头孢呋辛酯片中的聚合物杂质测定及控制

Determination and control of polymer impurities in cefuroxime axetil tablets

摘要

目的 研究头孢呋辛酯片中的聚合物杂质并建立聚合物杂质的控制策略。方法 用分子排阻色谱法建立头孢呋辛酯片中的聚合物杂质测定方法并进行适用性考察；通过液质联用鉴别头孢呋辛酯片中的聚合物杂质种类，推测其形成机制和结构；探索更加经济、有效地测定和控制头孢呋辛酯片中聚合物杂质的方法。结果 建立了测定头孢呋辛酯片中聚合物杂质的分子排阻色谱法；经考察混合对照品溶液中头孢呋辛酯峰与头孢呋辛酯二聚体峰分离度大于1.5；头孢呋辛酯和头孢呋辛酯二聚体的LOD质量浓度分别为0.02463、0.03326 μg·mL^-1，分别相当于供试品浓度的0.012%、0.017%；流动相流速微小变动和柱温微小变动对测定方法专属性无影响；头孢呋辛酯片中鉴别出高分辨m/z分别为891.1914、896.1470、912.1207、1064.2597、1069.2160、1078.2754、1083.2314、1085.1896的聚合物杂质，部分聚合物杂质以不同离子形式存在，未发现二聚体以上的多聚体杂质；采用RP-HPLC法同时测定小分子杂质和聚合物杂质，RP-HPLC法分离效果比分子排阻色谱法更佳；头孢呋辛酯片中聚合物杂质来源于其原料药，可将聚合物杂质的控制前置至原料药。结论 建立了测定头孢呋辛酯片中聚合物杂质的分子排阻色谱法，经考察方法专属性、灵敏度和耐用性良好；头孢呋辛酯片中鉴别出3种不同聚合形式的二聚体杂质，未发现二聚体以上的多聚体杂质；RP-HPLC法可同时测定小分子杂质和聚合物杂质；头孢呋辛酯片中聚合物杂质主要来源于其原料药，可将聚合物杂质的控制前置至原料药；研究思路适用于其他头孢菌素类药物中的聚合物杂质研究。

Abstract

Objective To study the polymer impurities in cefuroxime axetil tablets and establish the control strategy of the polymer impurities. Methods A molecular exclusion chromatography method was developed for the determination of polymer impurities in cefuroxime axetil tablets, and its suitability was investigated. Column switching two-dimensional chromatography coupled with mass spectrometry was used to identify the types of polymer impurities in cefuroxime axetil tablets, to speculate on their formation mechanisms and structures. To explore a more economical and effective method for the determination and control of polymer impurities in cefuroxime axetil tablets. Results A molecular exclusion chromatography method was established to determine polymer impurities in cefuroxime axetil tablets. The resolution of cefuroxime axetil peak and the dimer peak of cefuroxime axetil in mixed standard solution was more than 1.5. The LOD concentrations of cefuroxime axetil and its dimer were 0.02463 and 0.03326 μg·mL^-1, respectively, which were equivalent to 0.012% and 0.017% of test sample concentration. Minor variations in flow rate of mobile phase and column temperature did not affect the specificity of the method. Polymer impurities with high-resolution m/z values of 891.1914, 896.1470, 912.1207, 1064.2597, 1069.2160, 1078.2754, 1083.2314, and 1085.1896 were identified in cefuroxime axetil tablets. Some polymer impurities exist in different ionic forms, and no polymer impurities above dimer were found. RP-HPLC method was used to determine both small molecular impurities and polymer impurities, and the separation effect of RP-HPLC method was better than that of molecular exclusion chromatography. The polymer impurities in cefuroxime axetil tablets originated from its raw material, and the control of the polymer impurities can be addressed at the raw material stage. Conclusion A molecular exclusion chromatography method is established to determine polymer impurities in cefuroxime axetil tablets with good specificity, sensitivity, and robustness. Three different dimer impurity forms are identified in the cefuroxime axetil tablets, with no polymers larger than dimers found. RP-HPLC method can be used to determine both small molecule and polymer impurities. The polymer impurities in cefuroxime axetil tablets originated from its raw material, and the control of the polymer impurities can be addressed at the raw material stage. The research approach is applicable to the study of polymer impurities in other cephalosporin drugs.

关键词

头孢呋辛酯片 / 聚合物杂质 / 分子排阻色谱法 / 液质联用 / 杂质富集

Key words

cefuroxime axetil tablet / polymer impurity / molecular exclusion chromatography / LC/MS / impurity enrichment

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