Chemistry Reference
In-Depth Information
ef
cient studies of low-dose, highly potent drugs formulated as dispersions. Although
sensitive, resonance Raman spectra typically exhibit a broadened appearance that reduces
their speci
city, and samples must be checked for potential UV laser damage [86].
Another sensitivity-enhanced Raman spectroscopic technique is coherent anti-
Stokes Raman scattering (CARS) microscopy, which has emerged as a highly sensitive
tool for chemical
imaging in biological applications and has now begun to
nd
applications in pharmaceutical development [87
-
90]. In CARS, the sample is excited
ω
pump
, a Stokes beam with frequency
ω
Stokes
, and a
by a probe beam with frequency
probe beam with frequency
ω
probe
are
chosen to be equal. When a sample is irradiated using a tightly focused laser with
ω
probe
. Typically, the frequencies
ω
pump
and
ω
pump
and
ω
pump
ω
Stokes
matches the frequency of a
Raman band, a strong signal is generated at the anti-Stokes frequency
ω
Stokes
radiation, and the frequency
ω
anti-Stokes
. CARS
uses tightly focused beams delivered via a microscope to achieve a phase matching
condition necessary for the coherent process in a narrow sample area, so that images may
be formed by moving the stage as in conventional confocal Raman microscopy.
Traditional CARS microscopy experiments produce an image for a single Raman
band and are sometimes made speci
c for a given molecule by isotopic labeling.
CARS microscopy has the advantage of very high sensitivity compared with other
methods of obtaining Raman spectral information, allowing imaging at video rates in
some applications [87]. A CARS study of a semi-solid dispersion of 15% (w/w)
paclitaxel in a blend of PEG and poly(lactide-
co
-glycolic acid) (PLGA) detected phase
separation between PEG and PLGA and provided evidence of the drug forming a
dispersion with the PEG in preference to the PLGA [91]. Newer broadband, multiplex
CARS microscopy methods allow for simultaneous imaging of multiple vibrational
bands, so that bands arising from a drug and a polymer could be imaged quickly in an
amorphous solid dispersion [92]. Studies of drug miscibility in a conventional amor-
phous solid dispersion employing a drug and a polymer using CARS have not yet been
reported but are expected to provide a useful tool in the future.
Other methods capable of accessing molecular vibrational quantum states have been
employed in studies of dispersions to a lesser extent, but hold promise for future
applications. Neutron vibrational spectroscopy (NVS), also known as inelastic neutron
scattering (INS), has been applied to study structure in mesoporous dispersions of
ibuprofen [93]. NVS detects the energy transfer to or from neutrons by a scattering
molecule, which depends on vibrational transitions, and allows more sensitive detection
of vibrational transitions in systems that involve hydrogen because of the high incoherent
scattering cross section of this element relative to other elements [57,94]. This effect is
useful in organic systems such as amorphous solid dispersions that contain a large molar
ratio of hydrogen. NVS produces spectra that are more sensitive to vibrational modes
involving hydrogen than IR or Raman spectroscopy and is consequently useful in studies
of hydrogen bonding [57]. NVS also offers extremely high resolution from 16 to
4000 cm
1
and detects all vibrational transitions, not just those allowed by optical
selection rules [93,94]. A major disadvantage of the technique is the requirement for a
neutron source and spectrometer, which are currently restricted to several major research
facilities because of their size and expense.
