Eutectic Coamorphous System of Enzalutamide and Acetyl Maltose: A Strategy for Improved Physical Stability and Aqueous Solubility

The low aqueous solubility of crystalline enzalutamide (ENZ) and the limited physical stability of amorphous ENZ present significant formulation challenges. In this study, we explore binary co-amorphous systems of ENZ with octaacetyl maltose (acMAL), focusing on the system having eutectic concentration (ENZ + 75 wt % acMAL) as a potential strategy to enhance both stability and solubility. Based on differential scanning calorimetry (DSC) studies of crystalline materials, the eutectic point was identified, while analysis of DSC thermograms of co-amorphous systems revealed pronounced deviations in values of glass transition temperature (<i>T</i>_g) from Gordon-Taylor predictions, implicating the existence of strong specific intermolecular interactions. FTIR studies confirmed the presence of heteromolecular bonding within the mixtures. Broadband dielectric spectroscopy (BDS) showed that, although acMAL increases ENZ molecular mobility, the eutectic co-amorphous formulation significantly suppresses recrystallization under isothermal conditions (<i>T</i> = 413 K), delaying crystallization onset by over 30 h and limiting crystallinity to ≤2% after 55 h. The eutectic ENZ + acMAL composition exhibited sustained supersaturation in both aqueous and biorelevant media, demonstrating a balanced combination of efficient drug release and superior stabilization against recrystallization. These results confirm that eutectic formation followed by co-amorphization of ENZ with acMAL effectively addresses the dual challenges of limited physical stability and poor aqueous solubility. This approach provides a mechanistically rational and transferable strategy for improving the performance of poorly water-soluble APIs in pharmaceutical formulations.