(T1530-11-70) Assessing the Impacts of Drug Loading and Polymer Type on In Vitro Dissolution and Flux Behavior of GDC-A Amorphous Solid Dispersions

Purpose: Developing amorphous solid dispersions has gained increasing attention as a strategy to improve oral absorption for compounds with solubility-limited bioavailability. However, there is a limited understanding for how drug is released from ASDs, especially for ASDs with higher drug load. The dissolution behavior has been explained in literature in terms of the limit of congruency (LoC) where the extent of drug released from ASDs can surpass the amorphous solubility by forming nanosized drug-rich colloidal species as both the drug and polymer are released congruently [1]. The LoC could be drug dependent and typically reported to vary from 5 – 40% [2]. At drug loads above 30-40% they cease to dissolve and the amount of drug released falls below the amorphous solubility. The objective of this study was to systematically investigate the impacts of drug loading and polymer type on the dissolution and permeation behavior of ASDs in biorelevant media.

Methods: GDC-A ASDs at different drug loads (DLs) using two different polymers, polyvinylpyrrolidone/vinyl acetate (PVPVA) and hydroxypropyl methyl cellulose acetate succinate (HPMCAS-MF), were prepared via spray drying followed by secondary drying in a vacuum oven overnight. Various testing, including powder x-ray diffraction (PXRD), thermogravimetric analysis (TGA), solid state nuclear magnetic resonance (ssNMR), modulated differential scanning calorimetry (mDSC), was performed to characterize the solid state properties of ASDs. ASD dissolution and flux behavior was studied with μFLUX™ apparatus (Pion Inc.) in fasted state simulated intestinal fluid (FaSSIF-v2) at pH 6.5. Size exclusion chromatography (SEC) was used for drug and polymer quantification.

Results: The crystalline and amorphous solubility of GDC-A in FaSSIF-V2 buffer at pH 6.5 was determined to be 5 µg/ml and 20 µg/ml, respectively. Incorporating polymers in the ASDs help prevent the drug from crystallization and maintain supersaturation above the amorphous solubility. As shown in Figure I, all ASD formulations have dissolution profiles above the amorphous solubility of GDC-A which is the maximum achievable free drug concentration irrespective of the polymer type. This could be attributed to the presence of drug-rich nanoparticles at different drug load and congruent release of both drug and polymer (Figure II). The amorphous solubility is independent of the amount of drug in the dissolution medium it can be derived that drug-polymer interaction is necessary for the formation of drug-rich colloidal aggregates. The nanodroplet generation not only depends on the drug load and drug-polymer interaction but also on the type of polymer. ASDs with HPMCAS-MF polymer exhibited similar dissolution behavior up to 50% DL (Figure 1a) whereas in case of PVPVA polymer a drop in concentration dissolved was seen above 20% DL (Figure 1b). Possibly the drug binds more strongly with HPMCAS than PVPVA which could be attributed to the hygroscopic nature of PVPVA compared to HPMCAS. No depletion of nanoparticles was observed within the biorelevant time frame and the flux rate is found to be consistent for all formulations having dissolution profile above the amorphous solubility (Table I).

Conclusion: Our study showed that a high limit of congruency was observed for both HMPCAS and PVPVA based formulations even at 80% drug load. No depletion of nanoparticles was observed within the biorelevant time frame and the flux rate was found to be consistent for all formulations. This study highlights the complex interplay between drug loading, drug-polymer interactions and shows the potential to design high drug loading ASDs without loss in dissolution performance.

References: 1. Saboo, S., et al., Congruent release of drug and polymer: A "sweet spot" in the dissolution of amorphous solid dispersions. J Control Release, 2019. 298: p. 68-82.
2. Que, C., et al., Insights into the Dissolution Behavior of Ledipasvir-Copovidone Amorphous Solid Dispersions: Role of Drug Loading and Intermolecular Interactions. Mol Pharm, 2019. 16(12): p. 5054-5067.

Dissolution profiles of GDC-A ASDs with different drug loading at target concentration of 50 µg/ml in FaSSIF-v2 at pH 6.5. (a) HPMCAS-based ASDs, and (b) PVPVA-based ASDs.

Figure II: Dissolution profile of (a) GDC-A-PVPVA and (b) GDC-A-HPMCAS-MF
at 20% DL

Table I: Flux measurement for HPMCAS-MF and PVPVA based GDC-A ASDs at different drug loading