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BACKGROUND With its reported side effects Desvenlafaxine succinate (DSV) is a good candidate to prepare prolonged release system. Such prolonged release could decrease the rapid DSV absorption after oral administration and reduce its exaggerated side effects. METHODS A prolonged release Desvenlafaxine succinate (DSV) multilayered system was prepared by ionotropic gelation using sodium alginate (SA) and calcium chloride as a cross-linker. DSV was incorporated simultaneously during the gelation stage and the formed beads were evaluated for shape and particle size. Thirteen formulation variables including pH, DSV: polymer ratio, cross-linker concentration and curing time were optimized for optimal drug entrapment. The optimized formula was evaluated ex vivo using the everted sac technique to predict DSV absorption through intestinal mucosal cells, follow the permeation and calculate its apparent permeability coefficient. RESULTS The optimum formulation variables were: pH (8-9), DSV: SA ratio (2:1), cross-linker concentration (5%w/v) and 30 min curing time. Multilayered beads coating using chitosan and SA was compared with uncoated beads or the innovator for DSV release. Coating of the beads greatly retarded DSV release with a release profile similar to that of the innovator. An optimized formula (T13) coated with 0.04% w/v of each of chitosan and SA was selected. The developed system gave rise to a prolonged release pattern with high similarity factor with the innovator. CONCLUSION The results of the current work can be applied to prepare controlled release systems of similar drugs that have intense side effects associated with their initial burst after oral administration.