Determination of Nitrosamine Impurities in Metformin Drug Substance and Drug Product

Metformin is a prescription drug used to control high blood sugar in patients with type 2 diabetes. NDMA (N-nitroso-dimethylamine) has been classified as a Group 2A compound, thereby defining it as “probably carcinogenic to humans.” FDA has set daily acceptable intake limits on NDMA in pharmaceuticals of 96 nanograms daily (immediate release (IR) dose is 0.038ppm based on 2550 mg maximum daily dose (MDD); extended release (ER) dose is 0.048 ppm based on 2000 mg MDD). 

An LC-ESI-HRMS method was developed and validated in conformance with ICH Q2(R1) for the detection and quantitation of eight nitrosamine impurities, including N-nitrosodimethylamine (NDMA), N-nitroso-diethylamine (NDEA), N-ethyl-N-nitroso-2-propanamine (NEIPA), N-nitroso-diisopropylamine (NDIPA), N-nitroso-di-n-propylamine (NDPA), N-nitroso-methylphenylamine (NMPA), N-nitroso-di-n-butylamine (NDBA) and N-nitroso-Nmethyl-4-aminobutyric acid (NMBA) in metformin drug substance and drug product.