A simple, sensitive, accurate and low cost effective spectrophotometric method has been developed for the determination of Tetracycline, Doxycycline and methyldopa in pure and pharmaceutical formulations. The method is based on the reaction of methyldopa with 4-aminoantipyren (4-AAP) in presence of potassium ferriecyanide (PFC) in an alkaline medium. Two optimization methods were applied to determine the optimum conditions of oxidizing coupling reaction variables; univariate and design of experiment (DOE) method. The conditions effecting the reaction; pH, buffer Volume, reagent concentration, oxidant concentration, type of buffer, order of addition, time of reaction and stability were optimized. The method was successfully applied to the analysis of the some drug tablets formulation.