Chemistry Reference
In-Depth Information
can impact the surface area with important implications for crystallization; it has been
demonstrated that smaller particles crystallize more readily than larger particles [7,50], and
this can be attributed to the faster surface crystal growth rates discussed earlier. Smaller
particles with a larger surface area-to-volume ratio will thus be more susceptible to
crystallization. The particle size and surface area of amorphous materials will be highly
dependent on the preparation method, in particular if they are spray dried versus melt
extruded. In addition, crystallization from glasses can be induced from surface heteroge-
neities induced, for example, by scratching [50], while milling of amorphous materials is
known to promote crystallization [51]. The possibility of forming glasses with quenched-in
nuclei, a common observation for metallic glasses [52
55] that has also been noted for
organic glasses [56,57], also needs to be considered. Trapping of these nuclei in the glassy
matrix can effect the crystallization tendency of a material in two ways. First, these nuclei
can act as seeds for crystal growth below
T
g
over extended time periods as the glass
undergoes either
-
-relaxation andmolecules diffuse to the nuclei [58,59]. Second, the
presence of nuclei can greatly enhance the crystallization tendency during reheating of a
glassymaterial. This occurs due to the fact that during cooling the nuclei were formedwhen
the nucleation rate was maximum, but the growth rate was relatively low. Upon reheating
above
T
g
, the quenched-in nuclei are exposed to the maximum growth rate resulting in
recrystallization of the undercooled melt [52]. Hence, the presence of nuclei in the glassy
state may play an important role in dictating crystallization tendency from the glassy state.
α
-or
β
5.4 ROLE OF ADDITIVES IN MODIFYING SOLID-STATE
CRYSTALLIZATION
Single-component amorphous drugs will typically crystallize much faster than the
desired shelf life of the product, making it necessary to formulate them with crystalliza-
tion inhibitors. It has been known for many years that combining an API with a polymer
to form an amorphous solid dispersion can yield a solid with improved resistance to
crystallization during processing and storage as well as enhanced dissolution properties.
Other additives may also be present such as surfactants, which are often added to
improve processing or drug release characteristics. In this section, the role of additives in
modifying crystallization behavior during storage of amorphous solid dispersions will be
discussed. However, before evaluating the mechanism of crystallization inhibition by
polymers, it is
first necessary to discuss miscibility in multicomponent systems.
5.4.1 Miscibility
For amorphous solid dispersions, it is very important to consider the miscibility of the
various components since miscibility, or a lack of miscibility, can dramatically affect the
crystallization tendency of the API [60,61]. Excipients can only modify crystallization
behavior to a substantial degree when present in the same phase as the drug. Miscibility has
been extensively investigated for polymer
solvent system blends of two or more poly-
mers [62]. Following conventions developed in this arena, a miscible solid dispersion
consisting of a drug and a polymer can be de
-
ned as consisting of a single chemically
