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Background <p>The present study aimed to develop, optimize, and evaluate an RP-HPLC method using a Quality by Design (QbD) framework integrated with a multi-colored analytical chemistry approach to enhance analytical performance and sustainability.</p> Methods <p>A three-factor, three-level Box–Behnken Design was employed to optimize critical method parameters, namely mobile phase composition, flow rate, and column temperature, with respect to retention time, peak asymmetry, and theoretical plates. Chromatographic separation was achieved using a Phenomenex C18 column (250 × 4.6&#xa0;mm, 5&#xa0;µm) with a mobile phase consisting of acetonitrile and 0.05% orthophosphoric acid in water (60:40, v/v) at a flow rate of 1.0&#xa0;mL/min. Detection was carried out at 212&#xa0;nm with a total runtime of 9&#xa0;min. The optimized method was validated as per ICH guidelines for specificity, linearity, accuracy, precision, sensitivity, and robustness. In addition, sustainability and overall analytical performance were assessed using the integrated Red–Green–Blue–White analytical chemistry framework.</p> Results <p>Under optimized conditions, Bempedoic acid eluted at 4.18&#xa0;min with excellent peak symmetry. The method exhibited linearity over the concentration range of 500–1500&#xa0;µg/mL (r<sup>2</sup> ≈ 0.9999; Y = 9285.08X − 27056). The mean recovery was 99.41%, and %RSD values were below 1%, confirming high accuracy and precision. The LOD and LOQ were found to be 2.91&#xa0;µg/mL and 8.81&#xa0;µg/mL, respectively. Robustness studies confirmed the reliability of the method under deliberate variations. The multi-colored analytical evaluation yielded red, green, and blue scores of 75, 56, and 81, respectively, resulting in an overall White Analytical Chemistry (WECA) score of 71, indicating a well-balanced method with strong analytical performance, good practical applicability, and moderate environmental impact.</p> Conclusion <p>The developed QbD-based RP-HPLC method is statistically optimized, precise, and reliable for routine analysis of Bempedoic acid in pharmaceutical formulations. The incorporation of the WECA approach further demonstrates that the method achieves a balanced compromise between analytical efficiency, environmental sustainability, and operational practicality, thereby aligning with modern regulatory and green analytical chemistry principles.</p>

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Design Space-oriented Development and Validation of a Robust RP-HPLC Method for Bempedoic Acid using Box–Behnken Response Surface Approach

  • 期刊论文

  • 发表日期：

    2026年5月28日

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  • Hemant Chikhale,
  • Rutuja Kothurkar,
  • Sreya Kosanam,
  • Raosaheb Ghegade,
  • Ramanlal Kachave

摘要

Background

The present study aimed to develop, optimize, and evaluate an RP-HPLC method using a Quality by Design (QbD) framework integrated with a multi-colored analytical chemistry approach to enhance analytical performance and sustainability.

Methods

A three-factor, three-level Box–Behnken Design was employed to optimize critical method parameters, namely mobile phase composition, flow rate, and column temperature, with respect to retention time, peak asymmetry, and theoretical plates. Chromatographic separation was achieved using a Phenomenex C18 column (250 × 4.6 mm, 5 µm) with a mobile phase consisting of acetonitrile and 0.05% orthophosphoric acid in water (60:40, v/v) at a flow rate of 1.0 mL/min. Detection was carried out at 212 nm with a total runtime of 9 min. The optimized method was validated as per ICH guidelines for specificity, linearity, accuracy, precision, sensitivity, and robustness. In addition, sustainability and overall analytical performance were assessed using the integrated Red–Green–Blue–White analytical chemistry framework.

Results

Under optimized conditions, Bempedoic acid eluted at 4.18 min with excellent peak symmetry. The method exhibited linearity over the concentration range of 500–1500 µg/mL (r2 ≈ 0.9999; Y = 9285.08X − 27056). The mean recovery was 99.41%, and %RSD values were below 1%, confirming high accuracy and precision. The LOD and LOQ were found to be 2.91 µg/mL and 8.81 µg/mL, respectively. Robustness studies confirmed the reliability of the method under deliberate variations. The multi-colored analytical evaluation yielded red, green, and blue scores of 75, 56, and 81, respectively, resulting in an overall White Analytical Chemistry (WECA) score of 71, indicating a well-balanced method with strong analytical performance, good practical applicability, and moderate environmental impact.

Conclusion

The developed QbD-based RP-HPLC method is statistically optimized, precise, and reliable for routine analysis of Bempedoic acid in pharmaceutical formulations. The incorporation of the WECA approach further demonstrates that the method achieves a balanced compromise between analytical efficiency, environmental sustainability, and operational practicality, thereby aligning with modern regulatory and green analytical chemistry principles.