Physical Aging Behavior of Hydroxypropyl Methylcellulose Acetate Succinate via Enthalpy Recovery Studies

Amorphous solid dispersions (ASDs) utilize the kinetic stability of the amorphous state to stabilize drug molecules within a glassy polymer matrix. Naturally, ASDs are subject to thermodynamic instability that manifests as phase separation between the drug and polymer. The complex relationship between ASD drug stability and physical aging is critical to ASD design and performance but remains understudied. This study investigates the physical aging behavior of hydroxypropyl methylcellulose acetate succinate (HPMCAS). When aged well-below the glass transition temperature (T_g) and upon re-heating, HPMCAS does not access the α-relaxation mechanism and completely devitrifies before T_g. This behavior supports the existence of an alternate equilibrium mechanism that is accessible well-below T_g. Furthermore, the aging rates of HPMCAS near T_g and well-below T_g are calculated and exhibit minor but notable differences, implying that physical aging readily continues even at aging temperatures 80°C below T_g and aging times up to 600 minutes.