One of the key factors in drug's efficacy is the value of their bioavailability that increases by the reduction of particle size through improvement of dissolution rate. In this study, raloxifene particle size was reduced by Rapid Expansion of Supercritical Solution (RESS). The effect of extraction temperature (40-80 degrees C), extraction pressure (10-18 MPa) and spray distance (5-10 cm) were investigated on size and particle size distribution of the nanoparticles. Particles were characterized using X-ray diffraction (XRD), Fourier Transform Infrared Analysis (FTIR), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM) and Dynamic Light Scattering (DLS). The average size of the unprocessed raloxifene particles was 45.28 mu m. After the process, depending on the experimental conditions, smaller particles were obtained, the smallest of which was 18.93 nm. In addition, dissolution rate study indicated that a 7-fold increase in dissolution rate could be obtained by particle size reduction of raloxifene using RESS. Response Surface Methodology was used for the optimization of the results and showed that the smallest particle size could be achieved at temperature of 50 degrees C, pressure of 17.7 MPa and spray distance of 10cm. (C) 2011 Elsevier B.V. All rights reserved.