From Chemistry to Clinic: Amorphous Solid-State Modification Strategies for Oral Azole Antifungals

Azole antifungals remain central to the management of superficial and systemic mycoses, yet the growing global incidence, rising resistance, and persistent treatment failures highlight the need for improved oral formulations. Current azole products are predominantly capsules or liquid preparations that have well-documented limitations with patient adherence and bioavailability. Traditional formulation efforts have relied heavily on crystalline solid forms because of their predictable behavior and established manufacturing pathways. However, this long-standing preference has restricted exploitation of alternative solid-state strategies capable of meaningfully improving aqueous solubilitya key determinant of oral bioavailability. Advances in analytical technologies have broadened interest in amorphous and coamorphous systems, but issues such as instability, hygroscopicity, and unpredictable dissolution behavior continue to limit their reliability. This review explores the expanding field of supramolecular solid-state design for azoles, with a focus on noncrystalline forms, particularly eutectic mixtures, as an underutilized but highly promising formulation approach. Eutectic systems occupy a unique microcrystalline space between the high solubility amorphous forms and the stable crystalline solids, offering enhanced solubility without the need for polymeric stabilizers that often complicate amorphous formulations. Despite more than six decades of sporadic investigation, their pharmaceutical potential remains considerably underexplored, especially for BCS II compounds, such as azoles. By consolidating current knowledge on azole solid-state chemistry, highlighting the limitations of existing formulation strategies, and evaluating the emerging rationale for intentional eutectic design, this review positions eutectic mixtures as a viable and impactful pathway for developing next-generation azole formulations with improved oral bioavailability and therapeutic performance.