The
aim of this study was to probe the dissolution mechanisms of
amorphous solid dispersions (ASDs) of a poorly water-soluble drug
formulated with a hydrophilic polymer. Ritonavir (RTV) and polyvinylpyrrolidone/vinyl
acetate (PVPVA) were used as the model drug and polymer, respectively.
ASDs with drug loadings (DLs) from 10 to 50 wt % were prepared by
solvent evaporation. Surface-normalized dissolution experiments were
carried out using Wood’s intrinsic dissolution apparatus, and
both drug and polymer release were quantified. ASDs at or below 25%
DL showed rapid, complete, and congruent (i.e., simultaneous) release
of the drug and polymer with dissolution rates similar to that of
the polymer alone. The highest drug loading at which congruent release
was observed is termed the limit of congruency (LoC) and occurred
at 25% DL for RTV–PVPVA. The ASD with 30% DL showed an initial
lag time, followed by a period of congruent release. At later times,
the release of drug and polymer became incongruent with polymer releasing
faster than drug. Higher DL ASDs (40 and 50%) showed slow release
of both drug and polymer, whereby the drug release rate was similar
to that of the neat amorphous drug. In cases where the release of
the ASD components was congruent or close to congruent, the drug concentration
exceeded the amorphous solubility, and liquid–liquid phase
separation (LLPS) occurred with the formation of colloidal, drug-rich
species. Solid state analyses of the ASD tablet surface by infrared
spectroscopy and scanning electron microscopy revealed that the partially
dissolved tablet surface remains smooth, and drug–polymer miscibility
is retained at low DLs; whereas, at a very high DL, the surface is
porous and enriched with amorphous drug. In concert, these observations
suggest that ASD dissolution and drug release at low DLs is governed
primarily by hydrophilic polymer; whereas, at high DLs, amorphous
drug controls dissolution. Fluorescence microscopy images of thin
ASD films suggested that ASDs at or below the LoC remain homogeneous
even after exposure to water. In contrast ASDs with DL above LoC undergo,
to various extents, water-induced amorphous–amorphous phase
separation (AAPS) leading to demixing of the drug and polymer. Correlating
the observations of the dissolution study with the solid state data
suggest that the ASDs with DLs higher than the LoC undergo AAPS in
the hydrating matrix on the surface of the dissolving solid during
dissolution, leading to separation of drug and polymer, the formation
of a drug-rich interface, and hence, incongruent and/or slow release
of the components. In contrast, low DL ASDs dissolve before AAPS occurs.
The competition between these two parallel and competing processes
on the surface of ASD solids, i.e., dissolution and AAPS, thus dictates
the overall release characteristics of the ASD formulations, which
is one of the most important considerations in designing formulations
with superior dissolution and absorption.