Effect of solvent evaporation on the liquid-crystalline order of itraconazole

Solvent evaporation techniques are widely used for the formation of amorphous-like solid forms of active pharmaceutical ingredients. This study investigates the effect of solvent evaporation on the structure of itraconazole (ITZ) – an antifungal drug and a model thermotropic liquid crystal that exhibits nematic and smectic phases when supercooled from the melt. Using X-ray diffraction, it is demonstrated that the solid phase of ITZ obtained via rapid evaporation of dichloromethane or chloroform reveals a smectic ( Sm ) liquid-crystalline order of a significantly higher degree than ITZ glass obtained by the conventional supercooling of liquid. Moreover, the degree of the ( Sm ) order may be tuned by adjusting the concentration of ITZ in the solution or the choice of solvent. The differences in the ( Sm ) structure between the solvent-evaporated and vitrified ITZ samples translate into their molecular dynamics – the first one exhibits shorter structural relaxation times relative to the second one around the glass transition temperature. The obtained results are in agreement with previous reports, which indicated the development of the highly ordered ( Sm ) structures in the ITZ-glycerol system derived by evaporation of dichloromethane from their solution. Nevertheless, the new insight has clearly shown that glycerol stabilizing the prominent liquid-crystalline order in ITZ is not required at all for its generation. This can be achieved from the pure ITZ-solvent system by fast evaporation of the solvent. Moreover, the presence of polyalcohol does not extend the long-term room temperature physical stability of the ITZ with strong ( Sm ) order. Our findings may be used for producing non-crystalline ITZ formulations offering improvements in drug solubility over the conventional crystalline form.