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<p>The detection and stringent control of N-nitrosamine impurities in pharmaceutical products are imperative for regulatory agencies and the global pharmaceutical industry, driven by the potent genotoxic and carcinogenic potential of these compounds. This study describes the development and rigorous validation of a highly sensitive Ultra-Performance Liquid Chromatography-Triple Quadrupole Mass Spectrometry (UPLC-TQ MS) method specifically designed for the quantification of N-nitroso-N-desmethyl methadone in Methadone Hydrochloride (HCl) tablets (10&#xa0;mg). Chromatographic separation was successfully achieved using an ACQUITY UPLC BEH Shield RP 18 stationary phase under an isocratic elution program comprising an ammonium acetate buffer and acetonitrile. Mass spectrometric detection was performed via electrospray ionization in the positive mode (ESI+) using Multiple Reaction Monitoring (MRM) to ensure maximum selectivity for the two isomeric peaks of the impurity. The analytical method was validated in strict accordance with the USP &lt; 1225 &gt; and ICH Q2(R1) guidelines. Linearity was demonstrated over a concentration range of 0.33 to 6.67 ng/mL, corresponding to 10–200% of the established specification limit. The limit of quantification (LOQ) was confirmed at 0.33 ng/mL (0.33 ppb), verifying the method’s capacity to quantify trace levels significantly below the acceptable intake level. Precision assessments yielded a cumulative relative standard deviation (RSD) of 3.7%, whereas accuracy studies demonstrated mean recoveries ranging from 87.5 to 93.5%. The proposed method represents a robust, specific, and reliable analytical tool for the routine quality control of Methadone HCL, ensuring patient safety through the effective monitoring of mutagenic impurities.</p>

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UPLC-TQ MS method development and validation for N-nitroso-N-desmethyl methadone detection in methadone hydrochloride tablets: a comprehensive analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Rama Krishna Myneni,
  • Govardhan Rao Thalluri,
  • K. Ramakrishna

摘要

The detection and stringent control of N-nitrosamine impurities in pharmaceutical products are imperative for regulatory agencies and the global pharmaceutical industry, driven by the potent genotoxic and carcinogenic potential of these compounds. This study describes the development and rigorous validation of a highly sensitive Ultra-Performance Liquid Chromatography-Triple Quadrupole Mass Spectrometry (UPLC-TQ MS) method specifically designed for the quantification of N-nitroso-N-desmethyl methadone in Methadone Hydrochloride (HCl) tablets (10 mg). Chromatographic separation was successfully achieved using an ACQUITY UPLC BEH Shield RP 18 stationary phase under an isocratic elution program comprising an ammonium acetate buffer and acetonitrile. Mass spectrometric detection was performed via electrospray ionization in the positive mode (ESI+) using Multiple Reaction Monitoring (MRM) to ensure maximum selectivity for the two isomeric peaks of the impurity. The analytical method was validated in strict accordance with the USP < 1225 > and ICH Q2(R1) guidelines. Linearity was demonstrated over a concentration range of 0.33 to 6.67 ng/mL, corresponding to 10–200% of the established specification limit. The limit of quantification (LOQ) was confirmed at 0.33 ng/mL (0.33 ppb), verifying the method’s capacity to quantify trace levels significantly below the acceptable intake level. Precision assessments yielded a cumulative relative standard deviation (RSD) of 3.7%, whereas accuracy studies demonstrated mean recoveries ranging from 87.5 to 93.5%. The proposed method represents a robust, specific, and reliable analytical tool for the routine quality control of Methadone HCL, ensuring patient safety through the effective monitoring of mutagenic impurities.