(486a) Exploring the Physical Aging Behavior of Hpmcas Via Thermal Analysis | AIChE

(486a) Exploring the Physical Aging Behavior of Hpmcas Via Thermal Analysis


Seo, Y. - Presenter, Princeton University
Priestley, R., Princeton University
A major challenge in the design and development of oral delivery drugs is the “solubility challenge,” where a substantial amount of newly discovered small molecule drugs exhibits low solubility, resulting in low bioavailability. One strategy to increase the bioavailability of hydrophobic small molecule drugs is to form an amorphous solid dispersion (ASD). In this approach, amorphous active pharmaceutical ingredients (APIs) are typically dispersed into an amorphous polymer matrix. The glassy polymer matrix kinetically hinders the recrystallization of the API, keeping the API in its amorphous state. Amorphous API exhibits increased bioavailability and aqueous solubility in comparison to its crystalline counterpart. However, despite their kinetic stability, ASDs often remain thermodynamically unstable with a preferential phase separation into API-rich and polymer-rich domains under certain environmental conditions. We hypothesize that this unfavorable phenomenon is primarily facilitated by the molecular mobility of the glassy polymer as the system undergoes structural relaxation.

In this study, we examine this hypothesis by analyzing the physical aging behavior of one of the most common polymer excipients in ASDs, hypromellose acetate succinate (HPMCAS), using conventional differential scanning calorimetry and fast scanning calorimetry. Through temperature scans across the glass transition temperature (Tg) and isothermal aging below the Tg, we compute the aging rate and observe the enthalpy recovery behavior on heating. Contrary to theoretical expectations, when it is aged well below Tg, HPMCAS exhibits a unique devitrification mechanism. In this mechanism, the enthalpy lost on physical aging is recovered notably before Tg, indicating a recovery process different from the alpha relaxation. More importantly, this process is not attributed to a secondary relaxation process as it is not discrete but rather continuous such that at longer aging times, the devitrification shifts towards the alpha relaxation process. This unique behavior suggests a relaxation mechanism that may directly influence the stability of drug molecules within the HPMCAS structure and impact ASD design, processing, and storage.