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.