The water activity a(T)[H2O] that corresponds to the transformation between hydrate and anhydrate forms of a drug is important to pharmaceutical process development; however, the traditional method for measuring a(T)[H2O] can be time-consuming. A thermodynamic model derived from the thermodynamic equilibrium in this study provides an easy way to predict the value of a(T)[H2O] at different temperatures through the solubility ratio of hydrate to anhydrate. The model also provides a new way to determine the solubility of the metastable form with accessible accuracy and offers a tool to study the activity coefficient of the solute. Experimental validation of the model was performed using the compounds theophylline and carbamazepine. The results illustrate that this new method is acceptably accurate and reproducible.