A sustainable approach for concurrent detection of nitrosamine impurities in Tolvaptan drug substance and tablet formulations using triple quadrupole mass spectrometry

N-nitrosamines are well-known carcinogens. Compounds containing secondary or tertiary amine functional groups are more susceptible to nitrosamine formation. 7-Chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol (CTB), a hydrolytic degradant of Tolvaptan (TVP), contains a secondary amine moiety, making it prone to forming its corresponding nitrosamine impurity, N-nitroso CTB (NCTB). In addition, secondary amine-containing compounds such as dibutylamine, dimethylamine, and diethylamine can lead to the formation of N-nitrosodibutylamine (NDBA), N-nitrosodimethylamine (NDMA), and N-nitrosodiethylamine (NDEA), respectively. A sensitive and selective triple quadrupole mass spectrometry (QqQ-MS) method was developed and validated herein for the simultaneous quantitative determination of NCTB, NDMA, NDEA, and NDBA in TVP drug substance. Chromatographic separation was carried out on a Zorbax Eclipse XDB-C18 column. The mobile phase was methanol-water (0.1% v/v formic acid). The technique was highly sensitive, allowing measurement at low levels of 1.6 ng/mL for NDMA, 25.3 ng/mL for NCTB, and 0.4 ng/mL for NDEA and NDBA. The reported approach is linear, precise and accurate in the range of 1.6–30.0 ng/mL for NDMA, 0.4–8.3 ng/mL for NDEA, 25.3–474.4 ng/mL for NCTB, and 0.4–8.3 ng/mL for NDBA. Moreover, the environmental impact of the new QqQ-MS method was evaluated from the green analytical chemistry methodologies, such as AGREE and BAGI.