Several matrix tablet formulations (hydrophilic-based, wax-based, and three-layer tablets) were designed for controlling the release of the highly water soluble drug, venlafaxine hydrochloride (VenHCl) for once-daily administration. The three-layer tablets consist of non-swellable, compritol-based middle layers containing the drug to which hydrophilic top and bottom barrier layers were applied. A 23 full-factorial design was employed for optimization and to explore the effect of different variables on the release rate of the drug from the three-layer tablets. The optimized levels of each independent variable were based on the criterion of desirability. The calculated values of f1 and f2 were 4.131 and 79.356, respectively; indicating that the release profile of the optimized PEO layered tablet formulation is comparable to that of the target release model. The pharmacokinetic parameters of VenHCl from the optimized three-layer tablet was compared to the marketed extended release capsule as a reference in healthy human subjects using a randomized crossover design. In this study, the 90% confidence interval for AUC0–24 and AUC0−∞ are within (0.8–1.25), which satisfied the bioequivalence criteria. It could be concluded that a promising once-daily extended-release three-layer tablet of the highly water soluble drug, VenHCl, was successfully designed.
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