Green Chromatography: A Comprehensive Review of Eco-Friendly Mobile Phases, Column Technologies, and Sustainability Metrics in Pharmaceutical Quality Control

Research Article

Abstract

High-Performance Liquid Chromatography (HPLC) and its ultra-high-performance variant (UHPLC) remain the dominant analytical platforms for identity, assay, related-substance, and stability-indicating testing in pharmaceutical quality control (QC), a position reinforced by both the United States Pharmacopoeia and the European Pharmacopoeia.This dominance carries a significant environmental cost, driven largely by the volume and toxicity of solvents consumed in reversed-phase HPLC (RP-HPLC). This review synthesises the current literature on the transition toward ecofriendly mobile phases and sustainable column technologies within standard pharmaceutical QC workflows. Solventsubstitution strategies—ethanol-water systems, propylene-glycol-modified phases, propylene carbonate, superheated water, and other bio-derived modifiers—are evaluated alongside instrumental and stationary-phase innovations such as sub-2 µm and core-shell particles, monolithic columns, narrow-bore formats, and the resurgence of supercritical Fluid Chromatography (SFC). The review also examines how greenness is now quantified through a rapidly maturing family of metrics—NEMI, the Analytical Eco-Scale, GAPI and its variants (Complex GAPI, MoGAPI), AGREE and AGREEprep, and newer practicality- and carbon-focused tools (BAGI, CaFRI, AGSA, GEMAM) — converging under the broader concept of White Analytical Chemistry, which balances environmental impact against analytical performance and practicality. Regulatory alignment with ICH Q14 and ICH Q2(R2) is discussed, together with an illustrative case comparison and the persistent gap between green mobile-phase chemistry and stationary-phase compatibility. The review concludes that eco-friendly chromatography in pharmaceutical QC is no longer an isolated academic exercise but an increasingly important consideration in analytical method development, and outlines priority areas—robust green-compatible stationary phases, automation-linkedgreenness scoring, and harmonized regulatory guidance—needed to consolidate this shift into routine practice.