Role of Dissolution Medium pH in the Release Behavior of Basic Drug-Copovidone Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) are one of the most effective formulation strategies for improving the release rate and bioavailability of poorly water-soluble drugs. However, the release rates of polyvinylpyrrolidone vinyl acetate (PVPVA) based ASDs typically decrease dramatically once a certain drug loading (DL) is exceeded. The purpose of this study was to evaluate the impact of dissolution medium pH on the release behavior of basic drug-PVPVA ASDs for ASDs with different DLs. Loratadine (LRD) and ritonavir (RTV) were used as model basic drugs. The surface area normalized release rates of drug and polymer from the ASD were measured in over a range of solution pH conditions from 1.6 to 7.5. The evolving phase morphology of the hydrated ASD compact surface was observed using confocal fluorescence microscopy. To provide insight into the gel layer pH, a pH indicator was added to the ASD and the gel layer color was observed following immersion in media of different pH values. Surface area normalized release rate measurements revealed that ASDs with low DLs, where release was controlled by the polymer, showed rapid and pH-independent release. However, ASDs with higher DLs exhibited pH-dependent release. From the confocal fluorescence microscopy imaging, formation of a drug-rich barrier layer at the gel layer-solution interface was observed for higher DL ASDs. Visual imaging of the gel layer suggested formation of a pH-gradient for LRD-PVPVA ASDs but not for RTV-PVPVA ASDs. In conclusion, for weakly basic drugs with highly pH-dependent solubility, the medium pH is expected to impact the release rate of higher DL ASDs where release is controlled by the drug-rich layer formed following hydration. In contrast, for low DL ASDs where the polymer controls the release, pH is anticipated to have less impact on release. This study contributes additional understanding of the release mechanisms of PVPVA-based ASDs.