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

Rationale The high resolving power of the Orbitrap mass spectrometer in a high‐resolution 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...

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Published in:Rapid communications in mass spectrometry 2023-01, Vol.37 (1), p.e9414-n/a
Main Authors: Kee, Chee‐Leong, Zeng, Yun, Ge, Xiaowei, Lim, Jing‐Quan, Teo Jessie, Hong‐Gek, Low, Min‐Yong
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container_title Rapid communications in mass spectrometry
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creator Kee, Chee‐Leong
Zeng, Yun
Ge, Xiaowei
Lim, Jing‐Quan
Teo Jessie, Hong‐Gek
Low, Min‐Yong
description Rationale The high resolving power of the Orbitrap mass spectrometer in a high‐resolution 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.
doi_str_mv 10.1002/rcm.9414
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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. 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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. 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subjects Chromatography
Data acquisition
Dichloromethane
Gas chromatography
Impurities
Mass spectrometry
Metformin
N-Nitrosodimethylamine
Pharmaceuticals
Resolution
Selectivity
title Analysis of N‐nitrosodimethylamine in metformin hydrochloride products by high‐resolution accurate mass gas chromatography mass spectrometry
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