Exploit the Flory-Huggins Theory and its interaction parameter to measure the contribution of each of the homopolymers of the graft copolymer Soluplus® to the solubilization of sulfamethoxazole (SMX) and nifedipine (NIF). The melting point depression for each crystalline drug in the presence of Soluplus® and each of its component homopolymers, namely poly(N-vinyl caprolactam) (PVCL), poly(vinylacetate) (PVAc), and poly(ethyleneglycol) (PEG), was measured at various drug levels using differential scanning calorimetry. Glass transition temperatures were calculated across the entire range for drug-polymer mixtures for comparison to the Gordon-Taylor prediction. The intersection of the melting point depression curve with the mixture glass transition curve provides an estimate of the solubility of the drug in the polymer. The solubility of these crystalline drugs in each homopolymer was calculated and a solubility in Soluplus® was estimated based on the homopolymer contributions. PEG 6000 exhibited a negative interaction parameter with SMX and NIF, indicating a relatively strong drug-polymer interaction. For PVAc, a small positive interaction parameter indicated a relatively weak drug-polymer interaction. The approach was not suitable for assessing the drug-PVCL interaction. However, other approaches could be taken to estimate the solubility of the drug in a polymer, including extrapolating the enthalpy of melting as a function of the volume fraction of the polymer to zero enthalpy to determine the maximum concentration miscible with the polymer and equating a parameter across the ideal solubility equation and the Flory-Huggins equation. The Flory-Huggins Theory allowed identification of the contribution of two of the homopolymers to the solubilization of NIF and SMX by Soluplus®, namely PEG and PVAc. PVAc and PVCL each demonstrated a weak interaction with each drug. However, PEG 6000 would substantially contribute to the drug solubilization due to its marked affinity for each drug. Display omitted •Flory-Huggins Theory was employed to identify the solubility in SMX and NIF.•MPD approach was utilized to access the solubility in each component homopolymer.•This work utilized such theory from an angle that was not touched before.