The thermodynamic properties and dissolution of indomethacin (INM) were analyzed as models for poorly water-soluble drugs. Physical mixtures of the most stable γ-form and metastable α-form of INM at various proportions were prepared, and their individual signal intensities proportional to their mole fractions were observed using X-ray powder diffraction and Fourier transform infrared spectrometry at standard temperature. The endothermic signals of the α-form, with a melting point of 426 K, and that of the γ-form, with a melting point of 433 K, were obtained by differential scanning calorimetry (DSC). Furthermore, an exothermic DSC peak of the α/γ-phase transition at approximately 428 K was obtained. As we computed the melting entropy of the α-form and that of its transformation, the frequency of the transition was quantitatively determined, which indicated the maximum of the α/γ-phase transition at an α-form proportion of 68%. Subsequently, the thermodynamic contributions of the α- and γ-forms were analyzed using a Van't Hoff plot for solubility in aqueous solutions at pH 6.8. The dissolution enthalpies for α- and γ-forms were 28.2 and 31.2 kJ mol-1, respectively, which are in agreement with the quantitative contribution predicted by the product of the temperature and melting entropy. The contribution of melting entropy was conserved in different dissolution processes with aqueous solvents containing lidocaine, diltiazem, l-carnosine, and aspartame as solubilizers; their γ-form Setschenow coefficients were -39.6, +82.9, -17.3, and +23.2, whereas those of the α-form were -39.7, +80.4, -16.7, and +22.7, respectively. We conclude that the dissolution ability of the solid state and solubilizers indicate their additivity independently.
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