The objective of this study was to enhance solubility and dissolution of lapatinib (LB) ditosylate (DT) using solid dispersions (SD) prepared by solvent rotary evaporation (SRE) and hot melt extrusion (HME). A series of models based on solubility parameter, the solid-liquid equilibrium equation, and the Flory-Huggins equation were employed to provide insight to data and evaluate drug/polymer interactions. Experimentally, nine SD formulas were prepared and characterized by various analytical techniques including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscope (SEM), solubility, and dissolution. It was found that both material attributes (e.g., drug loading and solid state) and process parameters (e.g., extrusion temperature) significantly affected manufacturability and solubility/dissolution behaviors. Among the formulas investigated, Formula #9 containing LB-DT, Soluplus®, and poloxamer 188 at a weight ratio of 1:3:1 was screened as the first ranked one. While comparing production routes, the SDs prepared by SRE showed more amorphicity as well as higher solubility/dissolution. This study provided the insight of introducing theoretical models to guide SD formulation/process development and illustrating the potential of bioavailability enhancement for LB-DT.