Chemistry Reference
In-Depth Information
Amorphous
drug
Solvated
drug
Crystalline
drug
Figure 6.3.
Theoretical energy differences between crystalline, solvated, and amorphous
materials. These energy differences give rise to very different physicochemical properties and
in vivo
performance.
Due to the lack of long-range order, amorphous materials are more energetic than their
crystalline counterparts (see Figure 6.3 for an illustration). This gives rise to certain
advantages of amorphous materials relative to crystalline materials, including higher
speci
c volume, higher solubility, and bioavailability, but also certain disadvantages,
including risk for lower physical and chemical stability. Conversion of the amorphous
phase to a crystalline form with signi
cantly lower solubility can lead to bioperformance
loss [41,42].
Many studies have demonstrated the advantages of formulating drugs as amor-
phous forms [43
53]. The success of amorphous solids as a supersaturating dosage
form depends on the choice of processing conditions to yield a pure amorphous solid
with no or minimal crystallization of the amorphous drug during storage and upon
dosing. In dissolution studies of amorphous solids, API solution concentrations much
higher than those achieved using the corresponding thermodynamically stable crys-
talline form are often observed, indicating that supersaturated solutions are being
generated [48]. Hancock and Parks demonstrated an apparent increase in the solubility
and dissolution rate of amorphous indomethacin relative to its crystalline
-
-poly-
morph [45]. The solubility of amorphous indomethacin was a factor of 5 higher
than that of the crystalline form. Similarly, Law et al. found the apparent solubility
of amorphous ritonavir to be 10-fold higher than that of its crystalline counterpart [50].
Typically, these increases in solubility will translate into an increase in oral absorp-
tion if the enhanced concentrations can be maintained long enough for absorption
to occur.
While an increase in solution concentration can be attained with a neat, unstabilized
amorphous solid, the longevity of the supersaturation achieved during dissolution of the
amorphous form is of critical importance, as dictated by the physiological conditions
discussed in Section 6.1. The theoretical solubility advantage of an amorphous material
(illustrated by Equation 6.4) [54] can be estimated using the experimentally determined
crystalline solubility (
C
eq
), the free energy difference between the crystalline and
γ
