Direct Visualization of Drug-Polymer Phase Separation in Ritonavir-Copovidone Amorphous Solid Dispersions Using In Situ Synchrotron X-Ray Fluorescence Imaging of Thin Films

Amorphous solid dispersions (ASDs) are new formulations currently being used in pharmaceutical industry. The ASDs, in which amorphous drug and polymeric excipients are intimately mixed at the molecular level, exhibit dramatically enhanced solubility and dissolution characteristics relative to their crystalline drug counterparts. In the process of achieving an ever-increasing drug loading (DL), it is noticed, however, that the drug release profile deteriorates significantly beyond a certain DL. As an example, a ritonavir–copovidone ASD achieves continuous and full drug release when DL ≤ 25 wt %. The release drops at 30 wt % and when DL ≥ 35 wt % there is virtually no drug release, behaving like a pure amorphous drug. In this Communication, the phase miscibility of ASD thin films has been investigated by in situ synchrotron X-ray fluorescence (XRF) imaging to elucidate the mechanism for the unique change in the extent of drug release as a function of DL. It is found that the drug release profile correlates ...