头孢拉定原料及制剂的聚合物杂质分析  

Analysis of polymer impurities in cefradine raw materials and preparations

作　　者：李进[1] 张培培[1] 姚尚辰[1] 胡昌勤[1] Li Jin;Zhang Pei-pei;Yao Shang-chen;Hu Chang-qin(National Institutes for Food and Drug Control, Beijing 102629)

机构地区：[1]中国食品药品检定研究院,北京102629

出　　处：《中国抗生素杂志》2019年第3期362-369,共8页Chinese Journal of Antibiotics

摘　　要：目的建立头孢拉定原料及制剂中聚合物杂质的分析方法。方法采用碱降解法制备头孢拉定强制降解溶液;采用高效凝胶色谱法(TSK G2000 SWxl)和柱切换-LC/MS法对头孢拉定强制降解溶液中的聚合物杂质进行分离和结构鉴定;采用Agilent ZORBAX SB-C_(18)型色谱柱,以磷酸盐缓冲液-甲醇为流动相,进行梯度洗脱,建立头孢拉定聚合物的RP-HPLC分析方法,采用二维液相色谱法和柱切换-LC/MSn法对该方法的专属性进行分析;进行方法学验证。结果在头孢拉定强制降解物中鉴定出头孢拉定二聚体、三聚体、四聚体;高效凝胶色谱法分离头孢拉定聚合物杂质时,易受到小分子杂质的干扰,同时分离的聚合物杂质色谱峰拖尾严重,存在肩峰,定量准确性差;RP-HPLC法分析头孢拉定聚合物杂质时,在20～22min范围内检出头孢拉定二聚体、三聚体、四聚体;方法定量限为500μg,最低检测限为150μg。结论高效凝胶色谱法不能对头孢拉定中的聚合物杂质进行有效质控,建立的反相色谱法分析头孢拉定聚合物杂质时专属性良好、灵敏度高、方法耐用性好,可用于头孢拉定原料及制剂的聚合物杂质质控;头孢拉定强制降解溶液可作为头孢拉定聚合物分析的系统适用性溶液。Objective To establish a method for the determination of polymer impurities in cefradine raw materials and preparations. Methods Using the base degradation method to prepare cefradine stress degradation solution, the high performance size exclusion chromatography method (HPSEC, using TSK-gel G2000SWxl column) and the Column Switching-LC/MSn method were applied to separate and identify the polymer impurities in cefradine stress degradation solution. A new RP-HPLC method for cefradine polymer analysis was established with an agilent ZORBAX SB-C18 column, using a mobile phase gradient elution by phosphate buffer and methanol. The specification of RP-HPLC method was assessed by the dimensional chromatography method and the Column Switching-LC/MSn method as well as other method validation experiments. Results A series of polymer impurities in cefradine stress degradation solution were identified including cefradine dimers, trimers, and tetramers. Polymer impurities were liable to co-elute with small molecular impurities severe tailing peaks and shoulder peaks were found, which made a poor quantification accuracy. Cefradine dimers, trimers, and tetramers were detected with the retention time from 20.0 to 22.0min when the RP-HPLC method was used to separate cefradine stress degradation solution. The limit of quantification (LOQ) was 500μg and the limit of qualification was 150μg. Conclusion The HPSEC method is not suitable for the quality control of polymer impurities in cefradine raw materials and productions, while the new established RP-HPLC method is specific, sensitive, and robust, which can effectively control the polymer impurities. Cefradine stress degradation solution can be used to identify polymer peaks as the system suitability solution.

关 键 词：头孢拉定 聚合物 杂质 柱切换-LC/MS:高效凝胶色谱 二维色谱 Β-内酰胺抗生素 

分 类 号：R978.1[医药卫生—药品]