Chemistry Reference
In-Depth Information
pH-dependent solubility pro
le dependent on its p
K
a
values. In addition, the solubility of
some drug molecules can be very sensitive to bile micelle concentration. Commonly
used polymers for amorphous solid dispersions have different solubility as a function of
pH. PEG, PVP, PVP
PVA, HPC, and HPMC are soluble at all pH conditions, while
HPMC-AS, HPMC-P, and EUDRAGIT L are enteric polymers that have very low
solubility under acidic conditions (
-
pH 5.5). EUDRAGIT E is soluble in buffer solutions
at pH values up to 5 and swells at higher pH values. Based on Newman et al.
<
'
s survey, the
most commonly used acidic mediums are 0.1 HCl and simulated gastric
fluid (SGF)
without enzymes [87]. Water and pH 6.8 buffer are most commonly used to characterize
the dissolution of amorphous solid dispersions at neutral pH, trailed by simulated
intestinal fluids (SIF) and surfactant solutions [87]. For an amorphous solid dispersion
containing a free base drug and a pH-independent polymer, an acidic solution such as
SGF or HCl may be an appropriate dissolution medium, while a pH 6.8 buffer may
provide better prediction for an amorphous dispersion containing nonionized drug in an
enteric polymer. If the solubility of the drug is highly dependent on micelle concentra-
tion, SIF or a surfactant solution is recommended.
The volume of the dissolution medium and the agitation speed are also important
factors for a dissolution test. The survey by Newman et al. shows that a wide range of
volumes from 25 to 1000 ml were reported, although the majority of the studies use
typical dissolution volumes of 500 or 900 ml for USP I and II [87]. The survey also
showed that a majority of the studies used an agitation speed between 50 and 100 rpm.
For early screening of amorphous solid dispersion intermediates, miniaturization of the
dissolution experiment is desired due to limited drug availability. Instead of standard
USP apparatus, small-scale dissolution studies in beakers or glass vials with magnetic
stirring could be considered to characterize and compare the dissolution of different
amorphous solid dispersions.
The sink condition is a critical component for a biorelevant dissolution method;
however, it appears to be underappreciated. Sink can be de
ned as utilizing a volume of
dissolution media that is 3
greater than the volume required for a drug to be saturated.
It was reported in a recent review that
-
10
×
“
only 8% speci
ed sink conditions, 6% speci
ed
non-sink conditions, and 86% did not specify the conditions used
[87]. The dissolution
behavior of amorphous drug is governed by the degree of supersaturation. Drug precipita-
tion can take place under supersaturated conditions and the rate of precipitation is affected
by the degree of supersaturation, drug physiochemical properties, and the interaction
between the drug and the polymer. In the early stage of amorphous solid dispersion
development, it is important to characterize the solubility of the crystalline and amorphous
forms of the drug of interest in dissolution media. The total drug concentration in a
biorelevant dissolution study is often dose dependent. For example, a total drug concen-
tration of 0.2mg/ml may be chosen to evaluate the dissolution of a formulation containing
50mg of drug in 250ml SGF. For many insoluble drugs, 0.2mg/ml could be above the
amorphous solubility limit. Understanding the sink condition is therefore critical to the
proper interpretation of dissolution data. It also helps in deciding if additional studies
should be conducted to further understand the dissolution mechanism. Dissolution studies
under nonsink condition at a drug load relevant to dose can be more discriminating than
studies conducted under sink condition, since the ability for a formulation to maintain
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