Study On Antisolvent-crystallization Of Cefbuperazone Sodium

Cefbuperazone sodium, a typical cephalosporin, is one of thebroad-spectrum antibiotics and demonstrates strong antibiotic action tomany kinds of Gram-positive, Gram-negative bacteria as well asanaerobic bacteria. Besides, it also possesses strong force of penetration,wide-distribution, which makes it a product owning a wide marketprospect.So far, according to published papers, the only crystallization methodof cefbuperazone sodium is lyophilization. Lyophilization, however, hasseveral problems including high energy consumption, high requirementfor the equipment, poor-clarity and high water proportion of the productsand so on. In order to solve all these problems, the crystallizationtechnology has been improved by using novel antisolvent-crystallizationmethod, while the possible related factors have been studied.To achieve high clarity and yields, the effects of all reactiveconditions on the final product were systematically studied. All theseconditions contain the ones in neutralization reaction of cefbuperazone（including salifiable agent，final pH value, reactive temperature, andreaction time） and the ones in crystallization of cefbuperazone sodium（feeding method, crystallization temperature, ratio of solvent andantisolvent, addition rate of antisolvent, stir speed） The research resultsdemonstrated the optimal conditions of the preparation process were asfollows: Salifiable agent was sodium bicarbonate; Reaction tempreturewas0℃;The pH was6.0-6.5at the end of the neutralization reaction ofcefbuperazone;The Aqueous solution of cefbuperazone sodium wasadded into the antisolvent；The antisolvent was acetone. The solvent wadwater；The ratio of water and acetone was1：50； stir speed was150r min^-1; Addition rate of antisolvent was0.5mL min^-1；and theantisolvent-crystallization tempreture was0℃。 On the optimalconditions of the preparation process，the acquired products were yieldedat87%，Liquid chromatography purity was97%，the clarity was less than1#，and Complied with the provisions of the Chinese Pharmacopoeia.As we know,the antisolvent-crystallization process was needed a large number of antisolvent.So dilution and cooling crystallization ofCefbuperazone sodium was studied in this paper. The research resultsdemonstrated the optimal conditions of the preparation process were asfollows: The antisolvent was ethanol the antisolvent-crystallizationtempreture was20℃. The ratio of water and ethanol was30g/g. On theoptimal conditions of the preparation process，the acquired products wereyielded at85%，Liquid chromatography purity was97%，the clarity wasless than1#， and Complied with the provisions of the ChinesePharmacopoeia.Meanwhile, cefbuperazone sodium crystal was first time prepared bydiffusion method; the characterizations of the crystal were studied. Thiswork lays the foundation for further preparation for high-qualitycrystalline cefbuperazone sodium product by using the crystal as seed.The paper offers the basic research for the further study andindustrial application. No similar research report has been published yet.