Chemistry Reference
In-Depth Information
polymer-rich layer is a slow process. These two release mechanisms may occur
simultaneously if the drug particles are partially dissolved in the polymer-rich diffusion
layer before being released. It is important to note that at low drug concentrations, the
release mechanism could be either carrier drug release or carrier-controlled release [72].
Using a similar model, Simonelli et al. described the rate of release of sulfathiazole from
compressed tablets containing PVP. The apparent solubility and the rate of dissolution of
sulfathiazole were signi
cantly increased when sulfathiazole was coprecipitated with
PVP, because coprecipitation resulted in the formation of a higher energy (amorphous)
form [76,77]. The proposed model describes a situation in which there is an external layer
of sulfathiazole at lower PVP weight fractions and a controlling PVP external layer at
higher PVP weight fractions. At low PVP fractions, the relative rates of dissolution
appear to fall on a plateau, indicating that in these cases the sulfathiazole dissolution rates
were not affected by the presence of PVP in the tablets. This implies that the surface is
covered by a sulfathiazole layer that is controlling the rate of dissolution. Although this
model is oversimpli
ed, the data from the study agreed well with the model and allowed
a detailed characterization of the dissolution process.
Numerous attempts have been made to enhance apparent solubility and prolong
supersaturation of poorly water-soluble drug compounds. Although a number of
mechanisms by which polymers inhibit drug crystallization have been proposed in
the literature, there is no consensus on the polymer property that is primarily responsible
for inhibiting crystallization and thus for maintaining supersaturation. It has been
suggested that molecular forces, which are critical to holding together a crystal lattice,
can be disrupted by the use of a polymer and the onset of crystallization (nucleation) or
the growth of a crystal can be delayed [78]. Important intermolecular interactions
between a polymer and a drug molecule include speci
c interactions such as hydrogen
bonding and nonspeci
c interactions such as hydrophobic interactions. Examples of
each of the above-mentioned interactions and their importance are as follows.
Speci
c Intermolecular Interactions:
An important interaction in the crystal
lattices of many molecules is hydrogen bonding. Typically, a hydroxyl or carboxyl
functional group (hydrogen bond donor) will interact with a functional group such as
an amide or a sulfonamide (hydrogen bond acceptor). Since these interactions are
critical to forming and maintaining a crystalline lattice, if these interactions can be
disrupted, the result is a delay to either crystal nucleation or growth. Naringenin/
Hesperetin (common flavonoids) amorphous solid dispersions have been shown to
have favorable hydrogen bonding characteristics, in which phenolic hydroxyls
(hydrogen bond donors) from each of the
flavonoids are able to hydrogen bond with
PVP (a hydrogen bond acceptor), which in turn leads to prolonged supersaturation in
in vitro
dissolution studies. A number of studies have demonstrated the importance
of speci
c interactions in preventing crystallization of amorphous solid disper-
sions [79
81]. Although most of these studies were performed in the solid state (in
the absence of aqueous media), these interactions may also be important for solution
crystallization inhibition. For instance, Kestur et al. studied the effect of different
polymers (PVP, PAA, and PVAc) on the crystalline growth rates of amorphous
bifonazole and nimesulide [82]. It was found that crystalline growth rates in the solid
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