Chemistry Reference
In-Depth Information
Inclusion of surfactant as a third component in drug/polymer dispersions manufac-
tured by HME was investigated by Ghebremeskel et al. [23]. Of the four ternary systems
to undergo
in vitro
dissolution testing, two systems (API/copovidone/Tween 80 and API/
HPMC E5/Tween 80) showed that surfactant had a positive effect on dissolution rate
relative to the corresponding drug/polymer mixture. The same surfactant did not change
the dissolution pro
le for an API/PVP K30/Tween 80 composition. Interestingly, an
API/HPMC E5/docusate sodium HME dispersion exhibited slower dissolution relative
to the drug/polymer reference, an effect that is opposite to that of Tween 80 added to the
same matrix. Surfactant was included at 10%w/w content in all test samples, and particle
size of milled extrudate was kept constant to remove these variables from the experiment.
This study demonstrates that drug release into solution from a multicomponent amor-
phous dispersion is sensitive to low levels of surfactant, but that the effect on dissolution
may not be favorable. The mechanism of surfactant effects was not investigated, but the
probable role of different micellar structures formed by surfactant and polymer was
discussed. Just as supersaturation pro
le of an amorphous solid is primarily kinetically
controlled, the kinetics of surfactant dissolution and aggregation (both in solution and at
interfaces) can be anticipated as contributing to the dissolution behavior of API from an
amorphous dispersion.
Recognizing the important bioavailability enhancement opportunity with a third
component, Shanbhag et al. report a high-throughput screening approach for ternary
mixtures that uses single-point dissolution measurements at the microscale to select
lead systems [24]. The screen successfully identi
ed API/polymer/surfactant compo-
sitions for pharmacokinetic assessment in rats by administering ground HME disper-
sions in a miniature capsule. An amorphous solid dispersion prepared by HME
produced similar oral bioavailability to a reference oral solution for the poorly soluble
compound.
Dissolution behavior of three-component extrudates containing poorly soluble drug
fenofi-
brate with two polymers was reported by Kalivoda et al. [25]. Hot melt extrusion
was used to prepare binary mixtures of feno
brate with copovidone and with HPMC,
plus different ratio ternary mixtures of feno
brate/copovidone/HPMC. All mixtures
generated amorphous dispersions suitable for downstream pelletization to generate
controlled pellet size. Dissolution testing was performed using USP II apparatus in
test media containing 0.1% polysorbate 80 surfactant, and the pro
les are provided in
Figure 10.9. For binary mixtures, supersaturation was greatest for the feno
brate/
copovidone dispersion (1/3 weight ratio), with a 12-fold solubility increase seen at
the 12 min timepoint, followed by a rapid decrease in dissolved fenofi-
-
brate/copovidone/HPMC dispersion (1/3/1 weight ratios) produced a similar super-
saturation effect to the copovidone reference, but with a prolonged period of
supersaturation. The authors postulate that HPMC introduced a gelling property to
the dispersion that complements the supersaturation performance of the drug/copovidone
dispersion. Such gelling may have limited the formation of crystal nuclei or growth in a
high supersaturated microenvironment, and slowed down the release of water-soluble
polymer away from drug and into the disperse phase. The example given by Kalivoda
et al. helps teach that controlling the local environment of the dissolving amorphous
solids is an important aspect of formulation optimization so that the supersaturation
brate. A fenofi-
