Physical Aging of Hydroxypropyl Methylcellulose Acetate Succinate Amorphous Solid Dispersions using Fast Scanning Calorimetry

Amorphous solid dispersions (ASDs) utilize the glassy state to kinetically stabilize drug molecules within a polymer matrix. However, physical aging of the polymer excipient impacts drug stability in ASDs, the extent of which remains unknown. To address this knowledge gap, we employed fast scanning calorimetry (FSC) to probe the physical aging behavior of spray-dried ASDs. Ritonavir was used as the model drug and spray dried with hydroxypropyl methylcellulose acetate succinate (HPMCAS) at 1, 5, and 10 drug weight percent by mass. The high scanning rates of FSC inhibited de-mixing effects at high temperatures, allowing for accurate glass transition measurements. Aging rate calculations showed that despite their expected kinetic stability, ASDs exhibited significant thermodynamic evolution deep in the glassy state (100°C below the glass transition) independent of drug content. However, increased drug content shifted the peak aging rate temperature closer to the glass transition. These behaviors indicated that drug presence has an overall minor influence on HPMCAS physical aging behavior except at temperatures near the glass transition, where ASDs exhibit faster aging rates compared to the pure polymer excipient.