Solid dispersions of saquinavir mesylate containing either Gelucire® 44/14 or poly(ethylene glycol) (PEG) 4000, or mixtures of each carrier with Tween 80 or polyvinyl pyrrolidone (PVP) K30 were prepared in order to enhance the drug dissolution rate. These systems were prepared by the melting method and characterized by X-ray powder diffraction, microscopical techniques, and Raman spectroscopy aiming to establish a relationship between physicochemical and dissolution properties under different cooling conditions. Modifications in degree of crystalline order/disorder over time were observed in preparations with both carriers. Overall, formulations cooled and stored at -20 °C showed less variation in dissolution rates than those at 25 °C. Although Tween 80 has enhanced the known self-emulsifying properties of Gelucire® 44/14, its combination with PEG 4000 displayed miscibility problems. The addition of PVP K30 was not the most effective approach in enhancing the dissolution in early steps; however, the drug dissolution was stable after 7 days of storage at 25 °C. The combination of PEG 4000 and PVP K30 maintained the dissolution properties for 60 and 90 days at 25 °C/95% relative humidity and 40 °C/75% (f₂ values >50), respectively.