GC-MS测定坎地沙坦酯中微量的N-亚硝基二甲胺和N-亚硝基二乙胺

Microdetermination of N-nitrosodimethylamine and N-nitrosodiethylamine in Candesartan Cilexetil by GC-MS

关键词:  坎地沙坦酯  气相色谱-质谱联用法  N-亚硝基二甲胺(NDMA)  N-亚硝基二乙胺(NDEA)

Key words:  candesartan cilexetil  GC-MS  N-nitrosodimethylamine (NDMA)  N-nitroso diethylamine (NDEA)

摘要:

目的 采用GC-MS直接进样法测定坎地沙坦酯中微量的基因毒性杂质N-亚硝基二甲胺（N-nitrosodimethylamine，NDMA）和N-亚硝基二乙胺（N-nitrosodiethylamine，NDEA）的含量。方法 采用单四极杆GC-MS，Agilent VF-WAX ms色谱柱（30 m×0.25 mm，0.25 μm），程序升温，进样口温度200℃，流速1.0 mL×min^-1；质谱采用电子轰击电离源（EI），电压为70 eV，离子源温度230℃、四极杆温度150℃，5~7 min检测离子为74（m/z）（NDMA），7~10 min检测离子为102（m/z）（NDEA）；以0.2 mol×L^-1氢氧化钠溶液溶解样品，以乙酸乙酯进行萃取。结果 NDMA、NDEA及相邻色谱峰之间分离效果良好，NDMA和NDEA分别在2.97~148.5 ng×mL^-1和3.00~150.20 ng×mL^-1线性关系良好，定量限分别为0.06，0.03 mg×g^-1，检测限分别为0.018，0.009 mg×g^-1；NDMA低、中、高浓度平均回收率（n=3）分别为86.3%，88.3%，91.4%，RSD （n=3）分别为0.9%，0.7%，0.4%；NDEA低、中、高浓度平均回收率（n=3）分别为88.1%，87.9%，91.7%，RSD （n=3）分别为0.9%，1.1%，0.2%。结论 建立的GC-MS测定坎地沙坦酯中NDMA和NDEA的方法准确度好，灵敏度高，简便可靠，对仪器污染小，可用于坎地沙坦酯中这2个基因毒性杂质的质量控制。

Abstract:

OBJECTIVE To establish a GC-MS direct injection method for the microdetermination of N-nitrosodimethylamine(NDMA) and N-nitrosodiethylamine(NDEA) in candesartan cilexetil. METHODS The GC-MS was used, and the separation was performed on a Agilent VF-WAX ms column(30 m×0.25 mm, 0.25 μm) with temperature programmed. The inlet temperature was 200℃ and the flow rate was 1.0 mL·min^-1. Mass spectrometry was used with EI source, the voltage was 70 eV, ion source temperature was 230℃ and quadrupole temperature was 150℃. The ion of 74(m/z) was detected for NDMA from 5 to 7 min, and the ion of 102(m/z) was detected for NDEA from 7 to 10 min. The samples were dissolved in 0.2 mol·L^-1 sodium hydroxide solution and extracted with ethyl acetate. RESULTS The separation between NDMA, NDEA and adjacent chromatographic peaks was effective. NDMA and NDEA revealed good linearities within the range of 2.97-148.5 ng×mL^-1 and 3.00-150.20 ng×mL^-1, respectively. The limit of quantitation of NDMA and NDEA were 0.06, 0.03 mg×g^-1 and the limit of detection were 0.018, 0.009 mg×g^-1, respectively. The average recoveries of NDMA were 86.3%, 88.3%, 91.4% at low, middle and high concentration, with the RSDs(n=3) of 0.9%, 0.7%, 0.4%, respectively. The average recoveries of NDEA were 88.1%, 87.9%, 91.7% at low, middle and high concentration, with the RSDs(n=3) of 0.9%, 1.1%, 0.2%. CONCLUSION The established GC-MS method for determination of NDMA and NDEA is accurate, highly sensitive, simple and reliable with less pollution to the instrument, and it can be used for the quality control of these two genotoxic impurities in candesartan cilexetil.