Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs

DSC, dielectric spectroscopy, and optical microscopy, are employed to analyze the equilibrium and out-of-equilibrium binary phase diagram of two antifungal azole compounds, fluconazole (FLZ) and econazole (ECZ), to study the physical stability of co-amorphous formulations that may allow co-administration and a faster dissolution of the poorly soluble ECZ compound. The two crystalline APIs form a eutectic equilibrium phase diagram with eutectic point at T _e = 351.1 ± 0.5 K and eutectic molar fraction of FLZ of x _FLZ,e = 0.22 ± 0.01. While amorphous FLZ has a strong tendency to crystallize, amorphous ECZ is kinetically stable during at least several weeks even as a supercooled liquid. Amorphous ECZ is found to display faster kinetic dissolution profile in water compared with crystalline ECZ. The glass transition (T _g) of the liquid mixtures depends linearly on composition, increasing by 4 K for every 10% increase in x _FLZ. The molecular mobility determined by dielectric spectroscopy is characterized by a single structural relaxation and a single Johari-Goldstein relaxation at all compositions, testifying the structural and dynamic homogeneity of the amorphous mixtures. The equimolar supercooled liquid mixture and FLZ-rich mixtures phase-separate over few days or weeks, with the FLZ-rich phase recrystallizing into bundles of rod-like crystallites surrounded by an almost pure amorphous ECZ matrix. The amorphous mixture at the eutectic composition remains instead kinetically stable during 6 months above T _g, and for at least 10 months in the glass state below T _g. Mixtures that have ECZ molar fractions of 0.9 or higher are kinetically the most stable ones (they remain amorphous during more than 14 months at room temperature) despite having the fastest molecular mobility both in the supercooled liquid and glassy phases. Their high kinetic stability is likely due to lower supercooling and lower supersaturation, leading to lower thermodynamic driving force, and to the dilution of the recrystallizing FLZ compound. These results help shed light on the stability of binary amorphous mixtures.