Abstract：
Recently, the potentially highly carcinogenic N-nitrosamines (NAs) have become the focus of pharmaceutical regulatory authorities, the pharmaceutical industry and researchers because trace amounts have been detected in some drug products (DPs), resulting in drug supply shortages. In the absence of sufficient analytical methods for the determination of multiple regulated low-molecular-weight NAs in various DPs, a robust, selective, sensitive and accurate method based on sample preparation by solid phase extraction, followed by liquid chromatography high-resolution mass spectrometry for the simultaneous analysis of 13 regulated low-molecular-weight NAs was developed. The best results for the cleanup were obtained using Strata X-C SPE cartridge. The proposed method was successfully validated according to the USP general chapter 〈1469〉, demonstrating its excellent linearity, accuracy and precision in wide analytical ranges, adjusted to NAs acceptable intake limits. The achieved limits of quantitation correspond to 30 % or less of the acceptable intake limits. The developed analytical method was applied to 16 commercially available DPs containing one to three active pharmaceutical ingredients with different physicochemical properties. Only N-Nitrosodimethylamine was detected in DPs containing ranitidine at levels exceeding the regulatory AI limits by 37.6 - 57.4-fold. In addition, the robustness of the method was confirmed on a considerable number of DPs containing different active ingredients, demonstrating the suitability of the analytical method for routine quality control of different DPs, thus mitigate the risk to human health.
摘要：
最近,潜在的高致癌性N-亚硝胺(NAs)已成为药品监管部门关注的焦点,制药行业和研究人员，因为在一些药品(DP)中检测到痕量，导致药品供应短缺。在缺乏足够的分析方法来测定各种DP中的多种调节低分子量NA的情况下，一个健壮的，选择性,基于固相萃取样品制备的灵敏准确方法，其次是液相色谱高分辨率质谱，用于同时分析13个调节的低分子量NAs。使用地层X-CSPE盒获得了最佳的清理结果。根据USP通用章节<1469>成功验证了所提出的方法，展示了其出色的线性度，在宽分析范围内的准确度和精密度，调整至NAs可接受的摄入量限值。所达到的定量限值对应于可接受的摄入限值的30%或更低。开发的分析方法适用于16种市售DPs，其中含有1至3种具有不同理化性质的活性药物成分。在含有雷尼替丁的DP中仅检测到N-亚硝基二甲胺，其水平超过监管AI限值37.6-57.4倍。此外,在相当数量的含有不同活性成分的DPs上证实了该方法的稳健性，证明分析方法适用于不同DP的常规质量控制，从而减轻对人类健康的风险。
