Hydrogels based on natural polymers have been widely applied as vehicles for controlled drug release because of their advantages and interesting properties. In this study, a physical hydrogel based on chitosan and chondroitin sulfate (CS) was formed under mild conditions to act as a potential device for the controlled release of theophylline (TH). In vitro CS and TH release studies at pH 2 and 8 were performed. Under acid conditions (pH 2), the fraction of TH released (ca. 0.87) was higher than that of CS (ca. 0.13). On the other hand, under basic conditions, the fractions released of both substances were similar (ca. 0.57). In addition, the system presented in this work was able to sustain the TH release in a controlled way for 30 h. The variation of the pH affected the mechanical properties and contributed to form ordered regions within the hydrogel network, as observed through compression tests and wide-angle X-ray scattering analysis. The experimental data and discussion presented in this article will contribute to the development of a new vehicle for controlled TH release; this ensures the efficacy of the drug and reduced the number of daily doses administered. (c) 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013