Organic Chemistry

Reaction of irbesartan with nitrous acid produces irbesartan oxime derivatives, rather than N-nitrosoirbesartan

Authors

Abstract

In October 2021, a number of batches of irbesartan and irbesartan hydrochlorothiazide finished products were recalled from the US market, due to the presence of unacceptable level of the probably carcinogenic nitrosamine N-nitrosoirbesartan. Nevertheless, there is no revealing of the exact structure of this hypothetical N-nitrosoirbesartan. In the current study, we performed a set of 10 reactions of irbesartan with nitrous acid under various conditions and found no trace of this hypothetical N-nitrosoirbesartan by a sensitive and accurate LC-MS method with limit of detection (LOD) of 30 ppb. With the use of LC-PDA/UV-high resolution MSn as well as 1D/2D NMR, the reaction products formed are found to be the two isomeric oxime derivatives of irbesartan, with the Z-isomer as the predominant product. Furthermore, no trace of this hypothetical N-nitrosoirbesartan can be detected in representative commercial batches of irbesartan. Despite of the fact that in silico evaluation suggests that the two irbesartan oximes may be controlled as regular impurities, analysis of representative irbesartan commercial batches by the LC-MS method indicates that the oximes are not detected (LOD: 30 ppb).

Version notes

Editorial changes to be more precise or accurate.

Content

Thumbnail image of Reaction of Irbesartan with nitrous acid produces  irbesartan oxime derivatives rather than N-nitrosoirbesartan_31 Jan 2022 Upload.pdf

Supplementary material

Thumbnail image of Supporting information with title.pdf
Supporting information
Supplementary figures and table.