The solubility of drugs in biological fluids is associated with pharmacokinetic properties (absorption, biotransformation and excretion), efficacy and toxicity. It is a fascinating and challenging task to uncover the intrinsic reason underlying the dissolution behavior of pharmaceuticals. The classical thermodynamic method estimates the drug solubility in liquid solvent via Solid-Liquid Equilibrium (SLE) equation plus activity coefficient models (UNIFAC, COSMO-RS, COSMO-SAC, etc), where the molar dissolution energy (partial molar excess Gibbs energy) of solute molecules in solution is calculated through activity coefficient models. The new method predicts the solute solubility via the transfer free energy (from solid phase to liquid phase) of solute molecules in terms of fusion properties and solute-solvent (liquid-liquid) interfacial tension, where the molar dissolution energy of solute molecules is determined by solute-solvent interfacial tension, and the solute-solvent (liquid-liquid) interfacial tension is obtained from the cohesive energy calculation results of COSMO-UCE (Conductor-Like Screening Model for Universal Cohesive Energy estimation) based merely on the molecular structure. The application of this model in solubility prediction of solid drugs in pure liquid solvents has been verified extensively with successful results. This model yields similar solute solubility representation performance as that of SLE + UNIFAC, and obtains much better solubility prediction results than SLE + COSMO-SAC.