Chemistry Reference
In-Depth Information
vibrations, leading to fairly intense Raman scattering and pronounced spectra. The Raman
bands of di
unisal seen in Figure 4.4 thus dominate those of all three of the polymers used,
despite the drug being the minor component of these dispersions. Although a signi
cant
amount of overlap between drug and polymer bands is observed, several speci
c bands for
di
unisal can be found in each of the three dispersions.
Confocal Raman microscopy has been widely employed in studies of pharmaceuti-
cal amorphous solid dispersions [80
82]. An example of confocal Raman microscopic
analysis used for chemical imaging of an amorphous solid dispersion is illustrated in
Figure 4.5. A dispersion containing 30% (w/w) of di
-
unisal in PVP was prepared by
rapid evaporation from acetone solution, and a piece of the thin
film obtained was
mapped using confocal Raman microscopy as shown in Figure 4.5a. The false-color map
imposed on the optical bright-
eld image in Figure 4.5a is obtained by dividing the band
area between 3060 and 3160 cm
1
(speci
c for di
unisal) by the area between 2845 and
3050 cm
1
(speci
c for PVP). This produces a band ratio plot that factors out other
in
uences on signal intensity (such as sample topology and density) and is thus useful for
assessing dispersion homogeneity. Raman spectra extracted from the high- and low-
intensity points of the map are compared in Figure 4.5b and illustrate the homogeneity of
the drug in the PVP at a spatial resolution of 10
m
dimensions in a dispersion cannot be completely resolved because of the diffraction
limit, it can be indirectly detected using conventional confocal Raman microscopy
systems by carefully comparing concentrations from a mapped region and looking for
spectral changes that correspond to concentration differences between the drug and the
polymer as in Figure 4.5. A study employing confocal Raman microscopic mapping of
nanocrystalline domains of the drug ebselen in PVP
μ
m. Although heterogeneity with sub-
μ
-
VA illustrates the effects that can be
observed in the case of sub-
m heterogeneity [82]. Because it can be focused onto a small
spatial area of a sample and obtain highly sensitive results for that region, confocal
Raman microscopy can also detect potential miscibility between a drug and a polymer
when other techniques cannot. For example, in the aforementioned study of a nano-
crystalline ebselen dispersion in PVP
μ
VA, confocal Raman microscopy detected the
presence of potential miscible amorphous regions in the dispersion that could not be
detected using other characterization techniques [82]. Confocal Raman microscopy
using 785 nm laser irradiation has been applied to study heterogeneity in dispersions of
dextran and PVP and in biopharmaceutical materials produced by lyophilization [83,84].
Biopharmaceutical formulations are similar in many respects to amorphous solid
dispersions of a small-molecule drug and a polymer, except that the larger molecule
is the drug (usually a protein) and the small molecules are excipients. More sophisticated
multivariate analysis methods such as the band target entropy minimization (BTEM)
method have also been applied in conjunction with Raman microscopy studies of
dispersions [85]. Confocal Raman microscopy can also be employed to study phase
transformations during dissolution of dispersions using suitable sample preparation (e.g.,
positioning of a dispersion particle between glass slides), yielding similar information to
that obtained using the aforementioned FPA ATR IR method.
In some cases, where poorly soluble but highly potent drugs must be delivered,
amorphous solid dispersions are prepared with low amounts of drug. The observation of
drug using conventional Raman (or IR) spectroscopic methods can then be problematic.
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