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<p>Mutagenic impurities pose significant safety risks and must be controlled to trace levels in pharmaceuticals. Although methods like HPLC and GC techniques are commonly used, specific analytical methods are required to accurately detect these impurities in drug substances or products. This study focuses on the identification and quantification of 1-(3-bromoprop-1-en-2-yl)-2,4-difluorobenzene (bromo impurity), a potential mutagenic impurity in posaconazole. Classified as a Class-3 impurity under the International Council for Harmonization (ICH) guidelines M7, the bromo impurity requires stringent control due to its potential mutagenic impurity. To address this, a sensitive and selective analytical method using gas chromatography coupled with tandem mass spectrometry (GC-MS/MS) was developed and validated. The GC-MS/MS method employs a thermal gradient elution program, a Rtx-624 (30&#xa0;m, 0.32&#xa0;mm, 1.80&#xa0;μm) consisting of 6% cyanopropylphenyl and 94% dimethylpolysiloxane, and helium as the carrier gas at a flow rate of 2.0 mL/min. The method exhibited excellent sensitivity, with a limit of quantification (LOQ) of 0.3 ppm and a limit of detection (LOD) of 0.1 ppm. Validation parameters, including accuracy (80–120%), precision, robustness, specificity, and solution stability, demonstrated that the method is highly reliable and suitable for routine quality control. This advanced GC-MS/MS method ensures the trace-level detection of mutagenic impurities, offering a robust analytical solution for regulatory compliance and enhancing pharmaceutical safety.</p>

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Sensitive GC-MS Quantification of Mutagenic Impurity in the Antifungal Drug Posaconazole

  • 期刊论文

  • 发表日期：

    2026年1月9日

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  • Anuradha Bhimireddy,
  • J. V. Shanmukha Kumar

摘要

Mutagenic impurities pose significant safety risks and must be controlled to trace levels in pharmaceuticals. Although methods like HPLC and GC techniques are commonly used, specific analytical methods are required to accurately detect these impurities in drug substances or products. This study focuses on the identification and quantification of 1-(3-bromoprop-1-en-2-yl)-2,4-difluorobenzene (bromo impurity), a potential mutagenic impurity in posaconazole. Classified as a Class-3 impurity under the International Council for Harmonization (ICH) guidelines M7, the bromo impurity requires stringent control due to its potential mutagenic impurity. To address this, a sensitive and selective analytical method using gas chromatography coupled with tandem mass spectrometry (GC-MS/MS) was developed and validated. The GC-MS/MS method employs a thermal gradient elution program, a Rtx-624 (30 m, 0.32 mm, 1.80 μm) consisting of 6% cyanopropylphenyl and 94% dimethylpolysiloxane, and helium as the carrier gas at a flow rate of 2.0 mL/min. The method exhibited excellent sensitivity, with a limit of quantification (LOQ) of 0.3 ppm and a limit of detection (LOD) of 0.1 ppm. Validation parameters, including accuracy (80–120%), precision, robustness, specificity, and solution stability, demonstrated that the method is highly reliable and suitable for routine quality control. This advanced GC-MS/MS method ensures the trace-level detection of mutagenic impurities, offering a robust analytical solution for regulatory compliance and enhancing pharmaceutical safety.