The selection of an appropriate matrix for the preparation of amorphous extrudate in hot-melt extrusion (HME) deals with the study of various solid-state properties of drugs and polymers. Therefore, it is necessary to have an appropriate knowledge of drug-polymer miscibility, the interaction between the drug-polymer on mixing, and Gibb's free thermal energy of mixing to screen polymers through thermodynamic phase diagrams, to be suitable amorphous matrix system for HME. Here, we evaluated the possibility of three different polymers, namely, Eudragit®EPO, polyvinyl alcohol (PVA), Kollicoat®IR (KIR) with Praziquantel (PZQ), with proper validation of the Flory-Huggins theory and construction of the phase diagram using the melting point depression approach to determine a suitable matrix for HME. The solubility parameter theoretical calculation approach was used as a preliminary study to validate the miscibility of PZQ with three different polymers. Theoretical and experimental validation studies using the Flory-Huggins interaction parameter value using the melting point depression approach and the effect of PZQ loading on the interaction parameter were systematically validated to predict thermodynamic phase diagrams and Gibbs free energy of mixing for screening these polymers for the preparation of amorphous extrudate. Using the phase diagram, the thermal processing temperature for the HME was determined using a T-φ phase diagram to obtain an appropriate matrix. The obtained extrudates were further validated through physical appearance, microscopic structure, thermal and functional group characterizations, followed by the PZQ assay. Thus, considering the solid-state properties, the processing parameters of HME were selected to obtain stable extrudates and an appropriate matrix for PZQ loading.