Nitrosamines Analysis in Pharmaceuticals

Shimadzu’s LCMS 9030 high resolution accurate mass instrument coupled to LC 40 liquid chromatograph was used for the chromatographic separation and identification of N nitrosodimethyl amine ( with N,N dimethylformamide ( Mass accuracy of less than 10 ppm was used to further ensure the specificity of NDMA and DMF NDMA and DMF were identified and quantitated in Metformin tablet formulation

N-Nitrosodimethylamine (NDMA) & NNitrosodiethylamine (NDEA) are simplest of Dialkylnitrosamines. They are continued to be released as a by-product and contaminant from various industries and from municipal wastewater treatment plants. Major releases of NDMA, NDEA have been from the manufacture of pesticides, rubber tires, alkyl amines, and dyes. Similarly, these compounds are produced as a byproduct in the manufacturing of Active Pharmaceutical Ingredients (API’s). These compounds are classified as a Group 2A carcinogen (probable human carcinogen) by the World Health Organization. Recently some drug products were discovered to have been contaminated with NDMA & NDEA. It is believed to have been introduced into the finished products as a result of the manufacturing process of the drug substance. This contamination, was far exceeding the regulatory exposure limits specific to drug products. Consequently, medical agencies across Europe as well as the US Food and Drug Administration (USFDA) withdrew all affected drug products from the market. Hence it is very essential to have a sensitive, specific, accurate, reliable & robust method by using suitable analytical technique. In this experiment the In this experiment the pharmaceutical API’s namely Valsartan, Losartan & Olmesartan-Medoximil prone to contamination with NDMA and NDEA are analyzed by using developed HSGCMS/MS method.

Due to their genotoxic potential, nitrosamine impurities are of concern to the regulatory agencies Several ARB drug products ( Losartan), Metformin, Ranitidine, Rifampin have been recalled due to the presence of one or more of nitrosamine impurities 1 This application note describes a highly sensitive and specific determination of eight nitrosamine impurities in Metformin drug substance and drug product using Shimadzu LCMS 8050 triple quadrupole mass spectrometer The limit of quantitation ( were estimated and compared with current Food and Drug Administration ( guidelines for the analysis in metformin drug substance and drug product All the N nitrosamines met or exceeded the range, linearity, and LOQ criteria set by the FDA

Sartan drugs such as valsartan, losartan, and Irbesartan are high blood pressure treatments that narrow blood vessels and block the action of angiotensin II, which regulates blood pressure by causing water and salt intake. The recent discovery of Nnitrosamine impurities known as potent carcinogens in several sartan drug substances has become a global issue. In addition, the AZBT that is an azido impurity known as a mutagenic and potentially carcinogenic substance, was also detected in sartans. As a result, the European Medicine Agency(EMA) and Health Canada(HC), which are responsible for supervising medicines, have recalled some sartan drugs. Besides to AZBT, there are various types of azido impurities such as AZBC, AMBBT, and AMBBC as shown in Fig. 1. In this regard, the Ministry of Food and Drug Safety in Korea (MFDS) has announced the 'Test method for AZBT in sartan drug substances using LC-MS/MS’ for the analysis of AZBT, one of the azido impurities. Also, in Europe, European Directorate for the Quality of Medicines & HealthCare (EDQM) suggested the test method, ‘AZBT impurity in Valsartan, Irbesartan, Losartan, Candesartan’. In addition, the official Medicines Control Laboratory(OMCL), the research institute from the Swissmedic, introduced ‘AZBT and AZBC test methods for sartan-type drug substances using LC-MS/MS’ based on EDQM’stest method. Accordingly, this application news describes the evaluation of LC-MS/MS method for analysis of four azido impurities (AZBC, AMBBT, AMBBC and AZBT) in losartan drug substance

The presence of Nitrosamine (NSA) as impurity has been detected recently in several drug substances and drug products. In 2018, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were detected in some Valsartan Active Pharmaceutical Ingredients (API) and Finished Dosage Form (FDF). This led to an ongoing investigation to check presence of NSA in pharmaceutical substances and products. One such drug is Metformin; it is used to control high blood sugar observed in patients suffering from type 2 diabetes.

Varenicline is a prescription medication used to treat smoking addiction. It is a high-affinity partial agonist for the α4β2 nicotinic acetylcholine receptor subtype (nACh) and has the capacity to reduce cravings and withdrawal symptoms. It is estimated that varenicline successfully helps, one of every eleven people who smoke; to remain abstinent from tobacco for six months. It is on the World Health Organization's List of Essential Medicines and is available as a generic medication. Varenicline Nitroso-Drug Substance Related Impurity (VNDSRI) is also known as N-nitroso varenicline. (Figure-1) USFDA has identified higher levels of this impurity in some Varenicline finished drugs to be above FDA’s acceptable intake limit in some samples of Varenicline finished drugs. To ensure the safety and quality of varenicline tartrate drug product and drug substance, the USFDA has developed and validated a method to determine the presence or absence of VNDSRI.

Drugs containing sartan APIs (active pharmaceutical ingredients), such as valsartan, candesartan, irbesartan, losartan and olmesartan, are used for treatment of hypertension and heart failure. Recently, US FDA has released findings of probable human carcinogens, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and Ni-Nitroso-N-methyl-4-aminobutyric acid (NMBA) in sartan drug products and the affected medicines have been recalled. These nitrosamine impurities can form during the production of sartans that contain a functional group known as a tetrazole ring under certain conditions. Additionally, the presence of the impurities in some sartans is possibly due to uses of contaminated equipment or reagents in the manufacturing process.