Research On Crystallization Technique Of Cefotaxime Sodium

In order to resolve the problems indwelling the industrial crystallization of cefotaxime sodium, such as low purity of the crystal product, difficult separation and the gelation & agglomeration phenomena in the process of crystallization, the investigation on the crystallization of cefotxime sodium has been performed. By means of the new crystallization technology developed in this work, the product, which is up to the standard, has been successfully synthesized.Cefotaxime sodium, which belonges toβ-lactam antibiotics, is a third generation, semisynthetic, broad-spectrum cephalosporin, and has still a wide market prospect at home and abroad at present. In the current work, by means of real-time observation by microscope, powder-XRD, SEM and FT-IR technology, the gelation andagglomeration phenomena in the process of crystallization have been investigated, and their effects on the crystallization process have been efficiently avoided by means of regulating the pH value of the mother solution, adjusting the crystallization temperature program and seeding, etc.By Cerius2, the crystal cell parameters, crystal system and space group of cefotaxime sodium were simulated. At first, possible space groups of cefotaxime sodium can be obtained by indexing its experimental X-ray power diffraction pattern. Subsequently, the crystal structure was determined based on the energy minimization principle; and the crystal habit was predicted by employing BFDH and AE models. The solid-liquid equilibrium behavior of cefotaxime sodium in 17 solvents was investigated, and the solubilities in 5 good solvents were determined by dynamic method. The model equations in pure solvents were established, and then the crystallization solvent system was selected according to solubility and products properties. The solubilities of cefotaxime sodium in water + S binary mixtures were also measured by dynamic method. And different model equations, such as empirical equation,λhequation and CNIBS/Redlich-Kister equation, were employed to correlate the solubility data.The metastable zone and induction time of crystallization were determined by laser monitoring method and the effects of operation conditions such as temperature, agitation and addition rate of dilute agent were examined. The solid-liquid surface tension and surface entropy factors were estimated based on primary nucleation theory. Combining with the surface morphology acquired by AFM (Atomic Force Microscopy), the growth mechanism of crystal surface was deduced as continuous growth. FBRM (Focused Beam Reflectance Measurement), PVM (Particles Visual Measurement), Malvern Mastersizer and SEM (Scanning Electronic Microscopy) etc were employed to investigate the nucleation, growth and secondary processes in the process of crystallization.Batch dynamic method was used to research the drowning-out crystallization kinetics behavior of cefotaxime sodium. The crystallization kinetic equations were established with size-dependent growth rate model and the correlation parameters of secondary nucleation and crystal growth rate equations were determined.Based on the investigation of the crystallization thermodynamics, kinetics and analysis of crystallization technique, the mathematical model of the drowning-out crystallization process was established according to the population balance equations and mass balance equations. The effects of operation conditions on the crystallization process and the quality of product were investigated in detail by both experiments and model simulation, and the optimal operation strategy was established.The new spherical crystallization technology was developed ascribing to the properties of the small crystal size and morphology of the cefotaxime sodium. On the premise of ensuring the quality of the product, the spherical agglomerated particles can be obtained by this technology, and the post-treatment procedures, such as filtration, transport, storage and granulation etc, can be efficiently improved. This technology can be applied in crystallization procedure of other pharmaceutical and biology products.No same report to above study results has been published in literature up to date.