Much interest has been expressed in this work on the role of water diffusivity in the release media as a new parameter for predicting drug release. NMR was used to measure water diffusivity in different media varying in their osmolality and viscosity. Water self-diffusion coefficients in sucrose, sodium chloride, and polymeric hydroxypropyl methylcellulose (HPMC) solutions were correlated with water uptake, disintegration, and drug release rates from trospium chloride immediate release tablets. The water diffusivity in sucrose solutions was significantly reduced compared to polymeric HPMC and molecular sodium chloride solutions. Water diffusivity was found to be a function of sucrose concentration in the media. Dosage form disintegration and drug release was to be affected by water diffusivity in these systems. This observation can be explained by hydrogen bonding formation between sugar molecules, an effect which was not expressed in sodium chloride solutions of equal osmolality. Water diffusivity and not media osmolality in general need to be considered to predict the effect of disintegration and dissolution media on drug release. Understanding the relevance of water diffusivity for disintegration and dissolution will lead to better parametrization of dosage form behavior in gastrointestinal (GI) aqueous and semisolid media.