Mechanical milling is a well-known method of solid-state amorphization of crystalline materials. Here, it is revealed that cryo-milling of itraconazole, a model thermotropic liquid-crystalline active pharmaceutical ingredient, leads to a preferred nematic order of molecules in solid particles instead of isotropic disorder − usually observed for most molecules that do not form liquid-crystalline mesophases. While standard quenching of itraconazole isotropic liquid down to room temperature results in the formation of glass with some degree of smectic order, cryo-milling easily destroys not only crystalline order but also smectic organization of molecules into layers, omitting the melting. The cryo-milled itraconazole samples exhibit faster α-relaxation and slightly slower δ-mode above the glass transition temperature. They are also more physically stable, with the stability dependent on the grinding time, below this temperature, with respect to the ordinary glass. The explanation for this behavior is believed to be increased short-range intermolecular disorder. Moreover, the cryo-milled particles with nematic order are better soluble than ordinary glass. Therefore, this work can guide the formulation of stable pharmaceuticals with nematic order/disorder and enhanced solubility.
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