Physical aging of hydroxypropyl methylcellulose acetate succinate via enthalpy recovery

Amorphous solid dispersions (ASDs) utilize the kinetic stability of the amorphous state to stabilize drug molecules within a glassy polymer matrix. Therefore, understanding the glassy-state stability of the polymer excipient is critical to ASD design and performance. Here, we investigated the physical aging of hydroxypropyl methylcellulose acetate succinate (HPMCAS), a commonly used polymer in ASD formulations. We found that HPMCAS exhibited conventional physical aging behavior when annealed near the glass transition temperature (T_g). In this scenario, structural recovery was facilitated by α-relaxation dynamics. However, when annealed well below T_g, a sub-α-relaxation process facilitated low-temperature physical aging in HPMCAS. Nevertheless, the physical aging rate exhibited no significant change up to 40 K below T_g, below which it exhibited a near monotonic decrease with decreasing temperature. Finally, infrared spectroscopy was employed to assess any effect of physical aging on the chemical structure of HPMCAS, which is known to be susceptible to degradation at temperatures 30 K above its T_g. Our results provide critical insights necessary to understand better the link between the stability of ASDs and physical aging of the glassy polymer matrix.