注射用哌拉西林钠他唑巴坦钠的聚合物杂质分析

目的：建立注射用哌拉西林钠他唑巴坦钠中聚合物杂质的分析方法。方法：采用降解法制备哌拉西林钠他唑巴坦钠强制降解溶液；建立高效凝胶色谱法，采用TSK G2000 SWxl凝胶柱，对强制降解溶液中的聚合物杂质进行分离；采用柱切换-LC/MS法鉴定聚合物杂质的结构，并评估高效凝胶色谱法分离聚合物杂质的专属性；采用CAPCELL MGⅡ C₁₈色谱柱，以磷酸盐缓冲液-甲醇为流动相，进行梯度洗脱，建立哌拉西林钠他唑巴坦钠聚合物的RP-HPLC分析方法；采用二维色谱法和柱切换-LC/MSⁿ法对RP-HPLC分析聚合物杂质的专属性进行验证。结果：在哌拉西林钠他唑巴坦钠强制降解溶液中鉴定出哌拉西林二聚体及其衍生物、三聚体；高效凝胶色谱法分离哌拉西林钠他唑巴坦钠聚合物杂质时，易受到哌拉西林水解杂质的共出峰干扰，方法专属性差；RP-HPLC法分析哌拉西林钠他唑巴坦钠聚合物杂质时，可对多种指针性聚合物杂质进行精准质控，专属性好。结论：高效凝胶色谱法不能对哌拉西林钠他唑巴坦钠的聚合物杂质进行有效质控，建立的RP-HPLC法可用于哌拉西林钠他唑巴坦钠原料及制剂的聚合物杂质质控；哌拉西林钠他唑巴坦钠强制降解溶液可作为聚合物杂质定位用系统适用性溶液。

Objective:To establish a method for determination of polymer impurities in piperacillin sodium and tazobactam sodium for injection. Methods:Degradation method was used to prepare the degradation stock solution of piperacillin sodium and tazobactam sodium;high performance size exclusion chromatography method(HPSEC,using TSK-gel G2000 SWxl column)and column switching-LC/MSⁿ method were applied to separate and identify the polymer impurities in degradation stock solution and the specification of HPSEC method was evaluated together;a RP-HPLC method for piperacillin sodium and tazobactam sodium polymers was established with a CAPCELL MGⅡ C₁₈ column,using a mobile phase of phosphate buffer and methanol by gradient elution. The specification of RP-HPLC method was assessed by two dimensional chromatography method and column switching-LC/MSⁿ method. Results:A series of polymer impurities in degradation stock solution were identified including piperacillin dimers,and its derivative,and trimers. Polymer impurities were co-eluted with small molecular degradation impurities in HPSEC with a poor quantification accuracy. A series of characteristic polymer impurities were detected and accurately quantified when RP-HPLC method was used to analyze degradation stock solution. Conclusion:HPSEC method is not suitable for the quality control of polymer impurities in piperacillin sodium and tazobactam sodium for injection,while the established RP-HPLC method is specific,which can effectively control the polymer impurities. The degradation stock solution of piperacillin sodium and tazobactam sodium for injection can be used to identify polymer peaks as the system suitability solution.

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