Objective: To investigate an unknown peak at relative retention time (RRT) 0.95 of N-nitrosodiethylamine (NDEA) of irbesartan API with the LC-MS/MS detection method. To elucidate the structure and origin of this unknown peak. Its structure was confirmed with a reference compound, and a method optimization strategy was proposed to eliminate the impact of this unknown peak. Methods: The unknown peak causing interference in the determination of NDEA within sartan drug substances was examined using a full scan method of LC-MS/MS analysis. The unknown peak at RRT 0.95 was validated by conducting high resolution LC-MS analyses and comparing with that of a reference sample. Additionally, a strategy for resolving this issue was proposed in the further investigation. Results: According to the LC-Q TOF MS results, the unknown peak at RRT 0.95 was confirmed to be 1-pentanamide, a trace regular impurity commonly existing in the sartan samples. As the extract mass of 1-pentanamide was 1 less than that of NDEA, the m/z value of an isotope in 1-pentanamide ([M+H]++1) was 103 and was equal to the m/z value of the main [M+H]+ isotope of NDEA under the MRM mode. Furthermore, the [M+H]++1 isotope ion of 1-pentanamide could occur a neutral lose by leaving a molecule of ethylene to generate the isotope ion of m/z 75, which was similar to NDEA in the MRM analysis under ESI positive mode. Therefore, when m/z 103 was used as the precursor ion and m/z 75 was used as the quantitative ion, 1-pentanamide will interfere with detection of NDEA. Conclusion: In the LC-MS/MS analysis for NDEA, the unknown peak observed at a retention time of 0.95 has been identified as 1-pentanamide. This compound is confirmed as a common trace impurity that regularly occurs during the production of sartan active pharmaceutical ingredients (APIs), rather than being another nitrosamine impurity. Subsequent research has revealed that employing a more selective quantitative model and choosing m/z 47 as the quantifier ion effectively avoid the unknown peak caused by 1-pentanamide.
CAI Hong
,
XIE He
,
LI Xiao-ling
,
ZHAO Shi-yi
,
JING Bing-jiang
,
JIN Jian-yang
,
CHEN Wen-bin
,
YE Jian
,
LI Min
,
LIN Jin-sheng
. Investigation and exclusion strategy of an unknown peak in N-nitrosodiethylamine detection of irbesartan by LC-MS/MS[J]. Chinese Journal of Pharmaceutical Analysis, 2025
, 45(2)
: 265
-274
.
DOI: 10.16155/j.0254-1793.2024-0383
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