Investigation into the genotoxic impurity, 1-methyl-4-nitrosopiperazine, in rifampicin

• Published in: Journal of pharmaceutical and biomedical analysis 2024-09, Vol.248, p.116303, Article 116303
• Main Authors: Tian, Ye, Tao, Xiaosha, Feng, Yuanyuan, Yin, Lihui, Ning, Baoming
• Format: Article
• Language: English
• Subjects: 1-methyl-4-nitrosopiperazine; Genotoxic impurity; LC-MS/MS; Rifampicin; Specified impurity
• ISSN: 0731-7085; 1873-264X; 1873-264X
• DOI: 10.1016/j.jpba.2024.116303

This study assessed the presence of the genotoxic impurity 1-methyl-4-nitrosopiperazine (MNP) in 27 batches of rifampicin capsules obtained from 11 manufacturers in China. While they were below the temporary limit of 5 ppm set by the US Food and Drug Administration, the observed levels (0.33–2.36 ppm) exceeded the acceptable threshold of 0.16 ppm. Building upon preliminary findings and degradation experiments, we concluded that MNP is a by-product of the oxidative degradation of rifampicin or is introduced via oxidation or nitrosation during the synthesis process involving 1-methyl-4-aminopiperazine. The pathways of MNP formation were confirmed in this study. Furthermore, we observed that the addition of antioxidants, sealed storage, and selection of dominant crystal forms can aid in controlling MNP levels. •Changes in MNP content were observed after rifampicin degradation.•Oxidation and nitrosation reactions are critical conditions for MNP formation.•Selection dominant crystal forms of rifampicin can aid in controlling MNP levels.•Adding antioxidants can help control MNP generation after rifampicin degradation.