Amorphous Solid Dispersions as Non-Equilibrium Materials

An amorphous solid dispersion is a molecular glass that the pharmaceutical literature specifies as though it were a solution: by drug, polymer and drug loading, occasionally with a glass transition temperature. Composition constrains such a material without determining it. Dispersions of identical composition differ in physical stability and in dissolution, and the difference depends on the path taken onto the energy landscape. We treat the dispersion as a kinetically arrested material and describe it using seven state variables. These variables capture the changes that occur during manufacturing, storage, downstream handling, and dissolution: thermal and relaxation state, mixing scale, residual order, water and residual solvent content, particle and surface structure, chemical integrity, and age. Against this description we grade every same-composition comparison we could identify, by the strength of the link between history and outcome. The comparisons do not agree on which preparation route yields the more stable or better-performing product. Where an outcome is explained, the explanation is a measured structural state—residual crystals, compositional heterogeneity, surface enrichment—rather than the route, which serves as a label for the states a process tends to produce. In single-component molecular glasses, preparation history survives in the configurational enthalpy and the relaxation spectrum at unchanged glass transition temperature and heat capacity, and predicts crystallisation. We found no equivalent measurement for a drug–polymer dispersion: none of the graded comparisons reported a fictive temperature, an enthalpy recovery or a relaxation time. Whether an entangled polymer preserves or erases the drug’s relaxation memory is the field’s outstanding question. Because the variables that carry history are seldom reported, we propose a minimum set of state descriptors, each with its detection limit and the length scale over which it was tested.