Structure and Process Relationships in Extruded Polymer Systems: Solid-State Remodeling of Oxymetazoline

Hot-melt extrusion (HME) is widely used in the development of drug–polymer systems, yet conventional preformulation approaches remain largely based on equilibrium conditions and may fail to predict material behavior under processing. In this context, the present study proposes a process-informed preformulation strategy to investigate structure–process relationships in extrusion-based pharmaceutical systems. Oxymetazoline hydrochloride (OXY), a thermally sensitive compound exhibiting concurrent melting and degradation, was used as a challenging model drug. Polymer selection was initially guided by Hansen solubility parameters (HSP), followed by experimental evaluation of extruded systems through thermal, solid-state, and rheological characterization. The results showed that, although HSP provided a useful initial ranking of drug–polymer compatibility, the solid-state outcomes after extrusion were not solely governed by thermodynamic miscibility. In particular, systems with lower predicted compatibility exhibited significant structural transformations, indicating a dominant role of kinetic and mechanical factors associated with melt processing. Rheological analysis further demonstrated that melt viscoelasticity influenced energy transfer and the extent of drug–polymer interactions during extrusion. Overall, this study demonstrates that thermodynamic predictions alone are insufficient to anticipate solid-state behavior in extrusion-processed systems. The proposed approach provides a framework for integrating theoretical and experimental tools to support the rational design of pharmaceutical materials under realistic processing conditions.