Chemistry Reference
In-Depth Information
vessel on a USP dissolution apparatus is 900ml. Therefore, not surprisingly, 60% of 40
surveyed dispersion case studies used 900ml media [87]. However, this may not re
ect
the physiological conditions within human as intestinal volumes are much smaller.
According to a recent study, volumes average 45ml (fasted)/686ml (fed) in the stomach,
105 ml (fasted)/54 ml (fed) in the small intestine, and 13ml (fasted)/11ml (fed) in the
large intestine [138]. Therefore, considering smaller and more physiologically relevant
volumes is recommended for biorelevant studies. A related consideration to volume is
whether or not sink is established under the experimental conditions. The USP de
nes
sink as three times the media required for saturation [95], which is a rule that should be
adhered to when conducting QC dissolution experiments.
In vivo
sink may, for certain
drugs, be established by permeation across the gastrointestinal mucosa; however, for
insoluble drugs such as BCS class II (poor solubility and high permeability) or especially
BCS class IV (low solubility and low permeability), sink may not be attained and lower
volumes should be considered in biorelevant experiments. Stir speed is important as it
will affect the unstirred water layer around the dissolving particle and thereby dissolution
rate. It was described in Section 6.4 and recently published that the most common stir rate
used in a USP apparatus is 100 rpm [87]. Stir speed is a dif
cult parameter to make
biorelevant as mixing in the
in vivo
situation will depend on a variety of factors, such as
species, feeding state, hydration state, GI motility, and therefore also age and medication-
related factors. The authors recommend that stir rate is adjusted empirically as IVIVR
correlations are developed. Stir speed may not be important for early studies, where rank
ordering is the objective, and in these cases it is recommended to keep it at a constant rate.
Finally,
flowchart outlined in Figure 6.6 recommends
considering characterization that usually will involve (i) speciation or, in other words,
detecting if any nanosized particles or aggregates are formed in the experiments, (ii)
concentration determination, and (iii) characterization of any solids remaining in the
experiment. Concentration determination is usually conducted via HPLC, UV, or other
similar methods [90] and any remaining solids isolated are usually analyzed for
crystalline/amorphous content by standard solid-state methods such as DSC and
PXPD. Recently, it has been published that submicrometer particles can form during
dissolution of amorphous dispersion, as discussed in detail in Section 6.4. These particles
can have signi
the dissolution design
cant impact on bioperformance and can make analysis of dissolution
experiments dif
cult. They can give erroneous results when using UV detection due to
particle scattering and falsely high results when using HPLC, if the particles and the
medium are not separated appropriately. As outlined in Section 6.4, ultracentrifugation is
recommended for isolating the solids if submicrometer particles are being formed in the
dissolution experiment and Table 6.6 outlines analysis methods to detect and character-
ize these submicrometer species.
In conclusion, we have illustrated that
in vitro
solubility and dissolution studies
represent an important link between formulation design and
in vivo
bioperformance. This
is especially true for supersaturating formulations such as amorphous dispersions. These
formulations are based on high-energy and metastable API forms and may therefore
crystallize
in vivo
, resulting in less than desired bioperformance. Well-designed bio-
relevant solubility and dissolution studies could serve as a resource-sparing alternative to
increase the probability of success of desired
in vivo
bioperformance. Therefore, it is
