布洛芬软胶囊的有关物质研究

Research of the related substances in ibuprofen soft capsules

目的:对布洛芬软胶囊中的杂质情况进行分析,考察了最大未知杂质的结构和来源。方法:采用高效液相色谱法测定布洛芬软胶囊中的已知和未知杂质;通过原料和制剂强制降解试验考察了样品中已知杂质和最大未知杂质的来源;采用LCMS联用鉴定最大的未知杂质的结构,并合成该未知杂质;MS和NMR确证了未知杂质的结构,推测其主要的裂解途径;模拟体内胃、肠的酸碱环境,考察未知杂质在体内的水解情况。结果:对比已知混合杂质对照品色谱图的保留时间,实际样品中存在已知杂质D、J、N和E;原料强制降解后可产生已知杂质D、J、N和E,最大的未知杂质仅由制剂强制降解后产生;通过结构的确证表明,未知杂质为布洛芬与辅料甘油发生反应脱一分子水缩合产生的布洛芬甘油酯,结构为2-(4-异丁基)苯基-6,7-二羟基-丙酸丙酯,在体内环境中不能水解形成布洛芬。结论:生产布洛芬软胶囊时应避免采用甘油作为辅料,布洛芬软胶囊有关物质检查法中应明确对布洛芬甘油酯杂质的限度控制。

Objective： To analyze the related substances in ibuprofen soft capsules and investigate the structure of the maximum unknown impurity. Methods： The known and unknown impurities were determined by HPLC method.Origins of the known impurities and the maximum unknown impurity were found after destructive experiment with raw materials and preparations. The maximum unknown impurity was identified by LC-MS method,and synthesized by chemical reactions. The structure of the unknown impurity was proved by MS and NMR,and the proposed degradation pathway was illustrated. The hydrolysis of this unknown impurity in vivo was studied by simulating the gastrointestinal acid and base environment. Results： Impurity D,impurity J,impurity N,impurity E and a new unknown impurity were detected during high performance liquid chromatographic analysis of ibuprofen soft capsules. Impurities D,J,N and E were degraded through raw material destructive experiment,but the unknown impurity was only produced during preparation destructive experiment. Based on the LC-MS and synthesis data analysis,the unknown impurity was characterized as ester glyceride by condensation reaction of ibuprofen and glycerol with removal of a molecule of water,and chemically described as 2-[4-（ 2-methylpropyl） phenyl]-propanoate. This impurity could not be hydrolyzed in in vivo alkaline condition. Conclusion： During the production of ibuprofen soft capsules,glycerol should be avoided as the excipient. And it is necessary to control the limit of 2-[4-（ 2-methylpropyl）phenyl]-propanoate in ibuprofen soft caplsules.