistent with the trend in HPLC. The relationship of the Henry constant with the mobile phase density and temperature was described by simplified lattice-fluid model as well, which was used to calculate the Henry constants of each section of SMB. Under linear condition, complete separation region of a pressure-gradient SF-SMB is a pentagon. On the basis of the equilibrium-dispersion model, a pressure-gradient SF-SMB model was designed for detailed simulation. The effects of switch time and column distribution on the SMB performance were investigated by numerical simulations. The results show that the product of S-citalopram could be achieved with the purity of 100%, the productivity of 3.15 g/(L·h), and the solvent consumption of 2.57 L/g at the feed concentration of 10 g/L.