Study On The New Coupling Crystallization Technology Of Cefuroxime Sodium

Cefuroxime Sodium is one of the second generation cepHalosporin, which is a market leader drug. It has been found that Cefuroxime Sodium products being used in clinical is unstable and has poor color that can easily bring side-effects. Through the study in this paper, a new type of coupling crystallization technology was developed to prepare Cefuroxime Sodium, which are more stable and of high quality. And a systematic research was carried out on the coupling crystallization process to achieve full optimization of the new technology.Firstly, crystal structure of Cefuroxime Sodium was resolved from high-quality XRPD data by simulation software-Materials Studio 4.4. Meanwhile, the crystal lattice parameters, crystal system and space group were determined. Its crystal habit was predicted by BFDH model. The structure of Cefuroxime Sodium was characterized using Thermogravimetry (TG), Fourier transform infrared spectroscopy (FT-IR), Differential Scanning Calorimeter (DSC). Crystal habits of Cefuroxime Sodium under different solvent systems were studied to screen out the best crystal habit. The effects of nucleation method, type of anti-solvent and ultrasound were also examined.The thermodynamics of Cefuroxime Acid and Cefuroxime Sodium was determined using the dynamic method. Their solubility in different solvents and at various temperatures were investigated, and then correlated by empirical equations. It could be concluded from the thermodynamics data, acetone and water system was not only suitable for the dissolution of Cefuroxime Acid but also for Cefuroxime Sodium crystallization. The theoretical maximum yield can reach 99% using acetone and water in anti-solvent crystallization. The impacts of different operating conditions (such as mixing intensity, the initial composition and temperature, etc.) on metastable zone width were explored, which provided basic data for the nucleation mechanism study during crystallization process of Cefuroxime Sodium.The degradation kinetics of Cefuroxime Sodium in hydrous solutions under atmospHeric condition was also systematically studied. The effects of initial concentrations, temperature, pH, and EDTA·2Na on degradation rate of Cefuroxime Sodium were determined respectively. In addition, the degradation reaction order, reaction rate constant, reaction activation energy and so on were obtained.Induction time of Cefuroxime Sodium in the acetone - water system was measured by laser method. Induction time decreased with increasing the initial components of acetone. By the relationship between supersaturation and induction time, homogeneous nucleation was the main nucleation way. Then diffusion-controlled growth mechanism was deduced according the primary nucleation theory.Finally, on the basis of the study on the morphology, crystallization thermodynamics, degradation kinetics and crystallization process of Cefuroxime Sodium, a new reaction-antisolvent-cooling coupling crystallization technology was developed to solve the product quality problems exiting in the present preparation technology of Cefuroxime Sodium. The operating procedure and time were shortened, and the quality of products was highly enhanced by new crystallization technology, significantly improved the capacity of the equipment.No same report to above study results has been published in literature up to now.