Simultaneous Determination of Eight Nitrosamine Impurities in Metformin Extended-Release Tablets Using the Agilent 6470 Triple Quadrupole LC/MS

Abstract

Determination of nitrosamine impurities in drug substances and drug products is a critical regulatory requirement, with required sensitivity limits posing immediate challenges in developing sensitive analytical methods. The list of APIs and drug products for nitrosamine determination has expanded beyond angiotensin II receptor blocker (ARB) drugs. This is evidenced by the recent recalls of metformin by various regulatory bodies like the U.S. Food & Drug Administration (FDA), European Directorate for the Quality of Medicines (EDQM), and Health Sciences Authority (HSA) due to the presence of N-nitroso-dimethylamine (NDMA).

In this application note, we have developed a highly sensitive, triple quadrupole-based, liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of eight nitrosamine impurities in metformin drug substance and drug products.

This application note describes a highly selective and sensitive LC/MS/MS method using the Agilent 6470 triple quadrupole LC/MS for the detection and quantification of NDMA, N-nitroso-diethylamine (NDEA), N-ethyl-n-nitroso-2-propanamine (NEIPA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-diisopropylamine (NDIPA), N-nitroso-methylphenylamine (NMPA), N-nitroso-di-n-propylamine (NDPA), and N-nitroso-di-butylamine (NDBA) impurities in metformin drug substance and drug products.