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

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.

Trace Level Quantification of 4-Methyl-1-nitrosopiperazin in Rifampicin Capsules by LC-MS/MS.

Rifampicin is a first-line anti-tuberculosis drug. However, in August 2020, the presence of 1-methyl-4-nitrosopiperazine (MNP), a nitrosamine impurity, was detected by the United Stated Food and Drug Administration (US FDA) in rifampicin capsules. Consequently, the development of efficient methods for the detection of MNP is an important objective. In this study, the MNP present in rifampicin capsules was detected using LC-MS/MS. A total of 27 batches from nine manufacturers in the Chinese market were tested, with MNP (0.33-2.36 ppm) being detected in all samples at levels exceeding the maximum acceptable intake limit of 0.16 ppm initially set by the FDA. However, after considering the associated benefits and risks, the FDA-approved limit was revised to 5 ppm; hence, all the samples examined herein exhibited MNP levels well below the required limit. Furthermore, the results of forced degradation experiments suggest that MNP is formed by the thermal degradation of rifampicin.