Assessing the Impacts of Drug Loading and Polymer Type on Dissolution Behavior and Diffusive Flux of GDC-6893 Amorphous Solid Dispersions

Abstract

It is desirable but remains challenging to develop high drug load amorphous solid dispersions (ASDs) without compromising their quality attributes and bio-performance. In this work, we investigated the impacts of formulation variables, such as drug loading (DL) and polymer type, on dissolution behavior, diffusive flux, and in vitro drug absorption of ASDs of a high T_g compound, GDC-6893. ASDs with two polymers (HPMCAS and PVPVA) and various DLs (20 – 80%) were produced by spray drying and their drug-polymer miscibility was evaluated using solid-state nuclear magnetic resonance (ssNMR). μFLUX™ apparatus was used to evaluate the dissolution and drug membrane transport of ASDs at target solution concentrations above the amorphous solubility.

Polymer release was monitored using a high-performance liquid chromatography (HPLC) equipped with a charged aerosol detector (CAD). Subsequently, bio-accessibility (%BioA) profiles of the ASDs were evaluated using a benchtop Gastro-Intestinal Model with an advanced gastric compartment (Tiny-TIM), capable of simulating the GI transit as well as in vitro drug dissolution and absorption. Good miscibility and physical stability were observed in ASDs with both HPMCAS and PVPVA even at a high DL of 80%. All GDC-6893 ASDs exhibited dissolution profiles surpassing the amorphous solubility of 20 µg/mL, regardless of the DL and the type of polymer used. Glass-liquid phase separation (GLPS) was observed for ASDs, even at the DL of 80%, and all of these systems reached the maximum achievable diffusive flux. Tiny-TIM results showed an improvement in the %BioA of GDC-6893 ASD compared to its crystalline counterpart however the drug loading and polymer type had no significant impacts on %BioA profiles.

Insights from this study suggest that although congruent drug and polymer release was not observed for both HMPCAS- and PVPVA-based ASDs at both 20% and 80% DLs, GDC-6893 and the polymer (HPMCAS or PVPVA) dissolved rapidly from high DL ASDs, followed by the occurrence of GLPS, resulting in the formation of nanosized colloidal species. The findings described herein highlight the importance of understanding both drug and polymer dissolution behavior, as well as in vitro drug absorption, which are essential for the rational design of optimal formulations with desired quality and bio-performance.

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Materials

GDC-6893 crystalline free base was made in house at Genentech Inc. PVPVA (Kollidon VA 64) was supplied by the BASF Corporation (Ludwigshafen, Germany). HPMCAS MF grade was acquired from Shin-Etsu (Totowa, NJ) and used as received. Fasted-stated simulated intestinal fluid (FaSSIF-V2) powder was purchased from Biorelevant (London, U.K.). FaSSIF buffer pH 6.5 was prepared in house by dissolving maleic acid, sodium hydroxide pellets and sodium chloride in purified water and pH adjustment was done.

Nivedita Shetty, Jonathan Hau, Shijia Tang, Po-Chang Chiang, Jia Liu, Wei Jia, Joseph W. Lubach, Karthik Nagapudi, Hao Helen Hou, Assessing the Impacts of Drug Loading and Polymer Type on Dissolution Behavior and Diffusive Flux of GDC-6893 Amorphous Solid Dispersions, Journal of Pharmaceutical Sciences, 2025, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2025.01.021.

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