Study On The Polymorphs And Crystallization Process Of Cefuroxime Acid

Cefuroxime acid, belonging to the second generation of cephalosporins, is commonly used as an active pharmaceutical ingredient for cefuroxime sodium and cefuroxime axetil. As it has a high antibacterial activity on gram-positive bacteria and gram-negative bacteria, it is widely used to treat various types of infections caused by susceptible bacteria. At present, the domestic product of cefuroxime sodium uaually has the stability problems, which could easily cause the discoloration of cefuroxime sodium. As cefuroxime acid is the raw material to manufactor cefuroxime sodium, the stability problem of cefuroxime sodium can be solved by using the high quality of cefuroxime acid. At present, the domestic products of cefuroxime acid usually have the quality problem, such as small crystal size, bad crystal habit, poor stability, filtration and drying problems etc. As the crystallization is the key step of controlling the quality of cefuroxime acid, it is necessary to study its polymorphs and optimize its crystallization process with theoretical analysis and experimental research.Two new polymorphs of cefuroxime acid were prepared, the structures and morphologies of different polymorphs were characterized and analyzed. The crystal hait of different polymorphs were predicted by using the BFDH model and AE model.The solubility of cefuroxime acid in acetonitrile + water and solvent S + water was determined using a synthetic method respectively. The cefuroxime acid solutions were simulated using the molecular dynamics method with the help of Materials Studio. The Alpelbat model, λh model and van’t Hoff model were applied to correlate the solubility of cefuroxime acid. The solution thermodynamic properties, such as dissolution enthalpy, dissolution entropy and dissolution Gibbs free energy were calculated based on the solubility data.The degradation data of different polymorphs of cefuroxime acid in solution state and solid state was determined with the help of HPLC respectively. The effect of the solution concentration, temperature, pH on the degradation of cefuroxime acid in solution was studied respectively.The concomitant crystallization of cefuroxime acid Form I and Form II was characterized by series of off-line and on-line tools. The concomitant crystallization zone was determined. Based on the data of the induction period of concomitant crystals, the nucleation and growth of concomitant crystals for Form I and Form II were analyzed by using the relevant theory.The relationship of the cefuroxime acid polymorphs was identified. The phase transition point between Form I and Form II in acetonitrile and water system was determined by using the phase transformation experiments. The solution-mediated transformation from Form I to Form II was monitored with the on-line Raman spectra and PVM, and its mechanism was also confirmed. The transformation kinetics of cefuroxime acid under different temperatures was studied with the JMA model. The effect of the operation factor such as solvent ratio, solid loadings and stirring speed on the transformation process was investigated respectively.On the basis of the results above, the coupling crystallization process was introduced. The effect of solvent ratio, crystal seed, temperature, acid volume, ripening time, stirring speed on crystallization process of cefuroxime acid was investigated respectively. The optimal operation schedule of the coupling crystallization was obtaind.The high quality of cefuroxime acid, which has a better crystal habit and a larger cryatal size, was obtained with the new crystallization technology. The new crystallization technology not only solves the problems of filtration process, product stability and other internal qualities, but also has one-way yield up to 88%. Thus it has been applied in production based on its significant economic benefits.No similar report on above has been published in literature up to date.