Development of a sensitive and stable GC-MS/MS method for simultaneous determination of four N-nitrosamine genotoxic impurities in sartan substances

Abstract

Recently, N-nitrosamines have been unexpectedly found in generic sartan products. Herein, we developed a sensitive and stable GC-MS/MS method with multiple reactions monitoring mode for the simultaneous determination of four N-nitrosamines in sartan substances, namely, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodibutylamine, and N-nitrosodiisopropylamine. The conditions of gas chromatography and mass spectrometry were optimized. The method was validated according to the International Council for Harmonization guidelines in terms of sensitivity, linearity, accuracy, precision, specificity, and stability. The limits of detection of N-nitrosamines in sartan substances ranged from 0.002 to 0.150 ppm, and the corresponding limits of quantification were in the range of 0.008-0.500 ppm, which met the sensitivity requirements for the limits set by the Food and Drug Administration of the United States. The internal standard curve of four N-nitrosamines showed good linearity of regression coefficients over 0.99. The recoveries of N-nitrosamines in selected sartan drugs ranged from 87.68 to 123.76%. The intraday and interday relative standard deviation values were less than 9.15%. Therefore, this proposed method exhibited good sensitivity and precision, high accuracy, and fast analysis speed, which provide a reliable method for quality control of N-nitrosamines in sartan products.

Development of a Sensitive Screening Method for Simultaneous Determination of Nine Genotoxic Nitrosamines in Active Pharmaceutical Ingredients by GC-MS

“…LODs were determined to be within the range 0.15–1.00 ppb ( Table 2 ); such low LODs are comparable to the results obtained with GC-MS/MS by Liu at al. [ 11 ] ( Table S5 ).…”

“…Therefore, trace-level analysis of nitrosamines is becoming an emerging topic of interest in the field of quality control. Till now, a wide range of quantitative analytical methods to measure nitrosamine traces in pharmaceuticals have been established, including gas chromatography with single quadrupole or tandem mass spectrometers (GC-MS/MS) with a headspace system or direct injection [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ], liquid chromatography–tandem mass spectrometers (LC-MS/MS) or high-resolution mass spectrometers [ 17 , 18 , 19 , 20 ], and liquid chromatography with UV detectors and supercritical fluid chromatography (SFC) [ 21 , 22 , 23 ]. Solid-phase extraction (SPE), solid-phase microextraction (SPME), and dispersive liquid–liquid microextraction (DLLME) are also commonly used with GC-MS to produce comparable results of the LOQ (range 0.5–1.5 ppb) to LC-MS/MS [ 24 , 25 , 26 ].…”

Comparison of EI-GC-MS/MS, APCI-LC-MS/MS, and ESI-LC-MS/MS for the Simultaneous Analysis of Nine Nitrosamines Eluted from Synthetic Resins into Artificial Saliva and Health Risk Assessment

“…The analytical conditions for GC and LC were optimized by referring to previous studies on the simultaneous analysis of nitrosamines using GC-MS/MS and LC-MS/MS, and the nitrosamine analysis guidelines of domestic and overseas countries. In previous studies using GC [13][14][15][16][17], the WAX column in which the stationary phase is ethylene glycol is used most frequently in the analysis of nitrosamines. We selected the DB-WAX UI (30 m × 0.25 mm, 0.25 µm) column accordingly.…”

“…In the past, the GC method mainly referred to the gas chromatography-thermal energy analysis (GC-TEA), which is a traditional method with a high selectivity for Nnitroso compounds using thermal decomposition [12]. However, since MS with a higher sensitivity than GC-TEA has been developed, GC-MS(MS) (single or tandem MS) has been applied to analyze nitrosamines in several studies, as well as in Method 521 of the U.S. EPA [13][14][15][16][17]. The LC method has been reported to enable the simultaneous measurement of nitrosamines eluted into artificial saliva and has been verified as an alternative to the traditional GC-TEA method of the EU [2].…”

validated LC-MS method for the estimation of genotoxic nitroso amines impurities in empagliflozin

“…Similarly, by-products formed in the drug synthesis process may be carried forward to the drug substances as Nitrosamine impurities (Ngongang et al, 2015). Solvents such as Dimethylformamide, Dimethylacetamide (DMF) or Diethylacetamide (DEA) may form potential NDMA and NDEA impurities (Liu et al, 2021). The use of DMF in the synthesis might lead to the generation of nitrosamine impurity (Parr & Joseph, 2019).…”