Chemistry Reference
In-Depth Information
8.2
IN VITRO
AND PHARMACEUTICAL CHARACTERIZATION
Based on the theorized way of working of amorphous solid dispersions, one of the most
important design elements is their ability to dissolve and supersaturate. This is initially
assessed
in vitro
through the use of dissolution protocols especially set up for that
purpose. However, a number of issues have been raised that complicate the appropriate
selection of a useful dissolution protocol. These concerns are associated with both the
nature of the solid dispersion themselves and the biorelevance of the selected apparatus
and media. While the use of traditional USP apparatus (i.e., USP I and II) as well as
compendial buffers or media for assessing drug release from solid dispersions is possible,
they are often suboptimal [63]. To address artifacts associated with rapid changes in
solubility of the compound as a function of time, expedited sample handling has been
suggested to optimize phase separation and dilution and include the use of rotating
syringes and microcentrifuge tube-based systems [64,65]. Likewise, systems designed to
produce a pH shift mimicking gastrointestinal passage are available using both single and
multivessel apparatuses [66
cial stomach duodenum (ASD)
systems [69,70] and the TIM approach offered by TNO [71
-
68], including the arti
74]. In many cases, these
approaches still fail to appropriately characterize solid dispersions both as a function of
their release properties and the ability to predict
in vivo
exposure. As reviewed by
Augustijns and Brewster, one reason that traditional methods are particularly unsuited for
solid dispersion testing and screening is that they are designed to maintain sink
conditions that may mask or confuse dissolution, supersaturation, and precipitation
dynamics [63]. Thus, one suggested element for dissolution methods for solid disper-
sions is that they are developed using a nonsink protocol. A second issue is related to the
hydrodynamics and mechanical stress associated with the dissolution process [63].
Hydrodynamics can affect the induction period associated with crystallization and
precipitation of a supersaturated solution by either increasing the drug diffusivity or
lowering the barrier to nucleation. Unfortunately, test systems re
-
ecting
in vivo
hydro-
dynamics are not yet available [75]. A third consideration is the impact of media and
especially the fact that biorelevant
fluids such as FaSSIF and FeSSIF may better simulate
dissolution in the gastrointestinal tract. Bevernage et al. compared the tendency of drugs
to supersaturate and precipitate in simple compendia buffers, simulated media, and
aspirated human gastric and intestinal
fluids [76
-
78]. In these studies, simple buffers
poorly correlated with human
cantly overpredicted super-
saturation stability and underestimated precipitation. While FaSSIF was useful compared
with aspirated human samples, FeSSIF underestimated precipitation relative to human
aspirates. Similar trends were observed for gastric precipitation with simulated
fluids in that they signi
fluid
(FaSSGF) more useful than simple SGF. Finally, the temperature of these assays has
been considered [54]. Generally, media are thermostated to 37
C; however, some studies
°
suggested that the temperature can in
uence the tendency of the system to supersaturate
with amorphous felodine forming supersaturated solutions at 25
C [79].
To these points, drug release from a solid dispersion in which itraconazole was
loaded into mesoporous silica was completed in both sink and nonsink methodolo-
gies [80]. In sink conditions, rapid dissolution occurred without an indication of
precipitation and added precipitation inhibitors had no measureable effects. By contrast,
C but not at 37
°
°
