Chemistry Reference
In-Depth Information
desorb from the crystal surface, and thus continues to inhibit growth even when no longer
present in the solution phase.
The studies conducted with sulfathiazole only extended to supersaturation ratios of
around 2. This is not necessarily representative of the levels of supersaturation that would
be anticipated following dissolution of an amorphous solid dispersion. The crystal growth
rates of felodipine were investigated as a function of
S
in the presence and absence of
different amounts of HPMC [140]. HPMC was found to adsorb to felodipine crystals, with
a plateau in the adsorption isotherm at a polymer concentration of around 1
μ
g/ml.
Quantitative crystal growth rate studies revealed that the impact of HPMC on felodipine
crystal growth rate plateaued at around this polymer concentration; thus, increasing the
polymer concentration much beyond this value did not lead to further inhibition of crystal
growth. The ability of HPMC to inhibit crystal growthwas found to be highly dependent on
S
. At lowvalues of
S
, HPMCwas quite effective at slowing crystal growth. However, at a
S
of 10, the supersaturation expected to be reached by dissolving an amorphous solid
dispersion, the highest concentration of HPMC reduced the crystal growth rate by only a
factor of about 2. Thus, in the presence of crystal seeds, HPMC was not able to prevent the
rapid desupersaturation of supersaturated felodipine solutions.
Studies with ritonavir have also shown that polymers aremuchmore effective at low
S
,
but lose effectiveness as the driving force for crystallization increases [145]. Thus, at a
supersaturation corresponding to the amorphous solubility of ritonavir, polymers could not
reduce desupersaturation rates to a large extent in solutions to which seed crystals were
added. Furthermore, it was observed that the chemistry of the polymers was very important
for determining how effectively they can alter the kinetics of crystal growth when present at
comparable concentrations. For ritonavir, the more hydrophilic and very hydrophobic
polymers were found to have little impact on crystal growth rates, while a group of
moderately hydrophobic polymers was found to be most effective at reducing the crystal
growth rate. The extent of inhibition was also dependent on the ionic strength of the
medium, as well as on the pH when the polymer was ionizable [146]. As the ionic strength
increased, the polymers became relatively more effective at inhibiting growth. For anionic
polymers, it was noted that they are bettermodi
ers of crystal growthwhen they are ionized,
relative to when no charge is present. It should also be noted that a polymer that is effective
for one compound may not be a useful inhibitor for another compound. For example,
PVP/VA was observed to be one of the better inhibitors evaluated for celecoxib and
efavirenz crystal growth, but it was completely ineffective for ritonavir [147]. Finally, it has
been observed that the optimum polymer for inhibiting nucleation may differ from the
optimumpolymer for delaying crystal growth [147]. This observation suggests that polymers
may interfere with different crystallization processes via different mechanisms and under-
scores further the general lack of understanding of how polymers disrupt crystallization.
5.7 SUMMARY AND OUTLOOK
With the increasing number of developmental compounds exhibiting poor aqueous
solubility, there is little doubt that amorphous solid dispersions will be more widely
used for enhancing oral drug delivery. Some of the main challenges that remain to be
