Nitrosamine impurities have provoked numerous global medicine recalls due to their possible presence during drug manufacturing or storage. Regarding formulation of nitrosamine impurities, a key risk involves reactions between nitrosating agents (nitrite) in excipients and vulnerable amines as impurities or degradants. Rapid detection across various sample types is essential to support pharmaceutical manufacturing. In this study, two methods were developed to detect nitrite in excipients and crucial secondary amines in active ingredient metformin hydrochloride at trace levels, respectively. The former method was developed based on the reaction of nitrite ions with 2,3-diaminonaphthalene to form 1-H-naphthotriazole (NAT), whereas the latter was based on amine tosylation. Mass spectrometric conditions were optimized using electrospray ionization in the positive mode. Multiple reaction monitoring transitions were determined at m/z 170 → 115 for NAT, and m/z 200.1 → 91 for dimethylamine (DMA) and 228.1 → 91 for diethylamine (DEA). These methods were validated using selected eight excipients or metformin hydrochloride in terms of specificity, linearity, accuracy, precision, robustness, limit of quantification (LOQ), and limit of determination according to the ICH guidelines. The results of the validation were within the acceptable criteria. Applicability of the methods was evaluated using 170 pharmaceutical samples donated by industries. The nitrite content in the excipients ranged from <LOQ to 4.74 ppm, with observed levels 1.3 to 6 times higher than the average (0.8 ppm) in the samples. The DMA levels in the metformin hydrochloride were within the limit (500 ppm) but varied significantly (0.2–209.2 ppm) among manufacturers. DEA was detected at lower levels (0.7–0.9 ppm). To mitigate the nitrosamine content in the metformin products, the excipient compositions were investigated by selecting those with low nitrite levels. As the types of impurities detected have become increasingly diverse and detection cycles have become more frequent, the requirement for preemptive safety management to relieve public anxiety is essential for regulatory aspects. Nitrite and secondary amines are crucial precursors to N-nitrosamine, and the suggesting approach could be a means to mitigate N-nitrosamine contamination.
Ahn et al. (Wed,) studied this question.