Chemistry Reference
In-Depth Information
Figure 1.5.
Various methods of producing the amorphous state.
of preparation of amorphous solids must be outlined in detail when reporting any value
of
T
g
.
In this regard, so far we have focused only on the preparation of an amorphous solid
by melting the crystalline form and then rapidly supercooling the melt to well below the
melting temperature so as to avoid crystallization. Indeed, this is the basis for using the
hot melt extrusion method to produce amorphous solid dispersions (ASDs), a topic that
will be discussed more fully in later chapters. However, as described in Figure 1.5, it is
also possible to produce amorphous forms by rapidly condensing molecules directly
from the vapor state at low temperatures, or by causing molecules to rapidly precipitate
from solution, where in both cases crystallization is kinetically avoided. Although
preparation from the vapor state is not currently used as a process to form amorphous
pharmaceutical products, there is evidence that such a method can lead to unusually
stable glasses [7]. Precipitation from solution to form an amorphous solid is the basis for
the widely used processes of lyophilization and spray drying (SD), where lyophilization
has proved particularly useful in forming sterile amorphous protein products for
parenteral use, and spray drying for the development of solid dispersions for oral
and pulmonary use. As seen in Figure 1.5, it is also possible to form the amorphous state
directly from a crystal by introducing mechanical stress that is suf
cient to create crystal
defects that eventually coalesce into a completely amorphous form [8]. Likewise, it has
been shown that amorphous forms can be created by the dehydration of crystal
hydrates [9] or by the desolvation of crystal solvates [10], where in both cases
the desolvated crystal lattice collapses because of the free volume left by removing
the solvent from the crystal lattice. Although such methods that disrupt the crystal lattice
have not yet been found practical for the preparation of pharmaceutical amorphous
systems on a large scale, the importance of such phenomena has been demonstrated
in situations where crystalline solids are inadvertently rendered partially amorphous by
processes such as milling and drying, leading to small amounts of disorder and unanticipated
