Mass transfer resistance in the mobile phase: Theory, data, and strategies to further improve the resolution power in pressure-driven liquid chromatography.

Since the emergence of liquid chromatography in the 1960s, the resolution performance of randomly packed columns has improved significantly. This progress is primarily due to the reduction in particle size and the continuous development of proprietary packing procedures for these fine particles. Despite these advancements, the performance of pressure-driven analytical columns has reached a plateau and remains significantly lower than the ultimate performance observed in electro-driven chromatography, where dispersion is limited solely by molecular diffusion. This performance gap stems from complex, inherent non-equilibrium phenomena that arise within the mobile phase under laminar flow conditions in modern packed columns. These phenomena are revisited, explained, and quantified in this review. First, mass transfer resistance in the mobile phase is defined and we examine the most relevant theories and models available in the past and recent literature. Next, we review the most significant experimental and simulated dispersion data on the mass transfer resistance in the mobile phase, both assessing the validity and challenging certain misconceptions of current models. Finally, this review presents an exhaustive list of practical strategies aiming at reducing the overall mass transfer resistance in the mobile phase in pressure-driven liquid chromatography. This offers critical perspectives for enhanced separation power of the next generation of liquid chromatography columns expected during the next decades.