Online Study And Application Of The Regulation Mechanism In Membrane Assisted Antisolvent Crystallization

As a low energy-consumption crystallization method,antisolvent crystallization has been widely used in medicine synthesis,ultra-pure crystal preparation and other fields.In view of the problem of uniform control of supersaturation in the conventional antisolvent crystallization method,although researchers have improved the micro-scale environment from the aspects of microfluidics and external force field regulation,it is only suitable for the preparation process of ultra-fine nanoparticles and lacks the function of crystal growth control,so it is difficult to prepare large-size high-purity crystals.The research shows that the pore and interface characteristics of microporous membrane can improve the mass transfer and mixing between the antisolvent and crystallization solution.However,the mass transfer characteristics of membrane assisted antisolvent crystallization process are not clear,and its interfacial mass transfer control mechanism needs to be studied intuitively and systematically,which provides the basis for the continuous preparation of high-end crystals such as medicine.In view of the above problems,this paper presents an online observation method of membrane assisted antisolvent crystallization process with high-speed camera,and reveals the mechanism of the construction of antisolvent liquid film on the membrane surface.The concentration range of visible liquid film is 0-60%by combining with the analysis of refractive index of antisolvent liquid film,which provides a direct qualitative study method for the analysis of liquid film thickness and the regulation of concentration gradient.Based on the flux data,continuity equation and NS equation,the mass transfer model of membrane assisted antisolvent crystallization was established,the mechanism of antisolvent mass transfer across membrane was revealed,and the linear relationship of concentration distribution along the length of hollow fiber membrane was verified.Further,high quality sodium chloride crystals were prepared by adjusting the thickness and concentration gradient of liquid film with pressure and flow field.With the increase of tube side pressure,the liquid film thickness increases along the radial direction;When the shell side velocity increases,there is a competitive relationship between the fluid shear force and the driving pressure of antisolvent across membrane,which makes the liquid film thickness increase first and then decrease.Through the fluid dynamics simulation of the micro scale flow field on the membrane surface,the stable formation of the liquid film and the control change of the concentration distribution were determined,which confirmed that the tube side pressure and shell side velocity were effective for the regulation of the antisolvent concentration distribution.Based on this,The high quality sodium chloride crystals with a size of 41.6μm and a coefficient of variation of 43.5%was obtained.The crystal with regular and clear morphology show the advantages of membrane assisted antisolvent crystallization in crystal preparation.Finally,membrane assisted antisolvent crystallization method was applied in the field of pharmaceutical crystallization to regulate the preparation process of cefuroxime sodium crystal.By adjusting the operation parameters,when the feed concentration was 12.4 wt%,the permeation rate was 20 kg·m^-2.h^-1 and the operational time was 4 h,the long rod crystal with an average size of 0.83μm was obtained.The coefficient of variation decreased from 65.30%to 28.18%.The color of the solution is nearly colorless,which is far lower than that of yellow No.6 standard colorimetric solution specified in Chinese Pharmacopoeia.The results showed that decreasing the permeation rate can reduce the nucleation,promote crystal growth,and effectively control the aspect ratio and quality of the crystal.Based on the advantages of membrane assisted antisolvent crystallization,the effect of operation time on the residual solvent,but it can strengthen the crystal growth process and reduce the average aspect ratio from 14 to 9.The higher the feed concentration is,the more products can be obtained,which is easy to agglomerate and lead to impurity entrapment;However,low feed concentration makes the crystal growth insufficient and the crystal size decreases slightly.In conclusion,the morphology,particle size distribution and color grade of cefuroxime sodium can be effectively regulated by membrane assisted antisolvent crystallization.The above research has establisheed the theoretical and application basis for precise control of drug and macromolecular crystallization process.