Because felodipine form I is used in marketed products, a co-solvent (ethyl acetate) is applied to enhance the solubility of poorly soluble form I in the present work. The solid−liquid equilibrium phase diagrams in pure and mixed solvents were established, and the effects of the solvent properties and intermolecular interaction on the solubility of felodipine were also studied. In pure solvent, the largest and smallest solubility data were obtained in ethyl acetate and toluene, respectively. The solubility increased to the maximum value at w = 0.8 with a mass fraction of ethyl acetate in (isopropanol + ethyl acetate) mixtures and then decreased with the increasing composition of the co-solvent. The modified Apelblat equation and the Jouyban−Acree model were applied to evaluate the solubility profile. All of the values of RAD were no more than 5%. More importantly, preferential solvation parameters (δ x1,3 ) of felodipine in (isopropanol + ethyl acetate) mixtures were calculated using the inverse Kirkwood−Buff integrals method. The results indicated that the values of δx 1,3 were all negative in ethyl acetate-rich and isopropanol-rich regions but positive in the composition of 0.45 < x 1 < 0.80. Felodipine is preferentially solvated by isopropanol in ethyl acetate-rich and isopropanol-rich regions. In the composition of 0.45 < x 1 < 0.80, felodipine is preferentially solvated by ethyl acetate.