<br>西格列汀药物制剂中三唑并吡嗪前体及其遗传毒性亚硝基衍生物分析的综合 UHPLC-MS 筛选方法,Journal of Pharmaceutical and Biomedical Analysis

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西格列汀药物制剂中三唑并吡嗪前体及其遗传毒性亚硝基衍生物分析的综合 UHPLC-MS 筛选方法
Journal of Pharmaceutical and Biomedical Analysis ( IF 3.1 ) Pub Date : 2023-11-10 , DOI: 10.1016/j.jpba.2023.115861
Jakub Jireš ₁ , Michal Douša ₂ , Petr Gibala ₂ , Jan Doubský ₂ , Daniel Pěček ₂ , David Mervart ₂ , Anna Kluk ₂ , Ardita Veseli ₃ , Stanislav Kalášek ₂ , Pavel Řezanka ₄

Affiliation

使用两种新开发的测定-亚硝基三唑并吡嗪（NTTP；7-亚硝基-3-（三氟甲基）–5,6， 7,8-四氢-[1,2,4]三唑并[4,3-]吡嗪)及其前体三唑并吡嗪(3-(三氟甲基)–5,6,7,8-四氢-[1,2,4]三唑并[4,3-]吡嗪）。三唑并吡嗪的测定方法此前未公开，NTTP的测定方法仅针对活性药物成分西他列汀的分析，而不是药物剂型。解决亚硝胺污染是世界各地监管机构的要求，因此对所有制药公司都至关重要。解决方案始终需要灵敏的分析方法。两种新开发的方法均使用液相色谱与质谱联用（三唑并吡嗪的情况下使用单四极杆分析仪，NTTP 的情况下使用三重四极杆分析仪）。三唑并吡嗪的分离是在 Acquity CSH C18 色谱柱上使用由 pH 4.2 缓冲的甲酸铵水溶液和乙腈组成的流动相实现的。使用正电喷雾和193选择离子监测进行检测。NTTP的分离是在Acquity HSS T3柱上使用由0.1%甲酸的水和甲醇溶液组成的流动相实现的。使用正电喷雾和多反应监测在/ 222.15→42.05（碰撞能量17 eV）和/ 222.15→192.15（碰撞能量11 eV）跃迁处进行检测。成功解决了先前在科学文献中未描述的 NTTP 和三唑并吡嗪特有的两个问题。在开发三唑并吡嗪定量方法时，使用-二甲基甲酰胺作为样品溶剂，解决了西他列汀自发降解为三唑并吡嗪和()–3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯的问题。通过提高柱温成功解决了由于 NTTP 旋转异构体的存在而导致的 NTTP 不良峰形问题。这两种方法均在西格列汀和西他列汀/二甲双胍药品生产的优化研究中使用。该研究的目标是在联邦药品管理局规定的严格立法限制下降低最终药品中的 NTTP 含量。多种解决方案的功效已得到证实，但由于Zentiva的知识产权保护政策而无法完全披露。相反，对最近发表的应对亚硝胺污染的策略进行了简要回顾。

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Comprehensive UHPLC–MS screening methods for the analysis of triazolopyrazine precursor and its genotoxic nitroso-derivative in sitagliptin pharmaceutical formulation

A case study on Sitagliptin drug products and Sitagliptin/Metformin drug products concerning contamination with -nitrosamines was performed using two newly developed analytical methods for determination of -nitroso-triazolopyrazine (NTTP; 7-nitroso-3-(trifluoromethyl)–5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-]pyrazine) and its precursor triazolopyrazine (3-(trifluoromethyl)–5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-]pyrazine). The method for determination of triazolopyrazine was previously unpublished, the method for determination of NTTP was published only for analysis of active pharmaceutical ingredient Sitagliptin and not the drug forms. Solving the -nitrosamine contamination is requested by regulatory authorities all over the world and thus is vital for all pharmaceutical companies. The solution always requires a sensitive analytical method. Both newly developed methods use liquid chromatography coupled with mass spectrometry (single quadrupole analyzer in case of triazolopyrazine and triple quadrupole analyzer in case of NTTP). Separation of triazolopyrazine was achieved on a column Acquity CSH C18 using a mobile phase consisting of aqueous ammonium formate buffered at pH 4.2 and acetonitrile. Detection was performed using positive electrospray and selected ion monitoring at 193. Separation of NTTP was achieved on a column Acquity HSS T3 using a mobile phase consisting of 0.1 % formic acid in water and methanol. Detection was performed using positive electrospray and multiple reaction monitoring at transitions / 222.15→42.05 (collision energy 17 eV) and / 222.15→192.15 (collision energy 11 eV). Two issues specific to NTTP and triazolopyrazine previously not described in scientific literature were successfully troubleshooted. Spontaneous degradation of Sitagliptin to triazolopyrazine and methyl ()–3-amino-4-(2,4,5-trifluorophenyl)butanoate was solved by using -dimethylformamide as sample solvent during development of the method for quantitation of triazolopyrazine. A bad peak shape of NTTP due to the presence of rotamers of NTTP was successfully troubleshooted by increasing column temperature. Both methods were used during an optimization study of manufacturing of Sitagliptin and Sitagliptin/Metformin drug products. The goal of the study was to decrease NTTP content in the final drug product under the strict legislative limit set by Federal Drug Agency. The efficacy of several solutions was proven, but could not be fully disclosed due to Intellectual Property Protection policy of Zentiva. Instead, a brief review of recently published strategies to cope with -nitrosamine contamination is presented.

更新日期：2023-11-10

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