Probing the moisture-induced drug recrystallization in hydroxypropyl methylcellulose-based amorphous solid dispersions.

Hydroxypropyl methylcellulose (HPMC), a widely used cellulose derivative, plays a central role in stabilizing drug-containing amorphous solid dispersions (ASDs), by inhibiting the drug recrystallization. However, the moisture sorption behavior of HPMC can compromise the physical stability of ASDs under humid conditions. This study examines how humidity, drug loading, storage time, and spatial location within the ASD together influence the recrystallization behavior of a model drug (naproxen) in HPMC-based ASDs prepared via hot melt extrusion. We hypothesized that moisture induced drug recrystallization is governed primarily by the water sorption characteristics of HPMC. To investigate moisture induced drug recrystallization, extrudates were stored for 14 days at 75% and 98% RH. All formulations remained fully amorphous (>99.5%) at 75% RH, whereas significant recrystallization occurred at 98% RH. Notably, recrystallization initiated at the extrudate surface, reflecting moisture driven structural gradients within the polymer matrix. These results establish a structure-property relationship linking HPMC hydration and increased chain mobility to drug recrystallization, providing a mechanistic insight relevant for designing robust moisture-resistant cellulose derivatives-based drug delivery systems.