Chemistry Reference
In-Depth Information
of the crystal, thus producing both kinetic and thermodynamic solubilities of the system.
Recent studies have described a thermal method of measuring the equilibrium solubility of
crystal drugs in various polymers, and have shown that these equilibrium solubilities are
generally quite low, suggesting that most practical amorphous solid dispersions with the
usual therapeutic dose ranges represent metastable solutions of API in polymer [47]. Thus,
it is critical that consideration be given to how one can maintain the physical stability of
amorphous API for periods required during the storage of the solid dosage form.
1.9 SOLID-STATE CRYSTALLIZATION FROM AMORPHOUS
DISPERSIONS
We have already mentioned that the critical steps in preventing solid-state crystallization
of an amorphous API are (i) inhibition of nucleation and crystal growth rates by reducing
molecular mobility of the API, and (ii) direct interaction of a nucleation inhibitor with the
API. The term direct interaction is used here since the formation of any miscible
amorphous dispersion generally requires interaction between the API and polymer, most
often through hydrogen bonding, whereas inhibition of nucleation requires interaction of
the polymer with the speci
c functional groups on the API that are critical for nucleation.
From the previous discussion of the amorphous state and amorphous mixtures, and
Equation 1.32, we can now see, in practical terms, how an amorphous excipient with a
high
T
g
and suf
cient miscibility with an API would be able to produce relatively high
values of
T
Tgmix,
, compared with the
T
g
of the API alone, and hence reduce the molecular
mobility of the API when stored at a particular temperature. Such a decrease in molecular
mobility of the API in turn might be enough to reduce tendencies for crystallization of the
API under the normally required storage conditions of 2
-
3 years. For example, if an
amorphous API has a
T
g
value of 320 K (47
°
C), alone, it would have to be stored near
0
Ctobeat
T
g
T
equal to at least about 50 K, roughly the temperature range where
diffusive molecular mobility is reduced to time periods suitable for preventing crystalli-
zation during storage over a few years. To store a sample of this API at 25
°
C for a few
years without crystallization, for example, one would need to raise the
T
g
of the system to
about 75
°
C (348 K) or higher, which according to Equation 1.32, and the individual
T
g
values would require a minimum of about 30%w/w of a miscible polymer having a
T
g
of
150
°
C (423 K). To store the sample at 40
C (313 K) for a few years, one would have to
°
°
raise the
T
g
to roughly 90
C (363 K) by using about 50% w/w of this polymer.
Figure 1.19 presents experimental studies of the percent of crystallization at 30
°
Cof
°
amorphous indomethacin with a
T
g
of 42
C (315 K) alone and mixed with PVPK90,
having an average molecular weight of about 1.5 million and a
T
g
of 180
°
C (453 K) [43].
Here, it can be observed that physical mixtures of the amorphous indomethacin and PVP
containing 5% w/w PVP exhibit identical rates of crystallization with indomethacin
alone. Such behavior was also observed at all concentrations up to 90% w/w PVP. Note
in Figure 1.19 that only 5% w/w PVP in the form of a miscible mixture prevents any
crystallization up to a period of 6 months, indicating a signi
°
cant reduction in the rate of
nucleation and crystal growth. It was shown further that increasing the amount of
polymer in the dispersion to 30% w/w PVP prevented crystallization for over 2 years.
