The methacrylate-copolymer Eudragit® EPO (EPO) has previously shown to greatly enhance solubilization of acidic drugs via ionic interactions and by multiple hydrophobic contacts with polymeric sidechains. The latter type of interaction could also play a role for solubilization of other compounds than acids. The aim of this study was therefore to investigate the solubility of six poorly solublebases in presence and absence of EPO by quantitative ultra-pressure liquid chromatography with concomitant X-ray powder diffraction (XRPD) analysis of the solid state. For a better mechanisticunderstanding, spectra and diffusion data were obtained by 1H nuclear magnetic resonance (NMR) spectroscopy. Unexpected high solubility enhancement (up to 360-fold) was evidenced in presence of EPOdespite of the fact that bases and polymer were both carrying positive charges. This exceptional and unexpected solubilization was not due to a change in the crystalline solid state. NMR spectra andmeasured diffusion coefficients indicated both strong drug-polymer interactions in the bulk solution and diffusion data suggested conformational changes of the polymer in solution. Suchconformational changes may have increased the accessibility and extent of hydrophobic contacts thereby leading to increased overall molecular interactions. These initially surprising solubilizationresults demonstrate that excipient selection should not be based solely on simple considerations of, for example, opposite charges of drug and excipient, but it requires a more refined molecularview. Different solution NMR techniques are here especially promising tools to gain such mechanistic insights.