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Three types of ionically crosslinked (with citric acid) chitosan discs were loaded with the highly water- soluble drug, sodium salicylate (SS) and the poorly water-soluble drug, indomethacin (Ind). In separate experiments the hydrated discs were immersed in a de-crosslinking solution comprising of different concentrations of calcium chloride, which induced a controlled erosion of the discs, a process which was optimized to synchronize the release rates of the two drugs over a predetermined period of time. The optimization was accomplished by manipulating six factors: chitosan MW, its amount in the formulation, the concentration of the crosslinker agent, the concentration of the de-crosslinking agent in the dissolution medium, its pH and its temperature. A computerized multifactorial definitive screening design analysis assisted in minimizing the number of experiments. The quotient of the SS to Ind release rates, the difference factor f1, the similarity factor f2 and the combination of f1 and f2 were determined as the experimental responses. The computerized prediction profilers that were used to simulate the contribution of the experimental factors and their effect on the experimental responses led to a successful erodible formulation with a concomitant release of the two drugs over 150 min.