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

In October 2021, an India-based pharmaceutical company withdrew a number of batches of irbesartan and irbesartan hydrochlorothiazide finished products 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 so called “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 “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 “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).

Current Status of Angiotensin Receptor Blocker Recalls

Losartan was the ninth most prescribed drug in the United States in 2016, and several other angiotensin-II receptor blockers (ARBs) are widely prescribed. Since July 2018, >2 dozen specific ARB products have been recalled owing to the presence of potentially carcinogenic nitrosamine impurities in selected lots. As is the case with all U.S. drug recalls, the ARB recalls have been voluntary on the part of the companies involved. In April 2019, the Food and Drug Administration categorized marketed ARB products with respect to nitrosamine impurities: (1) not present, (2) to be determined with no prior lots removed from the market (TBD), or (3) to be determined in the context of prior lots having been removed from the market (TBD*). The data were structured as hundreds of rows of products. Owing to the complexity of these data, more than a year into the recalls, it remains difficult for clinicians to understand which ARB products are free of impurities.

The influence of storage condition on nitrite, nitrate and vitamin C levels in vegetables

Vegetables are the main sources of nitrate and nitrite in food. The presence of nitrate and nitrite at a high level may cause a negative impact on health, because nitrite and nitrate when reduced to nitrite, may react with alkylamine to form carcinogenic nitrosamine. The influence of temperature and time of storage on nitrite, nitrate, and vitamin C contents in vegetables were investigated in this study. The vegetables were sweet mustard, bokchoy, spinach and lettuce obtained from a local market. Samples were stored at ±25oC and ±5oC. Analysis of nitrite, nitrate, and vitamin C was conducted in fresh samples, after storage for 24 and 48 hours. Nitrite was analyzed by spectrophotometry at 540 nm. Nitrate reduced into nitrite with Zn in acidic conditions and then analyzed as nitrite. Vitamin C was analyzed by titration with 2.6-dichlorophenolindophenol. During storage, nitrite and nitrate increased, while vitamin C decreased. Nitrite and nitrate content in fresh samples were 15.22 and 22.46 mg/kg (sweet mustard), 12.57 and 6.55 mg/kg (bokchoy), 20.26 and 90.60 mg/kg (spinach), 18.77 and 32.68 mg/kg (lettuce), respectively. Vitamin C content in fresh samples was 101.15 mg/100g (mustard), 92.17 mg/100g (bokchoy), 88.95 mg/100g (spinach), 40.03 mg/100g (lettuce). After storage for 48 hours at ±25oC, nitrite and nitrate increased 44.97% and 53.19% (mustard), 46.18% and 62.59% (bokchoy), 43.86% and 16.48% (spinach), and 41.05% and 47.09% (lettuce), respectively. Vitamin C decreased 67.57% (mustard), 24.68% (bokchoy), 81.25% (spinach), and 79.74% (lettuce). Storage at ±5oC, showed that nitrite and nitrate increased 27.54% and 35.08% (mustard), 13.75% and 43.51% (bokchoy), 19.59% and 10.60% (spinach), 19.85% and 25.16% (lettuce), respectively. Vitamin C decreased 30.88% (mustard), 6.05% (bokchoy), 60.92% (spinach), and 74.94% (lettuce). During storage, nitrite and nitrate increased more significantly at ±25oC than ±5oC while vitamin levels C decreased and were more effective at 25oC than 5oC.