A Comparative Study in Metformin Tablet Quality Assessment: LC-MS and LC-MS/MS Method Quantification of...

N-nitroso-dimethylamine (NDMA, acceptable daily intake limit 96 ng/day), a probable human carcinogenic impurity, has been reported in metformin formulations. In some cases, it is difficult to accurately detect its presence due to suboptimal extraction technique(s), coelution of other probable human carcinogenic impurities such as dimethyl formamide (DMF) and/or ionization suppression in mass spectroscopic measurements. In this study, we provided a simple method to address DMF artifact using an affordable high-performance liquid chromatography coupled with a single-stage mass spectrometer. The results were further confirmed by dual-stage mass spectrometry. The two developed methods can simultaneously identify NDMA in the presence of DMF with good linear range from 10 to 100 ng/mL (r ² = 0.971) and 1 to 10 ng/mL (r ² = 0.994), respectively. The accuracy, expressed as % recovery, was close to 100% with overall precision (%RSD) < 8. The two methods were linear in the presence of 100 ng/mL DMF with r ² = 0.996 and 0.98, respectively. Five commercial formulations of metformin tablets showed traces of NDMA below the regulatory limit (0-12 ± 0.2 ng/tablet) but appreciable amounts of DMF (50-653.5 ng/tablet), still lower than the permissible daily exposure limit (8.8 mg/day) based on the maximum daily dose of metformin (5 tablets, 2500 mg). Both methods proved reliable and informative in the quality control of the NDMA content in metformin tablets and provided reciprocal verification of results.