注射用头孢哌酮钠舒巴坦钠中N-亚硝基二甲胺测定与风险分析

Determination and Risk Analysis of N-nitrosodimethylamine in Cefoperazone Sodium and Sulbactam Sodium for Injection

目的四氮唑合成过程中有引入N-亚硝胺杂质的风险,除目前备受关注的沙坦类药物外,四氮唑结构在β-内酰胺抗生素中也有重要分布。本实验以结构特征为风险导向,评价四氮唑抗生素注射用头孢哌酮钠舒巴坦钠中的N-亚硝基二甲胺(NDMA)风险。方法建立液液萃取-气相色谱-串联三重四级杆质谱法对全国42个生产厂家260批样品进行测定,并对结果统计分析。结果方法提取操作简单,提取率高,重复性好,方法定量限低至0.005μg·g^(-1),且通用性强,可用于头孢哌酮钠舒巴坦钠及其他四氮唑环抗生素中NDMA测定与质量控制。260批样品中91批检出NDMA,占样品总数的35%;34批样品NDMA含量高于定量限,占样品总数的13%;4批样品NDMA含量接近拟定限度。结论首次在四氮唑抗生素中检出N-亚硝胺杂质,提示含四氮唑结构的抗生素药物中N-亚硝胺风险也应引起关注。本实验也可为其他以四氮唑环为结构特征的抗生素中NDMA风险评估提供借鉴。

OBJECTIVE To evaluate the risk of N-nitrosodimethylamine in cefoperazone sodium and sulbactam sodium for injection based on the characteristic of molecular structure since potential N-nitrosamines risk was identified in synthesis of the tetrazole ring and besides the well-known class of sartans,tetrazole ring is also common inβ-lactam antibiotics.METHODS The method of liquid-liquid extraction followed by direct injection for GC-MS/MS was established and subsequently applied to the testing of N-nitrosodimethylamine in 260 batches of samples from 42 manufacturers.The results were also analyzed statistically.RESULTS This method was convenient and had excellent versatility,which proved to be sensitive,selective,accurate and suitable for the determination and quality control of N-nitrosodimethylamine in cefoperazone sodium and some otherβ-lactam antibiotics with structure of tetrazole.Ninety-one batches of samples were found to contain N-nitrosodimethylamine,which accounted for 35%of all batches and the content exceeded the level of limit of quantitation in 34 batches that contributed to 13%.The contents in four batches were closed to the acceptable limit and as a whole the risk was well controlled.CONCLUSION N-nitrosamines are detected in antibiotics with characteristic structure of tetrazole for the first time,which implies that the risk of N-nitrosamines in this class of drugs should be paid attention to.The research also provides an example to the risk assessment of potential N-nitrosamines in antibiotics with structure of tetrazole.