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<p>This study introduces a novel isocratic ultra-performance liquid chromatography method coupled with photodiode array and electrospray ionization mass spectrometry (ESI/MS) for the quantification of the antifungal drug Posaconazole (PCZ) and its four degradation products in tablet formulations. Employing an innovative Analytical quality by design (AQbD) approach, we established robust chromatographic conditions for precise measurement of degradation impurities resulting from forced degradation processes, such as acid/alkali hydrolysis, peroxide oxidation and thermal/photo degradation. A comprehensive risk assessment was conducted using failure mode effects analysis to identify critical analytical attributes (CAAs) and their impact on analytical target profiles (ATPs). The interactions between the identified CMAs (CMA1—retention time of PCZ and degradant peak; CMA2—resolution between degradant peaks) and ATPs were explored using a Box–Behnken Design (BBD), which led to the selection of optimal chromatographic conditions. These consisted of a mobile phase comprising 20&#xa0;mM ammonium formate buffer (pH 4.2), acetonitrile, and methanol (70:18:12 v/v/v), an X‑Bridge C18 column (150 × 4.6&#xa0;mm, 3.5&#xa0;µm), a detection wavelength of 260&#xa0;nm, a flow rate of 1.0&#xa0;mL/min, and an injection volume of 5 µL. Each risk factors were reevaluated, and control on each was relinquished. The validation of the method was performed according to ICH Q2 (R2) guidelines, confirming its specificity, precision, linearity, LOQ, LOD, and accuracy. The developed method was deemed stability-indicating and suitable for routine and stability testing of Posaconazole formulations.</p> Graphical abstract <p></p>

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QbD Steered Development and Validation of UPLC/MS Method with a Comprehensive FMEA Risk Assessment to Quantify the Degradation Impurities of Posaconazole from Tablet Formulation and Their Pathways

  • 期刊论文

  • 发表日期：

    2026年4月24日

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  • Surajkumar D. Jadhav,
  • Shailesh Wadher

摘要

This study introduces a novel isocratic ultra-performance liquid chromatography method coupled with photodiode array and electrospray ionization mass spectrometry (ESI/MS) for the quantification of the antifungal drug Posaconazole (PCZ) and its four degradation products in tablet formulations. Employing an innovative Analytical quality by design (AQbD) approach, we established robust chromatographic conditions for precise measurement of degradation impurities resulting from forced degradation processes, such as acid/alkali hydrolysis, peroxide oxidation and thermal/photo degradation. A comprehensive risk assessment was conducted using failure mode effects analysis to identify critical analytical attributes (CAAs) and their impact on analytical target profiles (ATPs). The interactions between the identified CMAs (CMA1—retention time of PCZ and degradant peak; CMA2—resolution between degradant peaks) and ATPs were explored using a Box–Behnken Design (BBD), which led to the selection of optimal chromatographic conditions. These consisted of a mobile phase comprising 20 mM ammonium formate buffer (pH 4.2), acetonitrile, and methanol (70:18:12 v/v/v), an X‑Bridge C18 column (150 × 4.6 mm, 3.5 µm), a detection wavelength of 260 nm, a flow rate of 1.0 mL/min, and an injection volume of 5 µL. Each risk factors were reevaluated, and control on each was relinquished. The validation of the method was performed according to ICH Q2 (R2) guidelines, confirming its specificity, precision, linearity, LOQ, LOD, and accuracy. The developed method was deemed stability-indicating and suitable for routine and stability testing of Posaconazole formulations.

Graphical abstract