Chemistry Reference
In-Depth Information
C
B
A-Crystalline
B-Spring
C-Spring and parachute
C
eq
A
Time
Figure 6.4.
Graphical illustration of spring and parachute effect [60].
et al. [60] described the generation and stabilization of a metastable supersaturated state
using the
model (Figure 6.4). Higher energy forms such as
amorphous solids that transiently increase solubility relative to that of the stable
crystalline form were likened to the
“
spring and parachute
”
The higher energy state of amorphous
solids can translate into an increase in solubility and drug absorption, but rapid
crystallization back to the more stable and less soluble crystalline form can limit this
bene
“
spring.
”
; they
maintain supersaturation for an extended time period. The enhanced and prolonged
solubilization could lead to further increases in absorption and bioavailability.
The use of amorphous solid dispersions has become a well-known strategy for
inhibiting crystallization, as the amorphous solid dispersions can have increased physical
stability over neat amorphous material. For example, the crystallization tendency of
AMG-517, an insoluble compound, was tested on a neat amorphous drug and various
drug loads in a HPMC-AS (hydroxypropyl methyl cellulose acetate succinate) solid
dispersion. It was found that the HPMC-AS polymer slows the crystallization rate of
amorphous AMG-517 [61]. Polymers can prevent or delay crystallization of amorphous
drug during dissolution (
in vitro
and in the GI) as well as stabilizing amorphous drug
against recrystallization in solid dosage forms to provide adequate shelf life. Higher
concentration
t [60]. Additives that inhibit crystallization were described as
“
parachutes
”
les may be attained with amorphous solid dispersions compared
with those achieved with the pure amorphous API, indicating that certain polymer
excipients function to further enhance solution concentrations by inhibiting API
crystallization in solution. Using beagle dogs as an animal model, Law et al. studied
the absorption of poly(ethylene glycol) (PEG)
-
time pro
-
ritonavir amorphous solid dispersions
with different drug loadings [51]. The PEG
-
ritonavir solid dispersions were prepared
using the solvent evaporation
-
fusion method. Amorphous solid dispersions containing
10
cant increases in exposure over crystalline drug. For
example, a 10% amorphous solid dispersion exhibited increases of 22- and 13.7-fold in
-
30% drug exhibited signi
