NITROSOAMINE IMPURITY AS CARCINOGENIC

Dr. Dhrubo Jyoti Sen, Dr. Pruthviraj K. Chaudhary, Shloka V. Chaudhary and Dushaynt P. Chaudhary*

ABSTRACT

Nitrosamine impurities may increase the risk of cancer if people are exposed to them above acceptable levels and over long periods of time, but a person taking a drug that contains nitrosamines at, or below, the acceptable daily intake limits every day for 70 years is not expected to have an increased risk of cancer. Ten nitrosamines found in food are carcinogenic (can cause cancer) and genotoxic (may damage DNA. DNA (deoxyribonucleic acid) is capable of copying itself and carries the instructions for all the proteins used to create and sustain life). Nitrosamines are a group of organic chemicals formed by the interaction of nitrites with amines or amides inside the body; they have been found to cause cancer in animals. The mechanism of carcinogenicity results from enzymatic α-hydroxylation with cytochrome P450 where dealkylated primary nitrosamine is formed. The unstable primary nitrosamine further decomposes to diazonium 3, a DNA alkylating agent, which is a carcinogen. N-nitrosamines are carcinogenic impurities most commonly found in groundwater, treated water, foods, beverages and consumer products. The recent discovery of N-nitrosamines in pharmaceutical products and subsequent recalls pose a significant health risk to patients. Initial investigation by the regulatory agency identified Active Pharmaceutical Ingredients (API) as a source of contamination. However, N-nitrosamine formation during API synthesis is a consequence of numerous factors like chemistry selection for synthesis, contaminated solvents and water. Furthermore, apart from API, N-nitrosamines have also been found to embed in the final product due to degradation during formulation processing or storage through contaminated excipients and printing inks. The landscape of N-nitrosamine contamination of pharmaceutical products is very complex and needs a comprehensive compilation of sources responsible for N-nitrosamine contamination of pharmaceutical products. Therefore, this review aims to extensively compile all the reported and plausible sources of nitrosamine impurities in pharmaceutical products. The topics like risk assessment and quantitative strategies to estimate nitrosamines in pharmaceutical products are out of the scope of this review.

Keywords: DNA, carcinogen, genotoxic, nitrites, N-nitrosoamine, primary, secondary, tertiary amine, quaternary amine.