One among many technologies to colonic delivery of non-steroidal anti-inflammatory drugs (NSAIDs) to reduce early morning complications associated with arthritis was pH dependent colon specific delayed release system. The current investigation was projected to develop and optimize pH sensitive colon specific delayed release microspheres formulation of flurbiprofen which facilitate release of the drug in colonic region and minimize the premature release in the upper gastrointestinal tract. A Box-behnken design was chosen to optimize process and formulation variables. The selected dependent and independent variables were the amount of flurbiprofen(X1), Eudragit® S-100(X2) and stirring speed(X3); and Particle size (YPS), entrapment efficacy (YDEE), % flurbiprofen release at 5th h (Y5) and 10th h (Y10) respectively. Scanning electron microscopy study revealed that developed colon target pH sensitive microspheres formulation was smooth and spherical. Fourier transform infra-red spectroscopy has revealed that flurbiprofen was dispersed in polymer in its optimized formulation without any measurable interactions. Accelerated stability studies on the optimized formulation revealed that there was no significant difference in YPS, YDEE, Y5 and Y10 before and after study. The flurbiprofen loaded microspheres based on pH sensitive approach can be preferred for the better management of early morning complications associated with the rheumatoid arthritis.