The objectives of this study were to evaluate the effects of different media ionic concentration strengths and pH on the release of theophylline from a gel forming hydrophilic polymeric matrix. Theophylline extended release (ER) matrices containing hypromellose (hydroxypropyl methylcellulose (HPMC)) were evaluated in media with a pH range of 1.2-7.5, using an automated USP type III, Bio-Dis dissolution apparatus. The ionic concentration strength of the media was varied over a range of 0-0.4 M to simulate the gastrointestinal fed and fasted states and various physiological pH conditions. Sodium chloride was used for ionic regulation due to its ability to salt out polymers in the midrange of the lyotropic series. The results showed that the ionic concentration strength had a profound effect on the drug release from the K100LV matrices. At pH 1.2 theophylline releases increased significantly within the first hour from 28% in water to 48% in the medium with ionic strength of 0.49 M. The K4M, K15M and K100M tablets, however, withstood the effects of media to the same extend at all ionic concentration strengths investigated. The similarity factor f2 was calculated using drug release in water as a reference. For the K100M matrices, f2 values of 74 (pH media), 80 (0.2 M media) and 72 (0.4 M media) suggested that it was the most resilient of all the matrices studied here. DSC hydration results explained the theophylline release from their HPMC matrices. Despite an increase in the percentage of bound water for the tablets made with high viscosity polymers K4M, K15M and K100M, they were, however, resilient to the ionic concentration strength effects as they were still able to form a strong gel layer. This methodology can be used as a valuable tool for predicting potential ionic effects related to in vivo fed and fasted states on drug release from hydrophilic ER matrices.