Sustainable method development: Applying Analytical Quality by Design and comprehensive green chemistry principles in the HILIC method for caffeine and paracetamol analysis

Abstract Despite extensive development and widespread use, existing methods for analysis of caffeine and paracetamol overlook their environmental impact. Furthermore, these methods were not developed using the Analytical Quality by Design approach, leading to a significant gap in understanding critical separation factors. Moreover, the absence of a hydrophilic interaction liquid chromatography (HILIC) method for the simultaneous analysis of caffeine and paracetamol, integrating Analytical Quality by Design and a comprehensive green approach, presents an exciting opportunity for innovation and advancement in the field. In this paper, we report an efficient and sustainable HILIC method for caffeine and paracetamol analysis, which is based on Analytical Quality by Design, green and white chemistry principles. Optimal chromatographic conditions were adjusted using an InertSil Diol column with the mobile phase of acetonitrile and ammonium acetate buffer. The method was validated according to the International Council for Harmonisation guidelines, and its applicability in the analysis of Panadol Extra® tablets was confirmed. Relative standard deviation values were 0.07–0.28% for accuracy and 0.45–0.54% for precision. The environmental footprint and effectiveness of the method were evaluated through assessments of triple-color analysis which showed the dominance of green, blue, and white with scores of 0.66, 85.0, and 83.3, respectively. These parameters confirm that the method is eco-friendly, reliable, accurate, and precise for future use in the analysis of dosage forms containing caffeine and paracetamol. This is the first time that the Analytical Quality by Design approach has been combined with green and white chemistry principles, creating a strong synergy for the development of environmentally friendly methods.