Esomeprazole sodium was a proton pump inhibitor (PPI) synthesized using omeprazole sulfide. In this paper, we used a static-analytic method to analyze the solubility of our own synthesis of esomeprazole sodium in ethyl acetate, acetonitrile, methyl isobutyl ketone, ethanol, methanol, and in the (ethanol + ethyl acetate) mixtures between 278.15 and 328.15 K. A group of thermodynamic models were selected such as the Jouyban-Acree equation, the modified Apelblat equation, and CNIBS/R-K equations. All equations can be well applied and the modified Apelblat equations are relatively better. We determined the thermodynamic properties of esomeprazole sodium using the van't Hoff equation furthermore, including the entropy, Gibbs energy, and enthalpy.