Chemistry Reference
In-Depth Information
1. Define desired outcome
6. Define characterization
Discovery
IVIVR/IVIVC
Product characterization
Speciation
Concentration determination
Solids characterization
2. Decide on objective
5. Decide on experimental
parameters
Solubility
Biorelevant dissolution
QC dissolution
Volume
Sink condition
Stir speed
3. Decide on testing
equipment
USP apparatus I, II, III, and IV
Dual chamber
Membrane methods
4. Define media
Biorelevant
Not biorelevant
QC media
Figure 6.6.
Flowchart and decision process for designing dissolution experiments for an
amorphous dispersion.
evaluations. However, focusing on early-development biorelevant dissolution studies,
there are several equipment types to consider: (i) USP apparatuses I
IV, (ii) dual
chamber methods, or (iii) membrane methods. As recently reviewed, the USP appara-
tuses are most frequently used with USP II (paddle method) being used in 74% of 40
reviewed cases [87]. The USP approach offers the advantages of common use,
simplicity, and translatability. Dual chamber or phase methods offer the advantage of
better simulating pH changes from the stomach to the small intestine and membrane
methods add the biological sink of intestinal permeability as an additional compo-
nent [87]. The latter two are more complex but may give rise to better IVIVR.
As Figure 6.6 indicates, the next step is to select media and three main options are
usually considered: (i) biorelevant, (ii) nonbiorelevant, and (iii) a variety of QC media.
Focusing on the former two, biorelevant media were described in Section 6.1 and in
recent literature [9,28
-
30]. The authors are advocating a stage-dependent approach to
media selection. In discovery, where the objective is to rank order compounds, the more
simple USP media [27] may be used. Later in development, when the objective is to
attain IVIVR, more complex media [9,28
-
30] may give rise to better correlation.
Recently, 40 dispersion case studies were reviewed showing the low pH media and
buffers did not give rise to IVIVR [87].
In selecting experimental conditions, three main considerations are listed in
Figure 6.6: media volume, sink conditions, and stir speed. The standard dissolution
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