Concentrations, volumes and excess chemical potentials can be seen in Table . We obtained the excess chemical potentials from solvation free energy calculations . Volumes were obtained from the state in the alchemical path where the solute was fully coupled The sum of all the elements in a row should yield 1.0, a probability of 100 %. A good free energy estimate is obtained when the states along the alchemical path contain configurations that can be found in other intermediate states. In these situations, the phase space overlap is non-zero, which results in non-zero offdiagonal elements. Here, however, the phase space overlap plot shows that there is no overlap between the states λ i , 4 ≤ i ≤ 17 indicating poor free energy estimates will result. to the rest of the system. The experimental aqueous solubility of ASA is approximately 0.038 % in water at 298 K , but our model predicts that ASA is effectively insoluble in water (Figure ). While all-atom simulations can yield solubility estimates given adequate simulation time and a correct method, the computed solubility will be that dictated by the underlying energy model or force field, and will not necessarily match experiment. Here, we use GAFF, a general-purpose force field with known limitations ; apparently, here, the right answer for the force field is not correct. Perhaps this is because of limitations in describing the solid state, as the force field is parameterized for liquid state simulations. Indeed, classical fixed charge force fields have shown severe limitations for polymorph prediction for these reasons . Also, point partial atomic charges regularly used in molecular dynamics do not describe electrostatic interactions in a solid particularly well . In the case of the ASA crystal, it is possible that its hydrogen bonds and π-stacking interactions add layers of complexity that are not properly described by GAFF.