Chemistry Reference
In-Depth Information
solid dispersions and also enhance polymer interactions. Parameters such as CMC, cloud
point, and interaction energies with the drug molecule can also in
uence the effective-
ness of the surfactant in the dispersion formulation [46b]. Compatibility between the
drug, polymer, and other additives in the solid dispersion is critical in the prevention of
phase separation within the matrix and optimal dissolution during contact with aqueous
media in the GI tract. The free energy of mixing between two components can be
described as follows (from Flory
-
Huggins theory for polymer systems) [4c]:
ln
ln
φ
A
r
A
φ
B
r
B
Δ
G
mix
RT
φ
A
φ
B
χφ
A
φ
B
:
(2.3)
This relationship depends on the entropy and enthalpy of mixing the drug (A) and
polymer material (B).
r
is the number of monomer units (for small-molecule drugs,
r
=
1),
φ
is the volume fraction of the components, and
χ
is the interaction parameter. The
greater the value of
, the higher the enthalpy value and the system is prone to
immiscibility. An increase in the entropic terms (
χ
(first two) favors mixing. Phase diagrams
to predict phase separation boundaries can be determined by plotting the free energy of
mixing and temperature versus volume fractions of mixture components.
As an example, the diffusion of the drug dexamethasone within systems of a triblock
PEO
PEO copolymer in conjunction with surfactants such as SDS, dodecyltri-
methylammonium bromide (DTAB), and polyoxyethylene(10)isooctyl phenyl ether
(TX-100) was investigated [47]. The interaction parameters between the surfactants
and block copolymer systems were calculated by iteration between the following
equations (assuming component 1 is the surfactant and component 2 is the polymer):
-
PPO
-
ln
α
1
CMC
mix
=
X
1
CMC
1
1
X
1
β
;
(2.4)
2
X
1
ln
α
1
CMC
mix
=
X
1
CMC
1
2
ln
f
1
α
1
CMC
mix
g=
1
X
1
CMC
2
1
;
(2.5)
1
X
1
1
CMC
mix
α
1
CMC
1
1
α
1
CMC
2
;
(2.6)
where
α
1
is the
mole fraction of component 1 in solution,
X
1
is the mole fraction of component 1 in the
mixed micelles, and CMC is the critical micelle concentration of respective components
and their mixtures. DTAB and SDS both had negative values of
β
is the interaction parameter between the surfactant and the polymer,
ranging between
3.0
and
4.0, demonstrating favorable synergistic behavior with the triblock copolymer.
When the copolymer alone was mixed with dexamethasone at low concentrations (i.e.,
below 0.2 mM), its solubilization in water doubled. However, at concentrations of 1mM
or greater, the drug release pro
β
le in aqueous media showed a decline in the time to reach
its maximum concentration, showing stronger associations between the polymer and the
drug. In the presence of surfactants, the diffusivity of drug increased with increasing
SDS, DTAB, or TX-100 concentration. This behavior was shown when all components
