Chemistry Reference
In-Depth Information
samples in a separate magnetic
field outside of the NMR magnet, but more recently the
approach has been streamlined by technical advances that allow for DNP to be performed
within the NMR magnet. DNP has seen an initial successful application to an amorphous
small organic molecule that is similar to an amorphous pharmaceutical system [141]. The
results of a DNP-enhanced SSNMR experiment performed on an amorphous dispersion
containing 16% (w/w) ezetimibe in mesoporous silica [122] are shown in Figure 4.13a.
The DNP-enhanced spectrum is obtained using continuous microwave irradiation of an
added radical from a 263 GHz continuous-wave gyrotron source that is coupled via a
transmission line to a 3.2mm MAS probe, with data acquired at a temperature of
100 K [142]. The rigid bis-TEMPO
bis-ketal (bTbK) biradical, where TEMPO is an
acronym for (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl, was used for DNP enhance-
ment in Figure 4.13a [143]. The biradical was soaked into the mesoporous solid
dispersion using 1,1,2,2-tetrachloroethane (TCE), and the sample was analyzed with
and without microwave irradiation to illustrate the signal enhancement as shown in
Figure 4.13a. The strong enhancement allows for
13
C signals for ezetimibe to be
observed in several minutes, when several hours are required for conventional meth-
ods [122]. The use of DNP enhancement in a typical polymeric amorphous solid
dispersion is illustrated in Figure 4.13b, where spectra are shown for a dispersion of
30% (w/w) di
-
unisal prepared in HPMCAS by rapid solvent evaporation [79]. The
biradical 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL) was used
for this experiment [143], with 16mM of the biradical impregnated into the dispersion
using deuterated dimethyl sulfoxide (d
6
-DMSO) as a solvent. Again, signal enhancement
is obtained for the spectrum obtained with continuous microwave irradiation. Although
illustrated here for simple 1D
13
C CP-MAS spectra, the DNP approach is expected to be
particularly useful in enhancing sensitivity for 2D SSNMR studies of amorphous solid
dispersions as well as allowing increased access to 1D and possibly 2D spectra of less
sensitive nuclei of interest such as
2
H,
15
N, or
17
O.
4.7 OTHER MOLECULAR SPECTROSCOPIC METHODS
In addition to SSNMR and vibrational spectroscopy, a number of other modes of molecular
spectroscopy employed in pharmaceutical research also have applications to amorphous
solid dispersions. Diffuse re
ectance (DR) UV
-
visible spectroscopy measures electronic
transitions in solids much as absorbance UV
-
visible spectroscopy does in solution [144].
DRUV
tting an
accessory capable of collecting diffusely scattering light from a powder to a conventional
UV
-
visible experiments on amorphous solid dispersions can be performed by
visible methods are particularly sensitive, since
drugs often contain conjugated bonds that absorb UV radiation in the 200
-
visible spectrometer [144]. DR UV
-
300 nm range,
while the polymers used to form dispersions often do not absorb as strongly in this region.
Pharmaceutical molecules with a visible color offer even more speci
-
city for the use of
DR UV
visible spectroscopy. For example, amorphous solid dispersions of tenoxicam
and
L
-arginine in PVP that exhibited a yellow color were readily characterized by DR
UV
-
visible spectroscopy, and the resulting spectral differences were interpreted as
ionization state changes arising from monoionization versus zwitterionization of
-
