The objective of the present study was to identify critical formulation parameters affecting the drug release from modified release wax matrix tablet of milnacipran hydrochloride employing the concept of design of experiments. The optimized amount of Compritol 888 ATO (intragranular) (X1), lactose (X2) and Compritol 888 ATO (extragranular) (X3) were determined employing simplex lattice design. The tablets were prepared using melt granulation technique. The in vitro drug release study was carried out in an acidic medium (pH 1.2) for 2 h and thereafter the dissolution study was conducted in phosphate buffer (pH 6.8). The selected dependent variables were the cumulative percentage of milnacipran hydrochloride dissolved at 1 (Y1), 8 (Y8), 16 (Y16) and 24 hr (Y24). Mathematical models, correlating the independent variables with dependent variables were evolved. Optimization was performed for the three independent variables using the stated target ranges; Y1≤20%; Y8=45±5%; Y16=72±5%; Y24=100%. The optimized amounts of Compritol 888ATO (intragranular) (X1), lactose (X2) and Compritol 888 ATO (extragranular) (X3), were found to be 60, 55 and 30 mg, respectively. The optimized formulation showed a release profile that was close to the predicted values. The drug was released by anomalous diffusion from the optimized formulation. Compritol 888 ATO (intragranular) (X1), lactose (X2) and Compritol 888 ATO (extragranular) (X3) were identified as critical variables. Keywords: Milnacipran hydrochloride, melt granulation technique, simplex lattice design, Compritol 888 ATO. Introduction Conventional oral drug delivery systems are known to provide an immediate release of drug. Hence, the effective concentration of the drug is not maintained for a long time at the target site. Therefore, modulation of drug release rate is required1. The development of oral controlled release delivery systems for highly water soluble drugs exhibit a significant challenge to the formulation scientists2. Most of the highly water-soluble drugs, if not formulated properly, may readily release the drug at a faster rate, and are likely to produce undesirable side effects on oral administration3. Swelling-controlled systems often are poor barriers to provide the desired release profile for freely water soluble drugs especially in the early sampling times, since a freely soluble drug diffuses easily through the hydrophilic gel network, a hydrophobic polymer or wax matrix is highly preferred. Their utility over hydrophilic polymer is advantageous as they shows good stability to the product at the varying pH levels4. Melt granulation can be explored to overcome formulation challenges.