Hidden mesoscale order in Posaconazole: A comparative study with Itraconazole

Liquid-crystalline-like ordering in amorphous pharmaceuticals can govern their molecular mobility, physical stability, and crystallization - properties that ultimately determine the performance of amorphous drug materials. Here, the azole antifungal drugs posaconazole (POS) and itraconazole (ITR) are used as model systems to investigate the interplay between mesoscale organization and molecular dynamics. Using ITR, which forms well-defined liquid-crystalline phases, as a reference, we reveal an analogous but hidden orientational order in amorphous posaconazole, despite the absence of a stable liquid-crystalline phase. Broadband dielectric and shear mechanical spectroscopy show that this order is accompanied by an additional slow process beyond the structural relaxation. Complementary atomic force microscopy (AFM) reveals stripe-like modulations of the local stiffness at the surface (≈ 2.5 µm for ITR, ≈ 1 µm for POS), attributed to frozen-in smectic layering in ITR and to surface-enhanced orientational order in POS. We further demonstrate that high-pressure helium treatment disrupts this ordering in both compounds, plasticizes the glass, erases the surface stripe patterns and measurably increases the tendency towards recrystallization. These results introduce noble-gas compression as an additive-free route to modify the mesoscale order of such rod-like molecular systems.