Although acetonitrile and methanol are the most popular organic solvents employed in reversed-phase HPLC, it is important to minimize the environmental impact of organic solvent usage during chromatographic analyses and the use of environmentally friendly solvents. Greener solvents, such as ethanol, are good organic modifiers and environmentally preferable solvents that may replace toxic solvents in many RP-HPLC applications, with good chromatographic properties. The present study describes a critical evaluation of core–shell columns packed with different particle sizes (5.0, 2.6, 1.7, and 1.3 μm), which was carried out to show the possibility of the reduction of solvent consumption and to show the possibility of replacing acetonitrile by ethanol in liquid chromatography. By comparing different columns packed with core–shell particles it was proven that the organic solvent consumption may be reduced six times obtaining the sufficient parameters of the analysis.