Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography–tandem mass spectrometry

Abstract

N-Nitrosodimethylamine (NDMA) has been detected in some drug substance and drug products containing sartans, ranitidine and metformin. N-nitrosodiethylamine (NDEA) has also been found to be present in some sartan medications. A method for the simultaneous detection of NDMA and NDEA in drug substances and finished products of sartans, metformin and ranitidine has been optimized using isotope dilution, clean-up procedure and gas chromatography–tandem mass spectrometry (GC–MS/MS). The purification of drug substances and excipients was efficient when utilizing precipitation and activated charcoal cartridges. Most of irbesartan, pimasartan, olmesartan, and candesartan were removed by precipitation using solubility difference, while valsartan, rosartan, metformin and ranitidine were completely removed after activated charcoal purification. Even when the extracts were injected in GC–MS/MS more than 100 times, the peak shape and sensitivity did not change, and no peak interference occurred. When a 0.10 g sample was used, the range of the lower limit of detection was 0.07−0.3 μg/kg, and the range of the lower limit of quantification was 0.3−0.9 μg/kg. The precision was in the range of 0.4–2.7 % for NDMA and 0.4–4.2 % for NDEA, and the accuracy was in the range of 95.0–105 % for NDMA and 93.6–104 % for NDEA. NDMA was detected with a concentration of 0.004 mg/kg in a valsartan and 0.012 mg/kg in a ranitidine, and NDEA was detected at concentrations of 0.009 and 0.008 mg/kg in irbesartan and rosartan. Otherwise, NDMA was detected at a concentration of 0.062 mg/kg in a fimasartan product and 0.009 mg/kg in a ranitidine product. This method is available for all drug substances and finished products of sartans; metformin and ranitidine.