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<p>The determination of preservatives like methylparaben (MP) and propylparaben (PP) in pharmaceutical syrups is critical for quality control. Traditional one-factor-at-a-time (OFAT) method development often fails to account for interactions between variables, leading to less robust procedures. This study aims to develop and validate a robust HPLC method for the simultaneous determination of MP and PP using a systematic Analytical Quality by Design (AQbD) approach. An initial risk assessment (Ishikawa diagram and Failure Mode and Effects Analysis) identified five critical method attributes (CMAs): mobile phase type, organic phase percentage, pH, flow rate, and column temperature. These CMAs were systematically optimized using a D-optimal design (34 runs) with resolution, retention time, and tailing factor defined as critical quality attributes (CQAs). Statistical analysis revealed that organic solvent type and percentage were the most significant factors affecting resolution. The Method Operable Design Region (MODR) was established, and the optimal conditions were predicted as 40&#xa0;°C, 1.5 mL/min flow rate, pH 6.1, and 67.7% methanol, achieving baseline separation within 6&#xa0;min. The method was validated per ICH Q2(R2) guidelines, demonstrating excellent linearity (R² &gt; 0.99 for both analytes), precision (%RSD &lt; 2%), and accuracy (recovery 98.2–99.8%). The method was successfully applied to quantify MP and PP in commercial pharmaceutical syrups, with results falling within expected ranges. The AQbD approach ensured a robust, well-understood, and reliable method, suitable for routine quality control and capable of withstanding minor variations in chromatographic conditions.</p>

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AQbD-assisted HPLC method for simultaneous determination of methylparaben and propylparaben in liquid oral dosage forms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Raneem Darraj,
  • Mohammad Haroun,
  • Ayat abbood,
  • Ibrahim alghoraibi

摘要

The determination of preservatives like methylparaben (MP) and propylparaben (PP) in pharmaceutical syrups is critical for quality control. Traditional one-factor-at-a-time (OFAT) method development often fails to account for interactions between variables, leading to less robust procedures. This study aims to develop and validate a robust HPLC method for the simultaneous determination of MP and PP using a systematic Analytical Quality by Design (AQbD) approach. An initial risk assessment (Ishikawa diagram and Failure Mode and Effects Analysis) identified five critical method attributes (CMAs): mobile phase type, organic phase percentage, pH, flow rate, and column temperature. These CMAs were systematically optimized using a D-optimal design (34 runs) with resolution, retention time, and tailing factor defined as critical quality attributes (CQAs). Statistical analysis revealed that organic solvent type and percentage were the most significant factors affecting resolution. The Method Operable Design Region (MODR) was established, and the optimal conditions were predicted as 40 °C, 1.5 mL/min flow rate, pH 6.1, and 67.7% methanol, achieving baseline separation within 6 min. The method was validated per ICH Q2(R2) guidelines, demonstrating excellent linearity (R² > 0.99 for both analytes), precision (%RSD < 2%), and accuracy (recovery 98.2–99.8%). The method was successfully applied to quantify MP and PP in commercial pharmaceutical syrups, with results falling within expected ranges. The AQbD approach ensured a robust, well-understood, and reliable method, suitable for routine quality control and capable of withstanding minor variations in chromatographic conditions.