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In-Depth Information
be explored to investigate the dissolution mechanism at dose-relevant concentrations.
This often requires the characterization of insoluble drug particles. Submicrometer drug
particles can form during the dissolution study under certain conditions and present
additional challenges for determining truly dissolved drug concentration. Having the
appropriate sample clari
cation method should be a critical component for any dissolu-
tion method for amorphous solid dispersion formulations. Animal PK studies can be
leveraged to test the biorelevance of the
in vitro
dissolution method before human studies
to derisk the clinical formulation. For amorphous solid dispersion formulations, physical
changes such as crystallization or amorphous
amorphous phase separation can take
place under stability conditions. The availability of a biorelevant dissolution method
could be extremely useful to define the failure mode without resorting to extensive
animal or human PK studies. Finally, dissolution of amorphous solid dispersions in
the human GI tract is a highly dynamic process that is affected by many factors that can
be dif
-
cult to mimic simultaneously. Although developing a predictive
in vitro
method
or establishing IVIVC may remain a challenging task for pharmaceutical scientists,
progress has been made with new tools and techniques that provide more quantitative
information.
6.5 SOLUBILITY AND DISSOLUTION MEASUREMENTS FOR
AMORPHOUS DISPERSIONS: SUMMARY, CONCLUSIONS, AND
RECOMMENDATIONS
It has been estimated that
ed as BCS II and
IV compounds, and therefore have low solubility [136], and that the problem is even
worse in discovery pipelines [137]. Consequently, there has been an increasing interest
in crystal (e.g., salts, cocrystals, and amorphous forms) and formulation engineering
(e.g., particle size control, nanoformulations, and amorphous dispersions) strategies to
mitigate poor solubility. The increased interest in these techniques needs to be seen in
light of the tight link between solubility, dissolution, and good oral absorption.
The latter is one (out of several) important prerequisite for a commercial oral drug.
The majority of crystal and formulation engineering approaches follow the strategy of
enhancing the time span between dissolution and precipitation (illustrated in Figure 6.1)
suf
40%of the world
'
s top oral drugs are classi
∼
40]. Among these
approaches, amorphous solid dispersions have proven especially successful, and as
recently reviewed, improved bioavailability in 82% of 40 amorphous dispersion case
studies [87].
As presented in this chapter, solubility and dissolution are intimately interconnected
but not identical properties. Solubility is a thermodynamic parameter and is de
ciently to enable drug absorption before precipitation [37
-
ned by
the concentration in solution in equilibrium with excess solids. As recently reviewed, a
major consideration when conducting solubility measurements is determining when
equilibrium is reached. Therefore, theoretically, measuring solubility would involve
sampling the solubility experiment as a function of time until the solubility and the solid
phase is constant. This is not a feasible method for amorphous materials as they are
inherently metastable phases [85].
