Chemistry Reference
In-Depth Information
Figure 2.12.
Phase diagram of a
two-component discontinuous
solid solution. (Adapted from
Ref. 3b.)
typically as 5% or greater miscibility of one component in another [3b], supersaturation
of the drug may be achieved to a greater extent due to the more intimate arrangement
between drug, polymer, and surfactant. Before conducting extensive studies for the best
solid dispersion components, a simple physical mixture can be quickly screened to gain a
qualitative understanding of the functionality by blending or granulating components
together and
filling into a capsule or compressing into tablet form. The prototype dosage
form can be studied in representative dissolution media and also simulated fed and fasted
conditions. The effectiveness of drug dissolution, solubilization, and precipitation
inhibition can be estimated by monitoring the concentration of drug in solution as a
function of time.
2.3.1 The
“
Spring and Parachute
”
Model
Drug bioavailability is dependent upon the propensity to remain soluble or supersaturated
in the gastrointestinal (GI) tract. In the supersaturated state, the drug maintains a high
thermodynamic activity and
flux through the intestinal tract, increasing its absorption.
Agents such as polymers or surfactants used alone in a solid dispersion may either improve
the aqueous solubility of a crystalline drug or improve the longevity of the dissolved
amorphous form. However, a combination of ingredients can be bene
cial in cases where
kinetic and thermodynamic approaches to stabilization require re
nement to achieve a
certain drug concentration, and where the solubilized drug is labile enough to precipitate
into more stable crystalline forms. For example, the oral bioavailability of tacrolimus and
itraconazole was found to increase with the use of solubilizers and precipitation inhibi-
tors [45]. To overcome this phenomenon, a combined
model to
improve drug solubility and stabilization over a longer time window has been proposed by
Guzman and several other researchers [46] to de
“
spring and parachute
”
ne a drug salt form, polymer, or surfactant
system to improve the solubility/supersaturation (or
“
spring
”
) and curtail the onset of
precipitation or crystallization by adding an inhibitor (or
“
parachute
”
) such as a polymer
(cellulosic, PVP, or PEG). The
is typically a higher energymaterial that facilitates
dissolution and supersaturation of the drug in the GI tract, and the
“
spring
”
is the
excipient that delays nucleation of the soluble high-energy drug form. Figure 2.13 explains
“
parachute
”
