Nitrosamines, or more correctly N-nitrosamines, refer to any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens. Although they are also present in some foods and drinking water supplies, their presence in medicines is nonetheless considered unacceptable.
The formation of nitrosamines is generally only possible when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable but can be formed in situ from nitrites (NO2) under acid conditions. Coincidently the solvents employed either were amines or contained traces of amines, and this likely afforded the observed NDMA and NDEA. However, during on-going investigations, it was also concluded that the possibility for nitrosamine impurity content was broader than simply the concurrent presence of nitrites and amines in the synthesis of the active pharmaceutical ingredient (API).
N-nitrosamines, which are derived from an alkyl, alkaryl, aryl, or cyclic amines, belong to a larger group of potent carcinogens known as N-nitroso compounds. It is a group they share with N-nitrosamides as shown in Figure 1, which are derived from N-alkylureas, N-alkylcarbamates, and simple N-alkylamides.
In order for a nitrosamine to form, both an amine source and a nitrosating agent need to be present. N-nitrosamines are formed in the nitrosation reaction from primary, secondary, and tertiary amines. Nitrosation of primary amines yields primary N-nitrosamines which are unstable at normal temperatures. They decompose according to the reaction and primary aryl amines yield stable aryl diazonium ions. Alkyl diazonium ions, on the other hand, are not stable in aqueous solution and break down to yield nitrogen and alkyl carbonium ions which can take part in a multitude of alkylation reactions.
Secondary nitrosamines also arise in the reaction of primary amines with nitrosating agents. In the reaction of nitrite with methylamine, N-nitrosodimethylamine is formed according to the reactions shown.
Tertiary amines can be converted to nitrosamines by dealkylative nitrosation. This reaction proceeds via methylene immonium ion intermediate which yields the nitrosamine after reaction with ionic nitrite and cleavage of the aldehyde group.
Evidence suggests that sources of nitrites or amines as unintentional contaminants of starting materials, reagents, and solvents – such as dimethylamine in the common solvent dimethylformamide (DMF) – may also provide circumstances in which nitrosamines may form. The carryover of nitrites or amines from subsequent steps may also afford opportunities for formation.
The chemistry of nitrosamine formation is quite complex, Therefore, NDMA, NDEA, and other structurally-related nitrosamines are suspected by regulatory authorities to act as carcinogens in humans and were subsequently detected in other medicines belonging to the sartan family, including: N-nitrosodiethylamine (NDEA), N -nitrosodiisopropylamine (NDIPA), N -nitrosoethylisopropylamine (NEIPA) and N -nitroso-N-methyl-4-aminobutyric acid (NMBA). More recently, nitrosamine impurities have been reported in pioglitazone, metformin and ranitidine containing products.
Nitrosamine impurity formation can be avoided by selecting proper reagents, catalysts, and solvents in the manufacturing of drug substances. Nitrosamine is a potential process impurity because of its extreme toxicity regulatory authorities put forth the expectation of appropriate risk assessment and control strategy. A thorough review of the synthetic process and quality of reagent is helpful for the control of such impurities.