Chemistry Reference
In-Depth Information
PAA and the hydroxyl group of acetaminophen relative to the carbonyl group of PVP.
These two examples suggest that the formation of speci
c interactions between the drug
and the polymer appears to in
uence the polymer
'
s ability to stabilize the drug in the
amorphous state.
The stabilization ability of a particular polymer also appears to depend inherently on
the crystallization tendency of the pure amorphous drug. Thus, it has been observed that
amorphous ketoconazole does not recrystallize upon reheating until the melting point,
and only by adding crystal seeds can recrystallization of the glass be initiated [84]. In the
presence of PVP, recrystallization of the amorphous drug, even in the presence of seed
crystals, could not be observed for up to 30 days of storage at room temperature and 52%
RH. In this instance, no specific drug-polymer interactions could be detected, so the
stability of PVP
ketoconazole solid dispersions was attributed to the stability of pure
amorphous ketoconazole. Ritonavir, in a solid dispersion with polyethylene glycol
(PEG) 8000, is another interesting example of a drug that forms a fairly stable glass. In
this solid dispersion, the PEG is crystalline and therefore in a different phase from the
drug. In spite of this phase separation, solid dispersions stored in the absence of moisture
at 25
-
C were stable for over 18 months [86], and this high stability can be attributed to
the stability of pure amorphous ritonavir in the absence of the polymer. These studies
show that polymers will be more effective stabilizers for compounds that are inherently
stable in the glassy state. Hence, the higher the crystallization tendency of the pure
amorphous drug, the greater the polymer must modify the amorphous phase of the drug
to prevent devitri
°
cation.
5.5 ASSESSMENT OF PHYSICAL STABILITY
There are a number of challenges inherent in assessing the physical stability of
amorphous solid dispersions. First, physical stability testing needs to be conducted in
order to evaluate which is the best polymer from the perspective of inhibiting crystalli-
zation, as well as promoting dissolution. Not only must a speci
c polymer type and grade
be selected, but the drug loading must also be determined. This can be a dif
cult task
given the number of potential polymers available, as well as restrictions on the amount of
drug substance available early in formulation development. A second challenge arises
from the typically low drug loading found in amorphous solid dispersions, whereby
signi
cant analytical limitations exist in detecting crystallization when the drug com-
prises a low overall weight fraction of the dispersion. Third, due to the lack of
rst
principle models that can accurately describe nucleation, growth, and overall crystalli-
zation kinetics in amorphous solid dispersion powders as a function of temperature and
water content, it is very dif
cult to perform accelerated stability testing and extrapolate
the results of these tests to predict stability under ambient conditions.
Crystallization can either be evaluated qualitatively or quantitatively. Qualitative
determinations are useful during formulation design, when it is often suf
cient to detect
if any crystalline material is present. Quantitative determination of crystallization
kinetics is important to set speci
cations for maximum crystallinity allowed, as well
as to help extrapolate kinetic measurements to longer time periods to ensure adequate
