头孢地尼原料及制剂的聚合物杂质分析

Analysis of polymer impurities in cefdinir raw materials and preparations

目的建立头孢地尼原料及制剂聚合物杂质的分析方法。方法分别采用0.1mol/L磷酸盐溶液和氯仿-三乙胺为溶剂,制备头孢地尼降解溶液;采用高效凝胶色谱法(HPSEC,TSK G2000 SWxl)和柱切换-LC/MSn法对头孢地尼降解溶液的弱保留值杂质进行分离和结构鉴定,并评估高效凝胶色谱法分析聚合物杂质的专属性;采用Diamonsil,C18型色谱柱,以0.25%四甲基氢氧化铵溶液(pH5.5)-甲醇-乙腈为流动相进行梯度洗脱,建立头孢地尼聚合物的RP-HPLC分析方法,采用二维色谱法和柱切换-LC/MSn法对其专属性进行分析,并进行方法学验证。结果在头孢地尼降解物中鉴定出头孢地尼二聚体及其异构体,以及若干小分子杂质;高效凝胶色谱法分离头孢地尼聚合物杂质时,小分子杂质与聚合物杂质共出峰,方法专属性与定量准确性差;RP-HPLC法分析头孢地尼聚合物杂质时,能够检出头孢地尼二聚体及其异构体,头孢地尼三聚体,专属性好。结论高效凝胶色谱法不能对头孢地尼的聚合物杂质进行有效质控,建立的反相色谱法分析头孢地尼聚合物杂质的专属性良好,可将头孢地尼降解溶液可作为聚合物杂质系统适用性溶液。

Objective To establish a method for the determination of polymer impurities in cefdinir raw materials and preparations.Methods Cefdinir raw materials were dissolved by a 0.1mol/L phosphate solution and the reagent chloroform-triethylamine respectively to prepare cefdinir degradation solutions.The High Performance Size Exclusion Chromatography(HPSEC,TSK-gel G2000SWxl)method and the Column Switching-LC/MSn method were applied to separate and identify the poor retention impurities in cefdinir degradation solutions and to evaluate the specificity of the HPSEC method.A new RP-HPLC method for polymer analysis was established with a Diamonsil C18 column,using a gradient elution by 0.25%tetramethylammonium hydroxide(pH5.5)-acetonitrilemethanol.The specificity of the RP-HPLC method was assessed by the two dimensional chromatography method and the Column Switching-LC/MSn method,and the RP-HPLC method was validated.Results Cefdinir dimer and isomers were identified in cefdinir degradation solutions,and some small molecular impurities were also detected.Polymer impurities were liable to co-elute with small molecular impurities by the HPSEC method,which made a poor quantification accuracy and specificity.Cefdinir dimer and isomers were detected by the RP-HPLC method with an effective specificity.Conclusion The HPSEC method is not suitable for the quality control of polymer impurities in cefdinir raw materials and productions,while the new established RP-HPLC method is specific,which can effectively control the polymer impurities.Cefdinir degradation solution can be used to identify polymer peaks as the system suitability solution.