(337bx) Calorimetry of Drug-Polymer Amorphous Solid Dispersions to Probe the Influence of Polymer Excipient Physical Aging

The “solubility challenge” presents an obstacle to progress in the development of oral delivery drugs as almost all newly discovered small molecule drugs exhibit low solubility and therefore, low bioavailability. Amorphous solid dispersions (ASDs) are a leading strategy to address this challenge. ASDs utilize the kinetic stability of the glassy state to stabilize small molecule active pharmaceutical ingredients (APIs) within a polymer matrix, enhancing the API bioavailability during oral drug delivery. However, the amorphous polymer matrix is subject to structural relaxation driven by thermodynamic instability. The resulting changes to its physical properties are referred to as physical aging. Physical aging directly influences ASD stability and performance, yet the extent and mechanism remains understudied.

My PhD work addresses this knowledge gap using calorimetry to probe ASD glassy behavior. The model polymer excipient was hydroxypropyl methyl cellulose acetate succinate (HPMCAS), an often-utilized excipient in pharmaceutical formulations. The model drugs were Ritonavir and Carbamazepine for their comparative interactions with HPMCAS. The physical aging behavior of HPMCAS exhibited a unique relaxation mechanism through which substantial thermodynamic evolution proceeded even at temperatures 80°C below the glass transition temperature. Spray-dried dispersions of HPMCAS with the model drugs at low concentrations reflected the same behavior with a dependence on drug-polymer interactions. These results highlighted the complex nature of structural relaxation in HPMCAS and the associated thermal analytical challenges. A complete understanding of the HPMCAS relaxation behavior would lead to the optimization of ASD design and stability.

My prior experiences pertain to the different constituents of the drug product approval process, namely in R&D, regulatory affairs, and manufacturing. I developed assay methods for antibody drug conjugates under GLP/GDP. I performed computational modeling of polymer systems in aqueous solution for drug delivery applications. I assembled a database of small molecule drug products to generate specific strategies for drug product approval via both domestic and international expedited approval pathways. I completed contract work to validate portable clean-in-place skids for solutions tank sterility at one of the largest manufacturing sites in the US. Outside of research, my PhD career focused on technical communication and safety practices/management.

Research Interests:

My research interest is the R&D of drug substances and products, particularly regarding drug substance/product stability and formulation design. I hope to leverage both my PhD research experience and my prior experiences in pursuit of a long career in pharmaceutical R&D.