Eco-Friendly AQbD-Driven HPLC: A Sustainable Approach to Method Development and Validation Using Green Chemistry

The integration of Analytical Quality by Design (AQbD) with Green Analytical Chemistry (GAC) represents a transformative approach in High-Performance Liquid Chromatography (HPLC) method development and validation. This review aims to provide a comprehensive overview of how AQbD frameworks can be systematically combined with GAC principles to achieve robust, reproducible, and environmentally sustainable analytical methods. AQbD facilitates method optimization through tools such as risk assessment, Design of Experiments (DoE), and Method Operable Design Region (MODR) establishment, while GAC focuses on minimizing hazardous solvent use, energy consumption, and waste production. This review evaluates peer-reviewed studies published between 2022 and mid-2025 that demonstrate AQbD-based HPLC and UPLC methods employing eco-friendly solvents, particularly ethanol and water, and assessing environmental sustainability using green metrics including AGREE, GAPI, AMGS, and Analytical Eco-Scale. Case studies on pharmaceutical analytes such as metronidazole, nicotinamide, irbesartan, metformin, and empagliflozin illustrate the practical implementation of these approaches, with several studies reporting high green scores and regulatory alignment with ICH guidelines. Despite significant progress, challenges persist, including inconsistent application of greenness metrics, limited availability of green solvent alternatives, and the need for integrated software tools that combine AQbD and GAC evaluation. This review highlights key methodological gaps and future opportunities, including extending AQbD-GAC approaches to complex matrices and integrating Artificial Intelligence (AI) to enhance optimization and sustainability. Overall, the convergence of AQbD and GAC not only ensures analytical reliability and regulatory compliance but also aligns with global sustainability goals and emerging eco-conscious scientific practices.