Chemistry Reference
In-Depth Information
example of the enhanced sensitivity of Raman spectroscopy to the drug versus the
excipients is provided by ibipinabant, a cannabinoid receptor antagonist [122]. This
substance was formed into an amorphous solid dispersion with PVP and then the
dispersion was formulated into a tablet so that the weight fraction of the drug present in
the tablet was only 1%. Despite the very low weight fraction of total drug present in the
tablet, using Raman spectroscopy it was possible to detect the presence of 5%
crystalline material, which equates to less than 0.05% of the total mass of the sample.
This was possible due to the extremely strong Raman scattering of ibipinabant with
distinct peaks in a spectral region where the excipients did not have any signal, as well
as discernable differences in the spectra of the amorphous and crystalline forms. By
constructing calibration curves for the percent crystallinity, it was also possible to
quantitatively monitor the crystallization kinetics as a function of time. Another
advantage of Raman spectroscopy is that it can be coupled with a microscope, enabling
high spatial resolution chemical images to be obtained. Raman mapping has been used
to discriminate between amorphous and crystalline domains in solid dispersions of
troglitazone with PVP [123]. This system is quite complex since troglitazone has two
asymmetric carbons and normally crystallizes as a mixture of two diastereomeric pairs,
namely, RR/SS and RS/SR. The RR/SS crystals could be distinguished from the
RS/SR crystals using Raman spectroscopy, as could the amorphous solid. Using
Raman mapping, the distribution of the crystalline and amorphous materials in the
solid dispersions subjected to different heating regimes could be evaluated. It was
found that the amorphous form of troglitazone coexisted with the crystalline RR/SS
and RS/SR forms in some of the solid dispersions. Thus, by using Raman mapping,
this complex system could be characterized in terms of the presence and distribution of
different diastereomeric pairs/amorphous materials in the presence of PVP.
Raman spectroscopy has also been used to monitor crystallization of amorphous
solids on contact with aqueous media [124], and thus can be used to help assess the risk
for crystallization during dissolution. By coupling a
fiber optic probe to a Raman
spectrometer, it is possible to remotely sample the system of interest. This enables Raman
spectra to be obtained from systems subjected to the experimental conditions of interest.
The crystallization kinetics of amorphous felodipine powder, slurried in a pH 6.8 buffer,
were monitored using a Raman immersion probe that was inserted into the slurry. By
obtaining spectra at frequent time intervals, the crystallization kinetics of felodipine
could be readily monitored.
It is more difficult to use IR spectroscopy for quantitation of crystallinity in
amorphous solid dispersion for several reasons, including sampling, the typically
strong IR absorption by the excipient, and the broader peaks present in the IR
spectrum. However, FTIR spectroscopy is a very useful technique to investigate the
state of mixing between the drug and the polymer in an amorphous solid dispersion
and to evaluate if speci
polymer interactions are present. As already
discussed, an amorphous drug can be either molecularly dispersed in the polymer
matrix or, if the system is only partially miscible, present as separate drug- and
polymer-rich domains. By evaluating drug
cdrug
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polymer interactions, FTIR spectroscopy
canbeusedtohelpunderstandifthedrugisinteractingwiththepolymeratthe
molecular level, or if the system shows little interaction. It is very important to obtain
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