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<p>Regulatory agencies prioritize the safety and efficacy of pharmaceuticals. In this context, our research aims to develop a simple, sensitive, and eco-friendly LCMS-compatible high-performance liquid chromatography stability indicating analytical method (SIAM) technique to identify impurities in Acalabrutinib (ACB) under various stress conditions. This method is designed in compliance with ICH QIA (R2) and Q3, incorporating Green Chemistry principles and Quality by Design (QbD). To optimize the method, an ideal split-plot design was used to evaluate critical method parameters (CMPs), followed by a central composite design (CCD) to refine the conditions. Statistical analysis revealed <i>p</i> values &lt; 0.001 for the model and 0.05 for lack of fit, indicating the most suitable statistical model for the evaluated responses (peak resolutions R1–R4). The optimized method attributes include an ACN:ammonium acetate buffer (pH 5) ratio of 50:50 (v/v), a flow rate of 0.8&#xa0;mL/min, and a column oven temperature of 35&#xa0;°C, derived from CCD. An isocratic elution method using the Waters e2998 HPLC Kromasil 100-5-C18 (250 × 4.6&#xa0;mm; 5&#xa0;µm) analytical column enabled superior separation of components, with a run time of 35&#xa0;min and a wavelength of 254&#xa0;nm. Stress studies revealed that ACB is sensitive to hydrolysis and photolytic conditions, with ACN identified as the most suitable diluent. Method validation was conducted according to ICH Q2 guidelines, and showed a correlation coefficient (<i>r</i><sup>2</sup>) exceeding 0.992, with RSD values (<i>n</i> = 6) ranging from 0.76 to 1.93% across the LOQ-150% range. Specificity studies confirmed no interference between impurities and active analytes. Through stress testing, 28 degradation products were identified, and the method was assessed for eco-friendliness using seven different tools, confirming its sustainable nature for pharmaceutical applications.</p> Graphical abstract <p></p>

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Integrating Quality by Design and Green Chemistry for Sustainable Drug Development: Acalabrutinib Stability Study

  • 期刊论文

  • 发表日期：

    2025年2月12日

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  • Anuj N. Nahata,
  • Himanshu Pawar,
  • Mital Patel

摘要

Regulatory agencies prioritize the safety and efficacy of pharmaceuticals. In this context, our research aims to develop a simple, sensitive, and eco-friendly LCMS-compatible high-performance liquid chromatography stability indicating analytical method (SIAM) technique to identify impurities in Acalabrutinib (ACB) under various stress conditions. This method is designed in compliance with ICH QIA (R2) and Q3, incorporating Green Chemistry principles and Quality by Design (QbD). To optimize the method, an ideal split-plot design was used to evaluate critical method parameters (CMPs), followed by a central composite design (CCD) to refine the conditions. Statistical analysis revealed p values < 0.001 for the model and 0.05 for lack of fit, indicating the most suitable statistical model for the evaluated responses (peak resolutions R1–R4). The optimized method attributes include an ACN:ammonium acetate buffer (pH 5) ratio of 50:50 (v/v), a flow rate of 0.8 mL/min, and a column oven temperature of 35 °C, derived from CCD. An isocratic elution method using the Waters e2998 HPLC Kromasil 100-5-C18 (250 × 4.6 mm; 5 µm) analytical column enabled superior separation of components, with a run time of 35 min and a wavelength of 254 nm. Stress studies revealed that ACB is sensitive to hydrolysis and photolytic conditions, with ACN identified as the most suitable diluent. Method validation was conducted according to ICH Q2 guidelines, and showed a correlation coefficient (r2) exceeding 0.992, with RSD values (n = 6) ranging from 0.76 to 1.93% across the LOQ-150% range. Specificity studies confirmed no interference between impurities and active analytes. Through stress testing, 28 degradation products were identified, and the method was assessed for eco-friendliness using seven different tools, confirming its sustainable nature for pharmaceutical applications.

Graphical abstract