Eutectic-Driven Recrystallization of Coamorphous Bicalutamide + Niclosamide Systems: Contrasting Stability above and below Tg.

Coamorphization is a promising strategy to enhance the physical stability of poorly water-soluble drugs. However, the relationship between composition, molecular dynamics, and long-term stability remains insufficiently understood. Here, we investigate coamorphous systems composed of bicalutamide (BIC) and niclosamide (NIC), focusing on how the eutectic composition defined in the crystalline state translates into molecular dynamics and long-term physical stability of the corresponding amorphous systems above and below the glass transition temperature (Tg). Thermal analysis revealed a eutectic point in the close vicinity of 25 wt % NIC, enabling safe melt-based amorphization of NIC without thermal degradation. Broadband dielectric spectroscopy showed that the addition of NIC does not significantly affect the molecular mobility of amorphous BIC, as reflected by comparable Tg values oscillating around 328 K, fragility parameters in the range of 85-92, as well as similar α-relaxation dynamics across all compositions. Despite these similarities, the physical stability of the coamorphous systems exhibits a pronounced composition dependence. Under accelerated conditions in the supercooled liquid state (T > Tg), the coamorphous system corresponding to the eutectic concentration displays the highest resistance to recrystallization. In contrast, long-term X-ray diffraction studies performed under glassy-state conditions (T < Tg) reveal a different stability ranking. These findings indicate that the stabilization observed for compositions corresponding to the eutectic point depends on the thermal regime and emphasize the importance of evaluating physical stability under both supercooled liquid and glassy state conditions.