Dichloromethane (DCM) is a useful and advantageous solvent used in pharmaceutical development due to its low cost, miscibility with other organic solvents, high volatility, and ability to solubilize drug molecules of variable polarities and functionalities. Despite this favourable behaviour, efforts to identify safer and more sustainable alternatives to hazardous, halogenated solvents is imperative to the expansion of green chemistry. In this work, bio-derived esters tert-butyl acetate, sec-butyl acetate, ethyl isobutyrate, and methyl pivalate are experimentally identified as safe and sustainable alternatives to directly replace DCM within thin-layer chromatography (TLC) in the analysis of small, common drug molecules. To elucidate the intermolecular interactions influencing retardation factors (Rf) a statistical thermodynamic framework, which quantifies the driving molecular interactions that yield empirical TLC measurements, is presented. Within this framework, we are able to deduce Rf dependence on polar eluent concentration, in the presence of a low-polar mediating solvent, between the stationary and mobile phases. The strength of competitive analyte-eluent (and analyte-solvent interactions) are quantified through Kirkwood-Buff integrals (KBIs); resulting KBI terms at the dilute eluent limit provide a theoretical foundation for the observed suitability of alternative green solvents for the replacement of dichloromethane in TLC.