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Direct Visualization of Drug–Polymer Phase Separation in Ritonavir–Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X‑ray Fluorescence Imaging of Thin Films
journal contribution
posted on 2019-09-30, 21:14 authored by Chenyang Shi, Luxi Li, Geoff G. Z. Zhang, Thomas B. BorchardtAmorphous
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 well with the amorphous–amorphous phase separation
(AAPS) onset. At a lower drug loading (up to 20 wt %), it takes more
than 12 h for AAPS to happen while in sharp contrast, it only needs
less than 10 min for DL ≥ 32.5 wt %. During AAPS, amorphous
drug accumulates on the surface of the film, which prevents further
dissolution from the interior of the ASD. The current study provides
a mechanistic understanding of the confounding drug release profile
of ASDs as a function of DL and opens the door for studying drug–excipient
(e.g., polymer, surfactant) interactions via XRF imaging in the future.