Considerations in the Development of Physically Stable High Drug Load API- Polymer Amorphous Solid Dispersions in the Glassy State.

In this Commentary, the authors expand on their earlier studies of the solid-state long-term isothermal crystallization of amorphous API from the glassy state in amorphous solid dispersions, and focus on the effects of polymer concentration, and its implications for producing high load API doses with minimum polymer concentration. After presenting an overview of the various mechanistic factors which influence the ability of polymers to inhibit API crystallization, including the chemical structure of the polymer relative to the API, the nature and strength of API-polymer noncovalent interactions, polymer molecular weight, impact on primary diffusive molecular mobility, as well as on secondary motions in the bulk and surface phases of the glass, we consider in more detail, the effects of polymer concentration. Here, we examine the factors that appear to allow relatively low polymer concentrations, i.e., less than 10%w/w polymer, to greatly reduce crystallization, including a focus on the heterogeneous structure of the glassy state, and the possible spatial distribution and concentration of polymer in certain key regions of the glass. This is followed by a review and analysis of examples in the recent literature focused on determining the minimum polymer concentration in an amorphous solid dispersion, capable of producing optimally stable high drug load amorphous dispersions.