The applicability of solubility parameters and solvent activity in the screening of binary solvent mixtures was studied. The solubility of indomethacin was measured in binary mixtures of dichloromethane, acetone, and ethyl acetate with methanol and ethanol. Solubility extremes in the mixed solvents were observed. The solubility maxima were related to the excess Gibbs free energy of the solvents and the hydrogen bonding term of the Hansen solubility parameter. The solvates of indomethacin were characterized with a confocal Raman spectrometer, and the desolvation of the solvates was investigated with thermogravimetry.