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Synthesis of nitrosamines derived from APIs or degradation products for application as analytical standards by the pharmaceutical industry

Grant number: 20/13804-4
Support Opportunities:Research Grants - Innovative Research in Small Business - PIPE
Duration: March 01, 2022 - November 30, 2022
Field of knowledge:Health Sciences - Pharmacy - Medicines Analysis and Control
Principal Investigator:Shaiani Maria Gil de Melo
Grantee:Shaiani Maria Gil de Melo
Host Company:Bind Pesquisa e Desenvolvimento Ltda
CNAE: Fabricação de produtos químicos orgânicos não especificados anteriormente
Fabricação de preparações farmacêuticas
City: Ribeirão Preto
Associated scholarship(s):22/01815-7 - Synthesis of nitrosamines derived from APIs or degradation products for application as analytical standards by the pharmaceutical industry, BP.PIPE


N-Nitroso compounds (NOCs) are a class of compounds characterized by a nitroso functional group. The class contains N-nitroso amines (nitrosamines), are known for their carcinogenic and mutagenic potential. Since the identification of the first contamination by nitrosamines in medicines in 2018, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), in valsartan, losartan, irbesartan, several other cases have been reported (ranitidine, pioglitazone, metformin, rifapentine, rifampin). This fact is associated with the mechanism of formation of nitrosamines, which requires only the presence of a source of amine, a nitrosating agent (nitronium ion) or oxidant and favorable conditions in the production process as a whole, from the manufacture of the API and until the drug formulation and packaging. Generally, manufacturing processes using amines and nitrites are common contaminants in reagents, excipients, and even water and processes. Faced with this current scenario of global concern, important drug regulatory agencies, such as EMA, FDA, and Anvisa (National Health Surveillance Agency), imposed control measures on companies. It was defined that all companies that hold a drug registration should evaluate all products in their portfolios about the risk of contamination by nitrosamines. So, it is necessary to evaluate route of synthesis of the API and also its structure and chemical reactivity and its degradation products for the possibility of nitrosation formation in the presence of nitrosating agents. From this analysis, it is necessary to determine which nitrosamines would be possible to form and carry over the drug. The carrying over of impurity, when possible, should be evaluated analytically through methods developed and validated using specific analytical standards. The technical feasibility of the project was evaluated based on the methodologies for obtaining N-nitroso compounds, which are known to be simple and low cost, being combined with the technical capacity of the team, there was low risk in the execution of the project. As well as the technical challenge, the commercial challenge of entering the market was also assessed. This was planned to be carried out through the collection of demands by the company already constituted by the partners, EPHAR, which currently performs general analytical services for several national pharmaceutical companies. Besides that, the presence of competitors was evaluated, it was found that some companies started efforts to produce the most common nitrosamine patterns. However, these standards do not reflect the real need of the sector since the formation of nitrosamines can occur from the structure of the API or its degradation products. Thus, given this scenario of mandatory nitrosamine evaluation, the technical and commercial feasibility of the proposal, since there is a lack of specific analytical standards for APIs, the main objective of this proposal is the development of a synthesis services platform of N-nitrous analytical standards derived from APIs and degradation products for pharmaceutical companies aiming to supply their need concerning their analytical development processes for the evaluation of nitrosamines. (AU)

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