Nitrosated Active Pharmaceutical Ingredients – Lessons Learned?

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO2

“…In a process such as fluidized bed granulation, where large amounts of air and heating conditions coexist, the various amines present in the API and the amine substructure in the API itself can be nitrosated, resulting in the formation of low molecular weight nitrosamine impurities and nitrosamine drug substance related impurities (NDSRIs), respectively. 9,44 When identifying nitrosating agents in elucidating the mechanism of N-nitrosamine formation in drugs, it is necessary to consider the possibility of nitrosamine formation and contamination throughout the manufacturing process without being limited by information on known nitrosating agents.…”

“…This study demonstrated that a trace amount of atmospheric NO 2 causes nitrosation of DMA. In a process such as fluidized bed granulation, where large amounts of air and heating conditions coexist, the various amines present in the API and the amine substructure in the API itself can be nitrosated, resulting in the formation of low molecular weight nitrosamine impurities and nitrosamine drug substance related impurities (NDSRIs), respectively. , …”

Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies

“…Investigations by the pharmaceutical industry have shown that these NDSRIs form predominantly by a reaction with trace nitrites present in excipients, but a complex picture is emerging with often multifactorial contributing factors. Increase of NDSRIs during the shelf life of the drug product has also been observed. − …”

New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity

“…Additional sources of nitrosamines are other solvents used in the synthesis, i.e., DMA ( N , N -dimethylacetamide) or TEA (triethylamine). This event resulted in the emergence of new analytical methods for detecting nitrosamines in ARB preparations. − It is noteworthy that during preparation of co-crystals or co-amorphous solid dispersions, there is no risk of generating nitrosamine contaminations, since the processes are solvent-free or carried out using safe solvents, usually alcohols. As mentioned, the interest in ARBs has recently increased, mainly due to the possible drug repurposing in the treatment of other diseasesimportantly, some patents on commonly used ARB compositions will soon expire. − In the following subsections, possible applications of ARBs in the treatment of COVID-19, Alzheimer’s, Parkinson’s, and several other diseases will be discussed.…”