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The aim of this investigation was to develop and optimize Claritromycin loaded with pullulan acetate for sustained release application by response surface methodology based on factorial design with reduced 2FI Model. Various parameters like RPM, Time, Drug (Clarithromycin) Concentration and Pullulan acetate concentration were optimized with respect to F5. It was found that RPM and Time were having more effect as compared to Clarithromycin and Pullulan acetate concentration for sustained release of the drug. The 3D response plot was drawn and optimum interactions were selected by feasibility and grid searches. The observed responses were coincided well with the predicted values by the experimental design. The optimized formulation F5 showed prolonged sustained release of Clarithromycin over 7 hours. The release profile of the drug loaded microsphere reveals that pH of the medium was influencing it at in vitro condition. In the optimized conditions, the sustained release can be reached up to 9 h. Therefore Pullulan acetate loaded with Clarithromycin is a useful polymerised materials for the development and formulation of pH sensitive drug.