High‐Performance Liquid Chromatography–Tandem Mass Spectrometry Method Development and Validation for Simultaneous Determination of Seven Nitrosamine and Azidomethyl‐Biphenyl‐Tetrazole Impurities in Losartan.

Nitrosamine‐related impurities (N‐nitrosomethylamino butyric acid [NMBA], N‐nitrosodiethylamine [NDEA], N‐nitrosodiisopropylamine [NDIPA], N‐nitrosomethylphenylamine [NMPA], N‐nitrosodibutylamine [NDBA], N‐nitrosodimethylamine [NDMA], and N‐nitrosoethylisopropylamine [NEIPA]) and 5‐[4'‐(azidomethyl)‐[1,1'‐biphenyl]‐2‐yl]‐2H‐tetrazole (AZBT) formed during the manufacture of sartan medicines have been classified into human mutagens and carcinogens after long‐term treatment. The study developed a simple, economical but highly sensitive procedure for the simultaneous quantification of seven nitrosamines and AZBT impurities in sartan pharmaceuticals. After extraction with methanol (MeOH) 50%, the compounds were analyzed with a reversed‐phase liquid chromatography–tandem mass spectroscopy with atmospheric‐pressure chemical ionization (APCI) mode (APCI[+] for nitrosamines and APCI[−] for AZBT), selected reaction monitoring, C18 column, gradient elution with 0.1% formic acid in water and in MeOH, respectively. The validated procedure obtained high extraction efficiency (>90%), wide linear range (0.2–50.0 ng/mL NMBA, NDEA, NDIPA, NMPA, and NDBA; 0.5–50.0 ng/mL NDMA and NEIPA; 2.0–100 ng/mL AZBT), limit of quantification < 10% of the acceptance level, recovery range of 85%–115% with relative standard deviation < 15% and minimum matrix effects for all impurities. The procedure was applied to test 16 commercial losartan samples. As a result, eight samples contained AZBT within the current regulatory limits, but no nitrosamine impurities were detected in all samples. [ABSTRACT FROM AUTHOR]