Chemistry Reference
In-Depth Information
experiments, particularly when using a UV-vis spectrometer coupled to a
fiber optic
probe to monitor solution concentrations. Ultracentrifugation or
filtration of the solution
with submicrometer membrane pore size (prior to solution concentration measurements)
to separate colloidal particles from the supernatant may be necessary to accurately
determine the drug concentration in the solution phase [54,106,117,118,126,131]. As
discussed in Section 6.4.2.2, the dynamic dialysis method may be used to determine drug
concentration without notable interference from these particulates.
The formation of drug-rich submicrometer particles upon dissolution of amorphous
solid dispersions also provides an alternative method of generating nanospecies and might
be important not only for oral drug delivery but also for other routes of delivery where it is
desirable to form drug-rich nanoparticles, such as pulmonary drug delivery [119,132]. It
has been suggested that colloidal species are important to the bioavailability enhancement
often seenwith amorphous solid dispersions [106,133,134]. Frenkel et al. proposed that the
formation of colloidal particles (especially particles with hydrodynamic radii less than
100 nm) may be responsible for the enhanced bioavailability of nonnucleoside reverse-
transcriptase inhibitors (NNRTIs) by promoting their absorption by particle-recognizing
microvilli cells in Peyer
s patches of mucosa-associated lymphoid tissue [133]. In addition,
Serajuddin et al. hypothesized that colloidal particles could dissolve during GI transit, thus
increasing bioavailability [134]. However, in order to take advantage of the properties of
colloidal dispersions, the submicrometer particles must be stabilized. Colloidal particles
may undergo coalescence since colloidal particles are generated through the formation of
highly supersaturated solutions. Polymers have been used to stabilize colloidal disper-
sions [106,120,121,127,135] and can also serve as crystallization inhibitors [59,84]. It has
been proposed that the size and stability of colloidal particles depend on solution conditions
(such as pH, buffer, and ionic strength) and the structure and properties of the molecules,
including the number of polar atoms, number of hydrogen bond donors and acceptors,
conformational
'
flexibility, and presence of ionized groups [119,133]. Analysis of aggre-
gate size distributions for NNRTI APIs under various physiological conditions demon-
strated dependence of aggregation size on solution pH [133]; at constant ionic strength,
aggregate size was found to increase with increasing pH (decreasing extent of ionization).
This dependence of particle size on drug and/or additive ionization, and thus on pH, may
have important implications for drug absorption since pH varies along the GI tract.
In summary, developing a biorelevant dissolution method is a critical activity for
amorphous formulation development. Different dissolution methods can be applied
based on the development stage to guide formulation selection and process development.
Since the number of dissolution conditions is broad, scientists should consider what set
of conditions best matches the needs for the questions they intend to answer. Under-
standing the properties of the drug molecule and the polymers are critical to the choice
of dissolution apparatus, testing conditions, and analytical methods. At early stages of
development, a simple one-stage dissolution experiment in UPS type I/II apparatus or
beaker/glass vials can be used to explore different formulation compositions for
solubility enhancement and provide a qualitative trend. At later stages, a more sophisti-
cated and resource-intensive dissolution system may be explored if a simple test does
not correlate with bioperformance in human or there is a desire for the
in vitro
test to
provide more quantitative information for
in vivo
prediction. Multiple techniques should
