Dissolution of poorly water-soluble active pharmaceutical ingredients (APIs) in polymeric blends plays an important role in the manufacturing of solid dispersions and solid solutions. The understanding of the dissolution is key for selecting the appropriate extrusion equipment, the operating conditions, and polymers or polymer blends as formulation excipients. The experimental procedure presented in this work for ketoprofen (KTO) and polymer excipients serves as a selection process to choose the best API-polymer formulation for Hot Melt Extrusion (HME) to target a specific drug release profile. KTO dispersion within the polymer was characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy, X-ray diffraction (XRD), and dissolution tests. KTO content was verified by high performance liquid chromatography (HPLC). Thermal characterizations show that a single phase amorphous solid solution (one glass transition temperature, Tg) was achieved under the HME processing conditions and screw configuration; and with the combination of polymer excipients; an extended release profile of KTO was achieved, releasing 100% of KTO in 24 hours. HME has been shown as an advantageous technique that can be used with hydrophilic and hydrophobic polymers as polymer excipients for the manufacturing of extended release dosage forms.