What Is Nitrosamine?
Nitrosamine is the generic name for amine derivatives that have the hydrogen atom on the amine nitrogen replaced by a nitroso group (-N=O).
Nitrosamines are found in trace amounts in the air, water, food, cosmetics, cigarettes, etc. Some of them are known to be carcinogens. Typical carcinogens are N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA).
In recent years, NDMA and NDEA have been detected as impurities in bulk pharmaceuticals for sartan and ranitidine drugs, leading to a product recall.
Uses of Nitrosamine
Nitrosamines are widely used in industry as plasticizers and additives. For example, N,N’-dinitrosopentamethylenetetramine (N,N’-Dinitrosopentamethylenetramine) is used as an organic foaming agent for rubber and other materials.
Nitrosamines are a group of compounds, many of which are known to be carcinogenic. For example, N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are known to be toxic substances found in tobacco.
While it is toxic, it may also be produced as an impurity in the manufacturing process of pharmaceutical products. In recent years, the risk of contamination has been evaluated and measures taken to reduce the risk of contamination. For the purpose of these tests and analyses, standard and mixed standard solutions of nitrosamines are used as control experiments, and outsourced testing is also actively conducted.
In addition, since there have been cases of contamination of food products, especially processed products, with trace amounts of nitrosamines, the risk of contamination is now being evaluated in areas other than pharmaceuticals.
Properties of Nitrosamine
In some cases, heme iron in meat promotes the formation of carcinogenic nitrosamines, and nitrosamines are also formed when meat is smoked. In addition, sodium nitrite and sodium nitrate, which are added to processed meats, are responsible for the formation of nitrosamines.
Cooking foods has been shown to alter the amount of nitrosamines in them; cooking at temperatures below 100°C (182°F) almost never increases the amount of Nitrosamines, while cooking at higher temperatures tends to increase it.
Types of Nitrosamine
Of the nitrosamines that have recently been implicated in pharmaceuticals and other products, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are the simplest in structure. In addition, N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitrosomethylphenylamine (NMPA), and N-nitrosoisopropylethylamine (NIPEA) have been found in active pharmaceutical ingredients and preparations, as well as N-nitrosodiisopropylamine (NDIPA) and N- N-nitrosodibutylamine (NDBA) have been identified as theoretical contamination hazards.
Tolerable intake levels (ng/day) for these compounds have been established by the Ministry of Health, Labour and Welfare (MHLW). Currently, manufacturers are requested to conduct voluntary inspections to ensure that the amount of nitrosamines in bulk pharmaceuticals is below the control level.
Other Information on Nitrosamine
Nitrosamine and Drug Manufacturing
Nitrosamines are known to be formed by the reaction of secondary amines with nitrous acid. In recent years, nitrosamines have been detected as impurities in pharmaceuticals. In sultan-based pharmaceuticals, this is thought to be due to the reaction of the solvent dimethylformamide (DMF) with nitrous acid.
The nitrous acid used in this reaction is added to quench the azide used in the formation of the tetrazole ring. NDMA has also been detected in ranitidine hydrochloride preparations and APIs. Ranitidine is a compound that has an N-dimethyl structure, the source of NDMA, and a nitro group.
Therefore, it is believed that in the case of ranitidine, the cause of NDMA formation is temperature and the structure of ranitidine itself. In fact, it has been reported that NDMA increases significantly in ranitidine when exposed to high temperatures.