Analysis of N‐nitrosodimethylamine in metformin hydrochloride products by high‐resolution accurate mass gas chromatography mass spectrometry

Abstract

The high resolving power of the Orbitrap mass spectrometer in a highresolution accurate mass gas chromatography (HRAM-GC-MS) system provides greater selectivity and sensitivity for the identification and quantification of volatile analytes at low parts per billion (ppb) levels. Hence, it can be applied for the analysis of pharmaceutical impurities like N-nitrosodimethylamine (NDMA) in metformin hydrochloride products (METs).Methods: Different METs extracted by a dichloromethane/aqueous system were analyzed by HRAM-GC-MS under softer electron ionization (EI) at 30 eV. The accurate masses of NDMA and its internal standard NDMA-d6 were analyzed by full scan and targeted selected ion monitoring modes under 60 000 and 30 000 full width at half maximum at m/z 200, respectively. Data acquisition and processing were managed by Xcalibur and Trace Finder software, respectively.Results: Limits of detection (LOD) and quantification (LOQ) at 10 and 20 ng/g were achieved, which is below the allowed daily intake of 32 ng/g. The mass errors measured from experimental data were within ±2 ppm of the theoretical values over a period of a week. Sample analysis showed that 180 out of 212 samples (85%) were below LOD and 15 out of 212 samples (7 %) were within LOD and LOQ. Only 17 samples (8%) were found to be above LOQ, comprising one active pharmaceutical ingredient (API), five immediate-release METs and 11 extended-released METs. Amongst these, seven extended-release METs and one API exceeded the daily allowed intake, 32 ng/g. Conclusions:The validated method has been successfully applied for NDMA analysis in various forms of METs. The method is rather straightforward without an additional clean-up step. The scope can also be extended to other volatile impurities in finished pharmaceutical products. | INTRODUCTIONNitrosamines in pharmaceutical products were widely reported in 2019 with the finding of N-nitrosodimethylamine (NDMA) in angiotensin receptor blocker drugs. 1 This small compound has been classified as a probable human carcinogen by the International Agency for Research on Cancer. 2 Since then, there have been extensive collaborative studies carried out by regulatory agencies and pharmaceutical companies to determine the NDMA content in metformin hydrochloride products (METs) after being alerted by the United States Food and Drug Administration 3 and the European Medicine Agency. 4 METs have been used to treat patients with

Development and validation of an analytical method for trace‐level quantification of genotoxic nitrosamine impurities in losartan and hydrochlorothiazide fixed‐dose combination tablets using ultra performance liquid chromatography triple quadrupole mass spectrometry

“…The U.S. Food and Drug Administration (USFDA) approved losartan and HCTZ fixed-dose combination tablets for the treatment of severe hypertension, which combines an ARB, losartan potassium, and a thiazide diuretic, HCTZ.10 Developing a technique for analyzing losartan potassium and HCTZ fixed-dose combination tablet formulations for the identification and quantification of eight potential genotoxic nitrosamines is challenging considering that losartan is formed by a tetrazole ring and HCTZ contains secondary amines in its heterocyclic ring that are susceptible to electrophilic N-nitrosation (Figure2). A number of laboratories, research centers, and government organizations globally have developed and published protocols for quantifying the amount of NDMA in drug substances or drug products using liquid chromatography (LC) and gas chromatography-tandem mass spectrometry (GC-MS/MS) or liquid chromatography-high-resolution mass spectrometry [11][12][13][14][15]. Over time, other analytical techniques were added, and NDEA, NMBA, and…”