High shear mixers are classically used for wet granulation because they provide granules with a high density and a high strength in a short granulation time. In this study, the high shear wet granulation process was employed using chlorpheniramine maleate as a model drug, since it represents an example of low dose drug employing 32 randomized full factorial design and optimized in terms of different properties using Response Surface Methodology (RSM) approach. The effect of binder concentration (X1) and dry mixing time (X2) at three levels on the granules and tablet properties was studied. Chlorpheniramine maleate tablets were prepared from the produced granules to evaluate the impact of dry mixing time and the binder concentration on the produced granules and tablet properties as well as tablet content uniformity. The results show that both evaluated variables had an impact on the produced granules and tablets as well as tablet content uniformity. The high shear mixer is found to be an efficient mixer for dry blending prior to the wet massing of a low dose drug formulation when impeller speed and chopper speed were carefully selected. The results of RSM optimization indicated that formulation containing 4.46% Binder concentration at a dry mixing time of 5 min, gave the most desirable properties for the produced granules and tablets. The observed results of the optimized formula were: Carr's Index:12.72%, Hausner Rati:1.14, angle of repose: 35.18°, hardness: 5.5 Kp, friability: 0.42%, disintegration time: 60 s, average of content uniformity: 112.18% with RSD: 4.6%, and d (0.9): 982 μ which are in consistence with the predicted results, having low values of standard error.