Elucidation of intermolecular interaction patterns in quaternary solid dispersion complexes of enzalutamide

Enzalutamide (ENZ) is commercially formulated as an amorphous solid dispersion (ASD) using a single polymer. This study investigated an alternative multicomponent ASD for ENZ to expand formulation options beyond single-polymer systems. While individual polymers showed limited efficacy, a binary polymer system composed of amino alkyl methacrylate copolymer E (Eudragit E [EUD-E]) and hydroxypropyl cellulose (HPC) enhanced supersaturation. To further improve performance, saccharin (SAC), which is known to form a co-amorphous system with ENZ, was incorporated. Dissolution testing of the quaternary ASD prepared by hot-melt extrusion showed that adding SAC markedly improved supersaturation. Spectroscopic analyses suggested the formation of an organized quaternary interaction network rather than isolated pairwise interactions. HPC disrupted characteristic π-π stacking of ENZ molecules by steric hindrance. EUD-E, which forms ionic interactions with SAC, established additional hydrogen bonds with the amide moieties of ENZ. These sequential and synergistic interactions promoted the formation of a robust quaternary complex. Furthermore, we indicated that SAC relaxes the globular structure of EUD-E, thereby facilitating drug release in solution-state. Since the amide groups and aromatic π-electrons of ENZ are common in many pharmaceutical compounds, this multicomponent strategy offers a promising approach for improving the bioavailability of diverse poorly water-soluble drugs.