Food and Drug Administration, Ministry of Health and Welfare, Executive Yuan, 161-2 Kunyang St., Nangang Dist., Taipei City 11561, Taiwan.
Food and Drug Administration, Ministry of Health and Welfare, Executive Yuan, 161-2 Kunyang St., Nangang Dist., Taipei City 11561, Taiwan.
J Pharm Biomed Anal. 2022 Nov 30;221:115003. doi: 10.1016/j.jpba.2022.115003. Epub 2022 Aug 22.
The probable carcinogenic nitrosamine impurities, such as N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), have been detected from various pharmaceuticals in recent years. The sensitive chromatographic methods, including liquid chromatography (LC) and gas chromatography (GC), have been applied for analyzing nitrosamines in the pharmaceutical substrates, such as sartans, ranitidine and metformin. In comparison of LC, the efficacy of GC for analyzing multiple nitrosamines in diverse pharmaceuticals will be limited or attenuated owing to the chemical properties of target analytes or matrix hinderance of pharmaceutical substrates. To extend the applicability of GC analysis for multiple nitrosamines in pharmaceuticals, this study presented a gas chromatograph tandem mass (GC-MS/MS) method for monitoring 14 nitrosamines within 44 pharmaceuticals, whereas the headspace-solid phase microextraction (HS-SPME) sampling mode was introduced. Chromatographic separation was achieved on a DB-heavyWax column (30 m × 0.25 mm; i.d., 0.25 µm), whereas the HS-SPME sampling mode with a 50/30 µm DVB/CAR/PDMS extracting fiber was applied for comparison of the direct injection mode. Meanwhile, the HS-SPME conditions were optimized to evaluate the effects of the parameters on analyzing total nitrosamines in pharmaceuticals by GC-MS/MS. The optimal conditions of HS-SPME were as follows: extracting solution of 90% NaCl, HS incubation time 1 min, SPME adsorbing at 80 ℃ for 30 min, and desorbing at 250 ℃ for 5 min. The limit of quantification (LOQ) for 14 nitrosamines in pharmaceutical matrices under the optimal conditions was 0.05 μg/g for the optimal HS-SPME, whereas the value was 0.05-0.25 μg/g for direct injection.
近年来，已从各种药物中检测到可能致癌的亚硝胺杂质，如 N-亚硝基二乙胺（NDEA）和 N-亚硝基二甲胺（NDMA）。已经应用了包括液相色谱（LC）和气相色谱（GC）在内的灵敏色谱方法来分析沙坦、雷尼替丁和二甲双胍等药物基质中的亚硝胺。与 LC 相比，由于目标分析物的化学性质或药物基质的基质干扰，GC 分析多种药物中亚硝胺的效果将受到限制或减弱。为了扩展 GC 分析在药物中多种亚硝胺的适用性，本研究提出了一种气相色谱串联质谱（GC-MS/MS）方法，用于监测 44 种药物中的 14 种亚硝胺，同时引入了顶空固相微萃取（HS-SPME）采样模式。在 DB-heavyWax 柱（30 m×0.25 mm；内径，0.25 µm）上实现了色谱分离，而 HS-SPME 采样模式采用 50/30 µm DVB/CAR/PDMS 萃取纤维，与直接进样模式进行了比较。同时，优化了 HS-SPME 条件，以评估参数对通过 GC-MS/MS 分析药物中总亚硝胺的影响。HS-SPME 的最佳条件如下：90%NaCl 提取溶液，HS 孵育时间 1 min，SPME 在 80℃下吸附 30 min，250℃下解吸 5 min。在最佳 HS-SPME 条件下，药物基质中 14 种亚硝胺的定量限（LOQ）为 0.05μg/g，而直接进样的 LOQ 为 0.05-0.25μg/g。
