Chemistry Reference
In-Depth Information
supersaturation can only be tested under nonsink conditions. In late-stage formulation
development, the QC test is usually conducted under sink conditions for the solid dosage
form and is provided to regulatory agencies [94,95].
Some published studies rely on biorelevant dissolutions alone to evaluate the
performance of amorphous solid dispersions. Tho et al. used pH 7.3 phosphate buffer
modi
ed with 1mM sodium taurocholate to evaluate the dissolution and release perform-
ance of ritonavir melt extrudates, comparing the performances with water and aqueous
buffer media [74]. In another study by Boetker et al., achlorhydric media (pH 3.5 acetate
buffer) were used to demonstrate the advantage of amorphous amlodipine over crystalline
forms [96]. Mehanna et al. studied the application of pluronic block copolymers in the
creation of amorphous solid dispersions of tadalafil. Ozaki et al. [97] used dissolution in
FaSSIF media to gauge the performance of these amorphous solid dispersions versus the
crystal form, showing a signi
cant increase in solubility and dissolution rate for the solid
solutions versus the free tadala
l and tadala
l comixedwith pluronic F-127 [98]. Lust et al.
studied the ef
cacy of multiple polymers as carriers for amorphous solid dispersions of
piroxicam with SGF as the dissolving media [99]. Amorphous dispersions of piroxicam
showed enhancement of both the rate and extent of dissolution versus the crystalline form.
In Ref. [97], the authors used FaSSIF to determine the supersaturation and rate of
crystallization of poorly soluble APIs formulated as amorphous solid dispersions versus
the crystalline forms.
For amorphous formula-
tions that form drug precipitates (nano- or micrometer-sized particles) during dissolution,
it is of great interest to determine solution concentration without interference from these
particulates. The dynamic dialysis method has been widely used to study the drug release
rate of nanoparticulate systems [100
6.4.2.2 Newly Developed Dissolution Protocols
105]. For example, Leo et al. studied the
in vitro
release of doxorubicin from doxorubicin
-
-
gelatin nanoparticles (submicrometer particles,
<
m) in the absence as well as presence of a proteolytic enzyme that degraded the
gelatin carrier [102]. Nagarwal et al. performed dynamic dialysis studies to measure the
release of 5-
1
μ
5-fluorouracil (5-FU) from chitosan-based nanoparticles targeted for ophthal-
mic delivery of 5-FU [103]. In this study, a membrane with a speci
c molecular weight
cutoff (MWCO), typically 12 KDa or less, was used to separate the donor and acceptor
compartments. The membrane served as a physical barrier to prevent diffusion of
nanoparticles from the donor to the acceptor side and drug concentration in the acceptor
compartment was monitored with time. To maintain sink conditions and prevent reverse
drug diffusion, the volume of the dissolution medium in the donor compartment was
about 10 times less than that in the acceptor compartment. The diffusion rate of the drug
from the donor to the acceptor compartment was determined using the concentration of
solubilized drug in the acceptor compartment, the permeability of the drug across the
membrane, and the area of the membrane. If the solution concentration in the donor
compartment is not replenished quickly by undissolved drug particles, diffusion becomes
dissolution limited.
The dynamic dialysis method can be used to characterize and compare the
in vitro
dissolution rate of different amorphous solid dispersion formulations of the same drug.
Upon dissolution of an amorphous solid dispersion in a biorelevant media, drug can exist
