Chemistry Reference
In-Depth Information
Figure 8.5.
Relative normalized oral bioavailability as a function of percent dissolved at 15min
for a number of itraconazole-containing formulations.
E100 and EUDRAGIT E100
VA formulation were superior in terms of the rate of
dissolution, they had the poorest oral bioavailability. The use of sink-based dissolution
methods can therefore obfuscate formulation selection if traditional paradigms are
followed.
The development of the marketed dispersion-based formulation for etravirine
(Intelence
), an anti-HIV therapy, also demonstrated the importance of dispersion
processing with regard to a useful biopharmaceutical effect and the essential role of
clinical testing in arriving at an optimal dosage form [43,44,103]. Etravirine is a poorly
water-soluble drug with a number of challenging physicochemical properties that impact
its ability to be formulated [44]. Initial screening studies found that the drug was not
orally bioavailable even when the crystalline API was milled into the Nanocrystal
formulation. This meant that early formulation assessments were completed using either
a PEG400 solution or a PEG4000 dispersion. These systems rapidly proved themselves
to be of limited value based on pill burden and low oral bioavailability. Based on the
possible utility of solid dispersions, additional screening was conducted on various
processing approaches [44]. Etravirine is a poor glass former and forms an unstable glass.
Attempts to render the drug amorphous were complicated by its temperature sensitivity
that precluded melt-based strategies. Furthermore, other techniques including spray
drying did not provide for useful amorphous material. Eventually, cryomilling appeared
to be the most suitable method with the amorphous phase generated by milling the API
for 3 h at
196
-
PVP
-
C [104]. While the
T
g
of the cryomilled material may have been
suggestive of good stability (
T
g
≈
°
C), the
T
g
/
T
m
suggested that a fragile glass was
generated [47]. In addition, when the material was stored in open conditions at 30
100
°
°
C
