Analysis and risk assessment of nitrosamines in sartans using GC-MS and Monte Carlo simulation

The precise detection of nitrosamines at very low levels in various substances is crucial because of their known toxicity and potential to cause genetic mutations. As a result, regulations have been established to evaluate the risk of nitrosamines and manage their presence in pharmaceuticals. In this study, we developed an analytical method involving solvent extraction and gas chromatography-mass spectrometry for the determination of N-nitrosodimethylamine and N-nitrosodiethylamine based on the internal standard method. According to validated results based on ICH guidelines, calibration curves spanned from 2.5 to 40 ng mL^-1 with a limit of quantitation of 0.015 µg g^-1 for N-nitrosodimethylamine and 0.003 µg g^-1 for N-nitrosodiethylamine, meeting the US FDA requirements. The method's relative recovery was 80-120%, with a relative standard deviation of ≤ 12%. Then, the levels of both nitrosamines were determined using the validated method in 84 samples of active pharmaceutical ingredients or finished products, including valsartan, valsartan methyl ester, sacubitril/valsartan, losartan, and telmisartan. Additionally, we utilized Monte Carlo simulation to assess the potential health risks associated with the use of sartans. According to the obtained results, the Hazard index values were found to be less than 1 indicating that children and adult users may not be at risk of health problems.