Abstract The solubility and dissolution enhancement of the poorly soluble drug ketoprofen (KTO) in polymer blends prepared by hot melt extrusion was studied using two different screw configurations while changing extrusion processing conditions. A number of different Soluplus and Kollidon SR blends were used as solid dispersion excipients. A design of experiments with three melt temperatures, three screw rotation speeds, and three fill factors was performed, and a phase‐gate methodology was implemented. Different characterization techniques such as differential scanning calorimetry, optical and polarized light microscopy, X‐ray diffraction, solid‐state nuclear magnetic resonance, and dissolution testing were used. The results from differential scanning calorimetry and X‐ray diffraction showed an amorphous solid solution. The characterization by solid‐state nuclear magnetic resonance indicated that KTO could interact with the polymer blend by hydrogen bonds and Van der Waals forces. An optimal processing window was found for each screw configuration achieving more than 80% drug release in 8 hr.