Chemistry Reference
In-Depth Information
Animal and human PK data are available in some of the published research to
compare with the dissolution data. There are two types of predictions for
in vitro
and
in vivo
data: IVIVR and IVIVC as brie
y described in Section 6.1. The former is a
broader, semiquantitative association between the two data sets and the latter is a more
rigorous, predictive mathematical model that describes the predictability of
in vitro
data
for
in vivo
performance. The vast majority of early developmental work with biorelevant
media focuses on IVIVR [22,33,115]. For example, modi
ed fasted duodenal (MFD)
fluid was used to determine the dissolution of several APIs from amorphous solid
dispersions of HPMC and HPMC-AS. Friesen et al. demonstrated a clear solubility
advantage for solid dispersions of drug made with varying grades of HPMC-AS versus
the crystalline API. Also described in the same publication is a comparison of the
in vitro
data with the
in vivo
data and demonstration of IVIVR [106]. Finally, modi
ed SGF was
used by Boghra et al. to determine the release rate of irbesartan from HPMC solid
dispersions. The data were compared with the dissolution rates of crystalline API from
suspension in the same media, showing an advantage for the amorphous solid dispersion.
Bioavailability enhancement in rabbit model (New Zealand gray) was also demonstrated,
establishing an IVIVR for the dissolution and animal PK [116].
6.4.3 Characterization of Species Generated during Dissolution
of Amorphous Solids and Their Impact on Performance
Many times when amorphous solid dispersion is dissolved in aqueous media, the
resultant solution is observed to be cloudy with a slight bluish color, characteristic
of the presence of a second light scattering phase. This observation is consistent with
studies in which supersaturating dosage forms, consisting of amorphous solid disper-
sions, are found to have a rapid dissolution rate [54,64,117,118] and submicrometer
particles are formed
in situ
upon dispersion in the aqueous media [119]. In particular, the
formation of drug nanosuspensions (submicrometer colloidal dispersions of pure parti-
cles of drug) is of interest in the context of better understanding of how amorphous solid
dispersions lead to enhanced bioavailability [119]. By investigating the properties of
solutions formed from the dissolution of amorphous solid dispersions of PVP and beta
carotene, Tachibana and Nakamura first reported that amorphous solid dispersions can
lead to the formation of colloidal particles [120]; since then, numerous researchers have
demonstrated that amorphous solid dispersions are capable of generating colloidal-sized
species when dissolved in aqueous solution [64,106,120
122].
Although the formation of colloidal dispersions from amorphous solid dispersions
has been widely reported, the formation mechanism and the factors in
-
uencing the size
and stability of these species are not well understood. In recent studies, it has been
demonstrated that when suf
ciently high supersaturated solutions are generated in
aqueous media, poorly water-soluble compounds can undergo liquid
liquid phase
separation (LLPS) [54,117,119]. When a certain concentration has been exceeded, a
dispersed phase that consists of submicrometer particles is produced, provided crystal-
lization does not occur
-
first. The LLPS concentration is consistent for a given medium
and temperature,
is predictable, and can be related to the theoretical amorphous
“
solubility
”
[119]. Since amorphous solid dispersions dissolve to generate supersaturated
