Configurational entropy suppresses crystallization in multicomponent molecular glasses

The formation of stable amorphous solids is fundamentally limited by crystallization from the supercooled liquid. An ideal stabilization strategy would be broadly applicable, independent of specific intermolecular interactions, and effective at high molecular loadings. Here we demonstrate that increasing configurational entropy through multicomponent molecular mixing provides a general physical route to suppressing crystallization in molecular glasses. Using equimolar mixtures of small biocompatible molecules, we show that increasing component number markedly reduces liquid fragility without increasing the glass-transition temperature. Above a critical component count, crystallization is arrested, yielding stable amorphous phases upon cooling and reheating. Applying this principle to pharmaceutical systems, we show that drugs crystallizing readily in isolation can be stabilized in the amorphous state at high loadings within multicomponent matrices, forming high-entropy amorphous drugs (HEADs). These results establish configurational entropy as a design parameter for controlling crystallization in molecular glasses suggesting a general stabilization strategy for amorphous molecular solids. Teaser: High-entropy molecular mixtures prevent crystallization, stabilizing amorphous drugs.