Aim The purpose of this research is to develop and optimize a novel gastro-retentive tablet of Eplerenone which has a short half-life of 4-5 hrs, and to study the maximum drug release up to 12 hrs by designing the amount of polymer by design of experiment. Materials The gastro retentive tablet of Eplerenone was compressed by using the wet granulation method, with three factors, a three-level Box-Behnken design was used to optimize by incorporating Sodium bicarbonate (X1), HPMC K15M (X2), and Carbopol 934p (X3). The design suggested 15 formulations of different concentrations of X1, X2, and X3, and their effect was monitored on Y1, Y2, and Y3.