Chemistry Reference
In-Depth Information
result, displayed a very low aqueous solubility. In water,
it
is less soluble than
marble [14].
Aqueous solubility alone is neither a necessary nor a suf
cient condition for an
effective, orally delivered drug, but it is one critical parameter that development scientists
have to account for. As most oral compounds are absorbed in the small intestine, the API
has to reach a concentration in the intestinal lumen suf
cient to drive it into the systemic
circulation. For compounds with higher gut permeability, a lower solubility may be
acceptable. Any compound, however, has to have a certain minimum solubility given
its permeability
nity even matters, because it will never
reach adequate levels at its target. Figure 7.1a illustrates this phenomenon for a
—
or no level of binding af
fictional
CompoundX.
F
a
, or fraction absorbed, is limited by both solubility (logarithmically scaled
on the
x
-axis) and permeability (measured in a Caco-2 cell culture model and scaled on the
y
-axis). Within a certain narrow range, in the case of the compound depicted, low solubility
can still result in acceptable
F
a
if the compound proves to permeate well. However, inmost
of the range of possible solubilities, solubility may affect whether Compound X will be
absorbed suf
ciently or not. Hence, the low solubility of crystalline telaprevir meant that,
effective as it was
in vitro
, it would be dif
cult to dose the drug in its crystalline state.
Later research, following the eventual commercialization of telaprevir, would inves-
tigate this Catch-22 as a generalizable trend. The problem, which we came to call the
potency
insolubility conundrum
, has long been widely recognized in the pharmaceutical
industry, which has responded with empirical attempts to understand and manage it. For
instance, the Biopharmaceutical Classi
-
2 matrix of com-
pounds, describing them as having high or low gut permeability and high or low
solubility, with different guidelines for each quadrant. Lipinski
cation System offers a 2
×
s Rule of 5 offers useful
rules of thumb to guide development decisions [9]. Only recently, however, have
explanations for the fundamental structural and thermodynamic connection between
potency and insolubility been elucidated [22]. The investigation that led to these
'
findings,
echoed the type of studies that could be conducted at the lead optimization phase of
discovery, in which the two possible explanations for a compound
'
s insolubility
—
its
hydrophobicity and its propensity to form tight crystal lattices
—
were analyzed sepa-
rately. The free energy of solvation
—
the transfer of the molecule from gas to solution
—
was distinguished from the free energy of sublimation
the transfer of the molecule from
crystal to gas. In Figure 7.1b, hydrophobicity is depicted on the vertical axis and tightness
of crystal lattice on the horizontal axis. Therefore, a compound in the lower-left quadrant
of the graph would readily dissolve in water. A compound in the upper quadrants would
likely be too hydrophobic for much aqueous solubility. But for compounds in the lower-
right quadrant, the cause of insolubility is not aversion to water but the strength of the
crystal lattice. Hence, disrupting this lattice could increase overall solubility. Hence, the
solubilities of itraconazole as well as telaprevir can be increased by two orders of
magnitude once the strength of the crystal lattice is eliminated as an obstacle. (Com-
pounds X, Y, and Z are
—
fictional data for illustrative purposes.)
findings, in turn, suggest a possible framework for addressing this problem
with alternate material forms that interrupt the normal, tight formation of a crystal lattice.
For telaprevir, cocrystals and amorphous dispersions were initially investigated, but
R&D management decided to move only amorphous dispersion into development.
These
