Design Of Experiments In Metformin Analytical Method Development: A Critical Review Of Aqbd Strategies And Optimization Approaches

Abstract

Metformin is widely used therapeutically and presents analytical challenges that make it an ideal candidate for applying Analytical Quality by Design (AQbD) and Design of Experiments (DoE) approaches in pharmaceutical analysis. This review focuses on reverse-phase high-performance liquid chromatography (RP-HPLC) and capillary electrophoresis (CE) methods for metformin and its fixed-dose combinations, emphasizing optimization strategies using Box-Behnken Design (BBD) and Central Composite Design (CCD). It evaluates method performance in terms of sensitivity, accuracy, and analysis time, comparing seven validated procedures for analytical efficiency, regulatory compliance, and environmental sustainability through greenness metrics like AGREE and Eco-Scale. The role of experimental design in controlling critical method parameters, risk assessment, and defining the design space is highlighted, while limitations such as inconsistent lifecycle management and underutilization of CE-MS are discussed. This synthesis offers practical recommendations to enhance analytical robustness, sustainability, and regulatory adherence, supporting the broader application of AQbD in pharmaceutical quality control.