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The introduction of core-shell particles over the last few years has led to a revolution in the analysis of small molecules where ultra-high efficiency separation can be achieved using traditional HPLC systems.When core-shell technology UHPLC columns are applied to the separation of proteins and peptides differentiation must be made between the use of standard pore core shell columns for peptide separations while using widepore columns for protein separations.This relates to the inability of proteins to fully penetrate "small-pore" porous media, necessitating the use of "widepore" column for intact protein separations.Separations using traditional widepore fully porous media are greatly impacted by protein diffusion leading to well-defined performance limitations.With widepore core-shell media diffusion rates are significantly different than fully porous media requiring new modeling of expected performance.For peptide separations diffusion is less of an issue and thus 100(A) core-shell columns can be used to maximize performance.In this presentation several separation example are presented to try to define how to improve separations of protein, peptide, and peptide maps to best characterize protein therapeutics.