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

Xiaosha Tao,Shangchen Yao,Lihui Yin,Wan-Hui Liu,Ye Tian

doi:10.3389/fchem.2022.834124

Xiaosha Tao, Shangchen Yao + Show 3 more

Open Access

https://doi.org/10.3389/fchem.2022.834124

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Abstract

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.

Highlights

Genotoxic impurities (GTIs), referred to as mutagenic impurities, are generally identified using the Salmonella typhimurium reverse mutation assay
An aliquot (3 μl) of the blank solvent and the rifampicin capsule test solution were injected into the LC-MS system and the corresponding chromatograms were recorded
The results show that peaks corresponding to the blank solvent, to rifampicin, and to any other related substances do not interfere with the MNP peak

Summary

Introduction

Genotoxic impurities (GTIs), referred to as mutagenic impurities, are generally identified using the Salmonella typhimurium reverse mutation assay (the Ames test). The administration of even very small quantities of drugs that contain genotoxic impurities can severely harm patients, especially those who require long-term medication. As such, these drugs must be strictly controlled, with the regulations for genotoxic impurities becoming more encompassing over the past few years; the requirements of drug-regulatory agencies in various countries have become more stringent in relation to genotoxic impurities.

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