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Synthesis and analysis of nitrosamines

Since the so-called "Nitrosamines (N-NAs) Crisis" emerged in June 2018, the European

Medicines Agency (EMA), and the Food and Drug Administration (FDA), together with the

rest of the regulatory agencies, began to carry out risk analysis, in order to identify the

different causes of the formation of these compounds and eradicate their presence, both in

active ingredient and in finished product. And in order to respond to many of the needs that

have arisen from these risk analyses, the Center for Applied Chemistry and Biotechnology

(CQAB), within the Pilot Plant and Biotechnology Area, has focused on the synthesis,

isolation and characterization of N-NAs and N-Nitroso compounds (NOCs) formed directly

on the corresponding active ingredients (APIs). Until now, N-NAs have been obtained in

active ingredients with great molecular diversity and application in different therapeutic

areas. These API nitrosamines are being used as standards when quantified by NMR.

Currently, several of the structures obtained are being used to address a large part of the

problem of identifying N-NAs in APIs and finished products, thus favoring their correct


Moreover, a new ultra-sensitive analytical method based on the FDA method was developed using

LC-MS/MS with HRMS for the quantification of six nitrosamine (NAs) impurities in different

drug substances (N-nitroso-dimethylamine, N-nitroso-diethylamine, N-nitroso-ethyl-isopropyl

amine, N-nitroso-diisopropylamine, N-nitroso-dibutylamine, and N-nitroso-N-methyl-4-

aminobutyric acid). This method improves the sensitivity of the FDA method up to about 20

times, being also reduced the analysis time to the half. Its high sensitivity and easy sample

treatment should be of relevance in the field of pharmaceutical quality control for determining

NAs impurities associates to the synthesis processes. Moreover, for the detection of other possible

nitrosamines formed as by-products due to the modification of the manufacturing processes, a

screening method in full scan mode was also developed showing a deteccion limits similar to the


Therefore, these two new methodologies provide a reliable method for routine control of

nitrosamine impurities in pharmaceutical industry.

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