Solid State Kinetics of Nitrosation Using Native Sources of Nitrite
Abstract
While many reactive species are known to cause N-nitrosation, trace nitrite (NO2-), which may be present in several excipients, is a source of nitrosating agents in pharmaceutical formulations. In this study we have found that the salt form of NO2- can influence the favored nitrosation conditions and final amount of nitrosamine being formed. Using native levels of NO2-, most likely present as ammonium nitrite (NH4NO2), in microcrystalline cellulose, we have determined the kinetics of nitrosamine formation in solid state with dimethylamine substrate present in metformin, used as model compound. It was found that the competing degradation of NH4NO2 into N2 and H2O limited the amount of nitrosamine formation to a great extent. Empirically modelling the kinetic data predicted reaching at maximum 1.6% conversion over a hypothetical 3-year shelf-life. These results also showed that using other sources of NO2- as spiking reagents, such as NaNO2, may lead to unrealistic worst-case situations when the main form of NO2- in the drug product (DP) under evaluation may be NH4NO2. As well, measuring NO2- in freshly manufactured excipients containing NO2- potentially as NH4NO2 may lead to biased high NO2- content, which is not representative of the actual amounts present at the time of DP manufacture.
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.