The aim of this study is to utilise an advanced surface chemical analysis based on X-ray photoelectron spectroscopy (XPS) to determine and characterise drug/polymer interactions in solid dispersions manufactured via hot melt extrusion (HME). Cetirizine HCl (CTZ) and verapamil HCl (VRP) were used as model cationic drugs while Eudragit® grade L100 and L100-55 polymers were used as anionic carriers. A molecular dynamics (MD) based simulation approach predicted drug/polymer interactions while scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS) mapping showed homogenous distribution of the drug particles onto the polymer matrices. Hot stage microscopy (HSM) characterised the solid state of the drugs in extruded formulations. XPS analysis revealed the strength and nature of interaction between the –NH₃ groups of the APIs with the –COOH groups of the polymers. The results obtained from XPS were supported by XRD and NMR studies. The estimation of non-protonated/protonated N atom (N/N′) ratios using XPS revealed the strength of the intermolecular interaction in drug/polymer extrudates which can be used as an efficient tool to study the drug/polymer interaction.