{"title":"Integrating Quality by Design and Green Chemistry for Sustainable Drug Development: Acalabrutinib Stability Study","authors":"Anuj N. Nahata, Himanshu Pawar, Mital Patel","doi":"10.1007/s10337-025-04391-x","DOIUrl":null,"url":null,"abstract":"<div><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 < 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 (<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><h3>Graphical abstract</h3>\n<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":518,"journal":{"name":"Chromatographia","volume":"88 3","pages":"257 - 276"},"PeriodicalIF":1.2000,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chromatographia","FirstCategoryId":"92","ListUrlMain":"https://link.springer.com/article/10.1007/s10337-025-04391-x","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍：
Separation sciences, in all their various forms such as chromatography, field-flow fractionation, and electrophoresis, provide some of the most powerful techniques in analytical chemistry and are applied within a number of important application areas, including archaeology, biotechnology, clinical, environmental, food, medical, petroleum, pharmaceutical, polymer and biopolymer research. Beyond serving analytical purposes, separation techniques are also used for preparative and process-scale applications. The scope and power of separation sciences is significantly extended by combination with spectroscopic detection methods (e.g., laser-based approaches, nuclear-magnetic resonance, Raman, chemiluminescence) and particularly, mass spectrometry, to create hyphenated techniques. In addition to exciting new developments in chromatography, such as ultra high-pressure systems, multidimensional separations, and high-temperature approaches, there have also been great advances in hybrid methods combining chromatography and electro-based separations, especially on the micro- and nanoscale. Integrated biological procedures (e.g., enzymatic, immunological, receptor-based assays) can also be part of the overall analytical process.
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