심민기 (중앙대학교 약학대학)

이동규 (중앙대학교 약학대학)

심민기 (중앙대학교 약학대학)

이동규 (중앙대학교 약학대학)

The detection of genotoxic nitrosamine contaminants in pharmaceutical products has emerged as a critical concern, particularly in type 2 diabetes combination therapies such as sitagliptin/metformin tablets. Among these, N-nitrosodimethylamine (NDMA), a well-established carcinogenic impurity, and 7-N-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (NTTP), a novel nitrosamine drug-substance-related impurity (NDSRI), have both been identified in commercial formulations. Nevertheless, no established analytical methods exist for their simultaneous quantification. This study therefore aimed to develop and validate a reliable analytical approach utilizing liquid chromatography-mass spectrometry (LC-MS) coupled with atmospheric-pressure chemical ionization (APCI). LC–APCI–MS provided superior sensitivity for NDMA than LC–ESI–MS, while both ionization modes were suitable for NTTP quantification. Both quadrupole time-of-flight (QTOF) and triple quadrupole (QQQ) MS systems satisfied regulatory validation parameters. However, GC–MS was not applicable to NTTP due to its low volatility and insufficient chromatographic resolution. Given the continued use of sitagliptin/metformin as a treatment for type 2 diabetes, the developed method provides a reliable solution for routine quality control and impurity monitoring to support consistent product safety and supply. This research was supported by a grant (23194MFDS086) from Ministry of Food and Drug Safety in 2025.

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