Study On Spherical Crystallization Process Of Ceftezole Sodium

Ceftezole sodium,as a semi-synthetic broad-spectrum antibiotic of firstgeneration cephalosporins,can effectively inhibit gram-negative and gram-positive bacteria.It is mainly used for the treatment of respiratory infection,urinary system infection,sepsis and peritonitis.However,the research on ceftezole sodium at home and abroad is mainly focused on clinical application,and there is a lack of basic research on the crystallization process and its mechanism,which leads to the problems with the products of ceftezole sodium on the market such as poor fluidity,uneven particle size distribution,serious product coalescence and low bioavailability.In this paper,the crystallization process of ceftezole sodium was systematically studied.Firstly,the crystallization thermodynamics of ceftezole was studied in this paper.The solubility of ceftezole in seven pure solvents including water,methanol,ethanol,isopropanol,acetone,ethyl acetate and acetonitrile and two mixed solvents including acetone + water and acetone + ethanol were measured by a static gravimetric method.The experimental solubility data of ceftezole in pure solvents were correlated by the Apelblat model and the NRTL model.Meanwhile,the modified Apelblat equation,the CNIBS/R-K model and the combined version of the Jouyban–Acree were applied for binary solvents.Besides,the mixing and dissolution thermodynamic properties of ceftezole in all the tested solvents were calculated based on the NRTL model and the experimental solubility data.Secondly,two spherical particles of ceftezole sodium were prepared by two different solvent crystallization methods in order to improve fluidity and reduce serious product coalescence in the crystallization process.The spherical particle products were systematically characterized by means of polarizing microscope(PLM),scanning electron microscope(SEM),Malvern mastersizer and powder X-ray diffraction(PXRD).With the characterization results,the differences in the properties of the products were compared and analyzed.Based on this analysis,the forming mechanisms of spherical crystals in the two methods were respectively proposed : spherical agglomeration and spherical growth,which laid a foundation for the development and optimization of the subsequent spherical crystallization process.Finally,the spherulite of ceftezole sodium was prepared by anti-solvent crystallization considering the crystallization thermodynamics and spherical crystallization mechanism.Meanwhile,the optimal operating conditions for the spherical crystallization of ceftezole sodium were determined and a new ceftezole sodium crystallization process was developed by investigating the effects of different mixed solvents,crystallization temperature,stirring rate and ratio of solvents on the morphology and the particle size.The results showed that the spherical particle produced by the new process was of the same quality with foreign products in the aspects of appearance,polymorph,fluidity and purity.With the technique,the product coalescence and fluidity has been improved and the particle size has been increased as well.