Chemistry Reference
In-Depth Information
Figure 1.23.
Comparison of dissolution rates and levels of supersaturation for a crystalline
compound and its amorphous dispersion with HPMCAS (reproduced with permission from Ref.
53. Copyright 2008, American Chemical Society).
formation of API
polymer amorphous dispersions can greatly inhibit solid-state crystalli-
zation during storage even at low polymer concentrations, and that the best polymers in this
regard tend to directly interact with the API through hydrogen bonding [48], it seems likely
that such polymers could also inhibit solvent-mediated crystallization after dissolution of
the API and polymer by such interactions in solution. A number of studies, indeed, have
shown that polymers, such as PVP, HPMC, andHPMCAS, added to an aqueous solution at
solution concentrations that might be expected from a typical API
-
-
polymer dispersion
signi
cantly inhibit nucleation, decrease the rate of crystal growth, andmaintain high levels
of supersaturation over extended periods of time [54,55]. That this actually occurs with the
dissolution of API
polymer dispersion is illustrated in Figure 1.23 [53]. Recently,
increasing evidence has been accumulated to suggest that supersaturation levels of
API administered as API
-
polymer amorphous dispersions can be maintained at high
levels by additional possible mechanisms. For example, as illustrated in Figure 1.24, it
has been suggested that API
-
HPMCAS systems upon contact with a dissolution
medium initially precipitate as complex high-energy colloidal noncrystalline phases
that can retard crystallization and produce a high degree of supersaturation [53]. This
behavior has been attributed to the relatively hydrophobic and surfactant-like nature of
HPMCAS, and in this regard it has also been suggested that it is likely that such
colloidal systems form during
in vivo
dissolutionbyinteractingwithcolloidforming
gastrointestinal materials such as fatty acid derivatives and bile salts. It has also been
recently shown that a relatively hydrophobic API, ritonavir, in PVP dispersion at high
levels of supersaturation can phase separate as a colloidal API-rich liquid phase that
resists crystallization and maintains high levels of supersaturation [56]. Greater
detailed discussion of all of these principles related to the inhibition of solid-state
-
