Crystallization Inhibition and Solid-State Stability in High Drug Loaded Amorphous Drug-Polymer Dispersions Above the Overlap Concentration.

Amorphous solid dispersions (ASDs) have been shown to be an effective formulation strategy for improving apparent solubility, dissolution rate, and hence oral bioavailability of poorly aqueous soluble drugs. In this perspective, we review recent progress in understanding the role of polymer concentration, particularly the overlap concentration, c*, in governing crystallization of high drug loaded ASDs. The overlap concentration, c*, is a threshold above which adjacent polymer coils start to contact. Recent work has shown that when polymer concentration is below c*, the presence of the continuous polymer-free amorphous drug domain allows crystallization to proceed similarly to neat drug, resulting in limited inhibition. Above c*, formation of a homogeneous polymer rich matrix suppresses crystallization, primarily by delaying the first nucleation event. Representative case studies demonstrate the generality of this framework across diverse drug-polymer systems, although limitations arise for sufficiently high molecular weight polymers. Overall, the c*-guided rheological approach provides a mechanistic basis for rational polymer selection and optimization in high drug loaded, and therefore reduced overall volume, ASD formulations.