An Analytical Method for Determining N-Nitrosodimethylamine and N-Nitrosodiethylamine Contamination in Irbesartan, Olmesartan and Metformin by UPLC-APCI-MS/MS in Tablet Dosage Form.

Abstract

N-nitrosamine pollutants are probable carcinogens. Regulatory agencies declared their presence in the drugs unsafe for human consumption and demanded their recall. Using ultra-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (UPLC-APCI-MS/MS) in tablet dosage form based on International Conference on Harmonization (ICH) tripartite guideline criteria, we aim to develop and test a new approach for identifying and validating nitrosamine-contaminants, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in irbesartan, olmesartan and metformin. The column was Phenomenex Luna-C18, 100 × 3.0mm and 3.0μm. A mobile gradient phase of formic acid in either water or methanol separated the impurities. NDMA and NDEA had retention times of 0.85 and 2.55min, respectively. The detector's linearity was established at concentrations ranging from 0.6 to 100ng/mL. R2 for NDMA and NDEA were 0.9996 and 0.9998, respectively, with a linear response function established at 0.6-100ng/mL. Limit of detection and limit of quantification for NDMA and NDEA were 0.35, 0.29 and 0.55, 0.37ng/mL, respectively. On average, recovery rates for NDMA and NDEA ranged from 96.0 to 98.4 and 96.2 to 98.0%, respectively. The relative standard deviation for NDMA and NDEA was 3.46 and 2.69, respectively. According to the ICH guidelines, the developed method was quick, sensitive and valid. The pharmaceutical formulations of irbesartan, olmesartan and metformin may be regularly examined using the approach provided here.