de Souza Gabriela Freitas Pereira, Araujo Vieira Matos Maria Fernanda, de Castro Aglio Tharcilla, Salles Airton Gonçalves, Rath Susanne
Institute of Chemistry, Department of Analytical Chemistry, University of Campinas, P.O. Box 6154, 13084-971, Campinas, SP, Brazil.
Institute of Chemistry, Department of Analytical Chemistry, University of Campinas, P.O. Box 6154, 13084-971, Campinas, SP, Brazil.
J Pharm Biomed Anal. 2023 Nov 30;236:115685. doi: 10.1016/j.jpba.2023.115685. Epub 2023 Aug 26.
In the last five years, the presence of N-nitrosamines in commonly used medicines has become a significant concern for patients, physicians, and the pharmaceutical industry, due to their carcinogenic properties, even at low concentrations. Analytical methods that enable the unequivocal monitoring of these compounds, with low detection limits and covering a range of drugs, are indispensable. The present work proposes a bidimensional liquid chromatography-tandem mass spectrometry method capable of quantifying eleven N-nitrosamines in lipophilic active pharmaceutical ingredients (APIs). The API is retained in the first chromatographic dimension, while the fraction containing the N-nitrosamines is transferred to the second chromatographic dimension and, after separation, to the mass spectrometer. The logP values for the APIs and N-nitrosamines enabled prediction of the APIs that could be separated from the target analytes. The method was validated and successfully applied for the quantification of 1-methyl-4-nitroso piperazine (MNP) and N-nitrosodimethylamine (NDMA) in rifampicin, a drug used to treat tuberculosis. Although NDMA was not detected in two pharmaceutical analyzed, MNP was found at concentrations of 0.44 ± 0.05 and 2.1 ± 0.3 µg g. Given the ability to apply the method to various APIs, together with its reliance solely on logP values for determining suitability, the proposed technique could be extended to the determination of N-nitrosamines in other drugs besides rifampicin.
在过去五年中，常用药物中存在的N-亚硝胺已成为患者、医生和制药行业的重大关注点，因为即使在低浓度下，它们也具有致癌特性。能够对这些化合物进行明确监测、检测限低且涵盖多种药物的分析方法是必不可少的。本研究提出了一种二维液相色谱-串联质谱法，能够定量测定亲脂性活性药物成分（API）中的11种N-亚硝胺。API在第一维色谱中保留，而含有N-亚硝胺的馏分转移到第二维色谱中，分离后进入质谱仪。API和N-亚硝胺的logP值有助于预测可与目标分析物分离的API。该方法经过验证，并成功应用于利福平（一种用于治疗结核病的药物）中1-甲基-4-亚硝基哌嗪（MNP）和N-亚硝基二甲胺（NDMA）的定量分析。尽管在分析的两种药物中未检测到NDMA，但发现MNP的浓度分别为0.44±0.05和2.1±0.3μg/g。鉴于该方法能够应用于各种API，并且仅依赖logP值来确定适用性，因此所提出的技术可以扩展到除利福平之外的其他药物中N-亚硝胺的测定。
