Liquid Chromatography Coupled with Supercritical Fluid Chromatography: Orthogonal 2D Chromatography for Complex Sample Analysis

Author(s)Margaux Sanchez, Julien Crepier, Karine Faure

This study delves into the challenges of online coupling, offering solutions to overcome peak distortion and enhance reliability in complex sample analysis. The resulting LC×SFC–MS/MS analysis allows differentiation of isomers in very complex samples, regardless of similar fragmentation patterns.

Combining liquid chromatography (LC) with supercritical fluid chromatography (SFC) in a two-dimensional (2D) setup offers high orthogonality and improved isomer separation—ideal for complex, neutral analytes. Although online LC×SFC remains rare because of chemical incompatibilities between dimensions, offline formats already show strong results in non-targeted analysis. LC×SFC–MS/MS enables isomer distinction even with similar fragmentation. Recent instrumental developments have shown that the modulation interface in online LC×SFC plays a major role in injection effects, and its simple modification can lead to a significant improvement of the separation quality. Performance has been enhanced to achieve a high level of coupling reliability, resulting in a promising future for new applications.