Abordagens para análise de n-nitrosaminas em medicamentos utilizando DPX-LC-MS e DART-MS
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2023-12-19
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Universidade Federal de Goiás
Resumo
N-Nitrosamines (NAs) are molecules characterized by a deprotonated amine group
linked to a nitroso group, usually formed through the reaction of secondary or tertiary
amines with nitrosating agents. NAs are commonly found as impurities in various
products, such as processed foods and cosmetics. These molecules are the subject
of study due to their potential mutagenic and carcinogenic properties. In 2018, NAs
were discovered in medicines containing the active ingredient valsartan. In sartan
medicines, the occurrence of NAs was initially linked to the synthesis of the active
pharmaceutical ingredient (API), as the reaction medium may contain precursor
amines for NAs, as well as a nitrosating agent. Through more in-depth studies, it has
been confirmed that the degradation of the API or its interaction with the packaging
material could lead to the formation of NAs. These discoveries prompted global
regulatory agencies to establish guiding principles regarding the presence and
maximum allowable concentrations of these molecules in such medicines. Aiming to
assess the content of NAs in medicines, efficient and sensitive analytical methods
have been developed. The challenge in analyzing NAs in medicines lies in the low
concentration of these analytes, as they are found in this matrix in the order of ng of
N-nitrosamine per mg of the medicines. The literature presents various
chromatographic methods coupled with mass spectrometry (MS) applied in such
analyses. Both liquid chromatography (LC) and gas chromatography (GC)
techniques provide sensitive and selective methods for the analysis of NAs in
medicines. However, LC methods have advantages over GC as it allows the analysis
of thermally unstable and non-volatile compounds. Due to the presence of the API in
the sample and the low concentration of these impurities, the determination of NAs
can be compromised by various factors, such as matrix effects, carryover effects, and
the compromise and contamination of the LC-MS system. Thus, the sample
preparation step proves to be important, aiming at the extraction, purification, and
pre-concentration of NAs. Additionally, advances in mass spectrometry have led to
the development of ambient ionization techniques designed to analyze samples that
are either unprocessed or minimally modified in their native environment. These
techniques enable the analysis of samples in situ, often in a non-destructive manner.
Another important factor currently is the adaptation of analysis protocols with
sustainable principles advocated by green chemistry, which aim to reduce the use of
solvents and samples, minimize risks, decrease energy consumption, and reduce
waste generation. Therefore, the present study introduces new approaches to the
analysis of NAs in medicines that have not yet been explored in the literature. Chapter
I demonstrates the use of a miniaturized sample preparation technique for the
separation and pre-concentration of NAs in medicines followed by LC-MS analysis.
Conversely, Chapter II presents the application of an ambient ionization technique
coupled with mass spectrometry for the assessment and quantification of NAs in
medicines.
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Citação
BATISTA JUNIOR, A. C. Abordagens para análise de n-nitrosaminas em medicamentos utilizando DPX-LC-MS e DART-MS. 2023. 116 f. Dissertação (Mestrado em Química) - Instituto de Química, Universidade Federal de Goiás, Goiânia, 2023.