Crystallization Process Of Cefazolin Sodium Pentahydrate

Cefazolin sodium (CEZ) is one of the first generation cephalosporins. It has been found that the amorphous form of CEZ being used in clinical is unstable and can easily bring side-effects. In this study, a new coupling crystallization technology was developed to prepare Cefazolin sodium pentahydrate (CEZP), a new and stable crystalline form (named asαform in this paper). Furthermore, a systematic investigation on the crystallization process of CEZP, including the crystal morphological analysis, dehydrates and decomposition dynamics, thermodynamics and kinetics of crystallization and crystallization process simulation, were performed in details. And finally an optimized crystallization technology for CEZP was presented.Firstly, aimed at solving the product quality problems exiting in the present preparation technology of CEZ, a new antisolvent-cooling coupling crystallization technology was developed.Then the morphologic behaviors of CEZ, including the crystal microstructure and crystal habit, were discussed in detail. From the SEM pictures, it is found that the CEZ crystals are often grown into the clubbed-like habit. By single crystal X-ray diffraction, the crystal structure was resolved. It falls into the orthorhombic system in the space group of C2221. By use of XRD, SEM, DSC and CSD analysis, the polymorph characteristic of CEZ was further investigated, and the transformation behaviors between different crystal forms of CEZ was monitored by in situ FBRM and PVM.The dynamics and mechanism of dehydration and decomposition of CEZP were studied by TG-DSC. It provides experimental data for determining the storage conditions of CEZP products.The crystallization thermodynamics of CEZP was studied by the laser method. The solubilities of CEZP in different solvents at different temperature were measured. The effects of the operation conditions on the width of the metastable zone were also explored. The liquate heat and crystallization heat were estimated. By using an Ubbelohde suspended-level viscometer, the viscosity data of CEZP in different solvents were measured. By using ReactIRTM, the dissolving process of CEZP was in situ monitored.The crystallization kinetics of CEZP was analyzed in detail by experiments and model simulation. The crystallization kinetic equations of CEZP were established and the correlation parameters of nucleation and growth rate equations were determined.By using the crystallization thermodynamic and kinetic data obtained above, the mathematical model of the crystallization process of CEZP was established based on the population balance and the mass balance equations. The model was solved by a numerical method. According to the simulation results and comparing the experimental data, an optimum schedule for preparing CEZP was put forward.By using the above optimized crystallization technology, high quality CEZP products were obtained. According the appraised results by SFDA, the validity period of CEZP was 24 months, longer than that of the present products used in clinical by 6 months. CEZP has been certificated as a fourth-catalog new medicine in China by the authorities.The industrial application of the new crystallization technology of CEZP developed in this study has been realized successfully. One domestic patent has been applied and the international patent is in applying.No same report to this study has been founded in literatures up to date.