Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Abstract

Regulatory requests that marketing authorization holders for chemically synthesized active substances risk assess their medicines for the potential presence of N-nitrosamines have led to a renewed interest in amine nitrosation. We have used published mechanistic and kinetic studies of amine nitrosation to assess the risk that traces of nitrite in the water used during active pharmaceutical ingredient (API) manufacturing could give rise to significant levels of N-nitrosamines. We conclude that the levels of nitrite typically found in water used for API manufacture are very low (<0.01 mg/L) and will not give rise to significant levels of N-nitrosamines through reaction with basic secondary amines (pK a > 9.5) in the majority of cases. The use of less basic amines, elevated processing temperatures, or low pH conditions in combination with elevated levels of nitrite have the potential to generate levels of N-nitrosamines that could lead to significant quantities being present in the isolated API if the downstream processing does not provide an adequate purge. The kinetic models described may be used to risk assess specific situations or processes. For example, the addition of traces of dimethylamine to a nitrosation reaction is predicted to lead to the rapid, quantitative formation of N-nitroso dimethylamine. Simple tertiary alkylamines can nitrosate via a dealkylative process, which is significantly slower than secondary amine nitrosation. Therefore, they do not represent a risk of N-nitrosamine formation under conditions where there is no significant risk of secondary amine nitrosation.

Deaminative chlorination of aminoheterocycles

“…Having established a protocol using various chloride sources, we turned our attention to explore the scope of the aminoheterocycle (Table 1). First, we engaged a panel of 4-and 2-aminopyridines (7,(12)(13)(14)(15)(16)(17)(18)(19)(20). Tuning the temperature turned out to be crucial to achieve satisfactory yields and accommodate functionalities such as halides (12,14), aromatic rings (16,17), an ester (15), a morpholine (18), a nitro (19) or a cyano (20).…”

“…First, we engaged a panel of 4-and 2-aminopyridines (7,(12)(13)(14)(15)(16)(17)(18)(19)(20). Tuning the temperature turned out to be crucial to achieve satisfactory yields and accommodate functionalities such as halides (12,14), aromatic rings (16,17), an ester (15), a morpholine (18), a nitro (19) or a cyano (20). Diazines, including pyrimidine ( Sandmeyer's limitations include explosive diazonium intermediates, limited functional group tolerance preventing its use for late-stage applications and being challenging for five-membered N-heterocycles.…”

“…More importantly, the formation of nitrogen-rich heteroaryl diazonium salts results in highly energetic compounds, which raise severe concerns about their safe handling 12 , 13 . Recently, awareness has also been raised by the use of aqueous nitrite solutions, which can lead to important levels of carcinogenic N -nitrosamines 14 . Altogether, these setbacks prohibited the translation of such a strategy in complex settings, and the perception of C( sp 2 )‒NH 2 as late-stage functionalization handles was abandoned.…”

Determination of dimethylamine and nitrite in pharmaceuticals by ion chromatography to assess the likelihood of nitrosamine formation

“…The nitrosylation of DMA to generate NDMA was used as a model reaction that could rise during API processing. Simulations based on the published kinetics of secondary amine nitrosylation have shown that higher nitrite levels may result in significant levels of N -nitrosamines at low pH or elevated temperature [ 10 ]. Therefore, limiting the two precursor compounds in drug substances or products can prevent the potential formation of NDMA and other nitrosamines.…”

Characteristics of low-nitrite pork emulsified-sausages with paprika oleoresin solution during refrigerated storage

“…However, if excess of sodium nitrite were taken by eating foods containing nitroso compounds, N-nitrosamine, a carcinogen, might be produced by combining sodium nitrite and amino acids or secondary amines in human's digestive system [8][9]. Furthermore, processed meats are classified as carcinogens by the World Health Organization (WHO) [10].…”