<p>Colonic mucus has gained interest as a dissolution compartment in the large intestine due to the large fraction of bound water. Notably, the mucus layer contains more water than what is freely mobile within the colonic lumen. Here, we studied solubility of a series of structurally and physicochemically diverse orally administered drugs. In total, 15 compounds were measured for their solubility in an artificial colonic mucus solution. Equilibrium solubility was measured using the traditional shake-flask method at 37°C in several important media for dissolution studies in the colon: the mucus solution, fed-state simulated colonic fluid (FeSSCoF) and the corresponding buffers. Molecular descriptors were generated by RDKit to identify the molecular features that might benefit from solubilization in the mucus solution. Of the studied compounds, 93% presented their highest solubility in the colonic mucus solution. Molecules with high lipophilicity were more likely to benefit from the solubilization potential of the mucus, herein identified to be a result of interactions with BSA and lipids in the system. To summarize, the large dataset investigated in this study clearly shows that the colonic mucus holds great potential as a dissolution compartment facilitating the drug absorption. Hence, the colonic mucus may drive absorption for poorly water-soluble compounds and should not only be viewed as a potential diffusion barrier for drug molecules and particles.</p> Graphical Abstract <p></p>