Chemistry Reference
In-Depth Information
AUC and
C
max
, respectively. The increase in solution concentration was higher than
that reported for pure amorphous ritonavir (based on
in vitro
study results) [50].
Similarly, an animal bioavailability study in dogs was performed to compare a capsule
containing 1:2 (w/w) itraconazole:HPMC-P (hydroxypropylmethyl cellulose phthalate)
amorphous solid dispersion, prepared by spray-drying, with those
filled with crystalline
itraconazole [62]. The itraconazole:HPMC-P amorphous solid dispersion exhibited
signi
cantly higher
C
max
and bioavailability than the crystalline material alone. The
C
max
was
35-fold higher compared with crystalline material, while the systemic
exposure was 511
17
-
∼
1911% of that observed from crystalline itraconazole. Finally, an oral
bioavailability study was performed in fasted cynomolgus monkeys using a spray-dried
amorphous solid dispersion of a poorly water-soluble drug molecule (AMG-517) and
HPMC-AS [47]. Pharmacokinetic studies of AMG-517 in capsule [15 wt% AMG-517
in HPMC-AS blended with 5 wt% SDS (sodium dodecyl sulfate)] in monkeys increased
AUC and
C
max
by 163 and 145%, respectively, in comparison to an OraPlus suspension
control,
-
cant improvement in exposure. In addition, this study
provides a view of the power of amorphous dispersions over crystal engineering
approaches, as AMG-517 is a sorbic acid cocrystal in the OraPlus vehicle that was
used for early clinical studies of the compound [63].
The above-mentioned case studies demonstrate that amorphous solid dispersions
provide improved physical stability over neat amorphous material and enhanced oral
bioavailability for poorly soluble compounds over crystalline APIs. We also illustrated
the physiological importance of solubility, dissolution, and supersaturation in formula-
tion design and characterization. The next section will discuss the impact of polymers on
dissolution and solubility of amorphous solids.
indicating a signi
6.3 THE RELATIONSHIP OF POLYMER PROPERTIES WITH
SOLUBILITY, DISSOLUTION, AND SUPERSATURATION
Numerous pharmaceutically acceptable polymers have been used as carriers to prepare
solid dispersions in the literature [64]. These polymers help maintain the amorphous state
of the drug upon storage and are critical to the dissolution and solubilization of the drug
upon
in vitro/in vivo
release. Although not an exhaustive list, the following
ve common
classes of polymers are found in the literature:
Cellulose-derived polymers [65] (i.e., methyl cellulose, hydroxyl propyl methyl
cellulose, and hydroxyl propyl methyl cellulose acetate succinate)
PEGs (polyethylene glycols of various chain lengths) and pegylated materials
such as surfactants [66] (i.e., poloxamer [67,68], vitamin E TPGS, Solutol
TM
/
Soluplus
TM
)
Acrylate-based polymers (i.e., EUDRAGITS
TM
)
Polyvinyl pyrrolidine-derived polymers/copolymers [69,70] (i.e., PVP or PVP VA)
Biodegradable polylactide/glycolide polymers
The general structure of each polymer class can be found in Figure 6.5.
