Chemistry Reference
In-Depth Information
be de
nitely assigned to the drug (such as a set of aromatic protons) can be correlated to a
13
C(or
1
H) resonance assigned to the polymer [25,119].When observed, such a correlation
provides direct evidence of short-range interactions between the drug and the polymer and
thus demonstrates miscibility.
The HETCOR-based approach to the study of drug
-
polymer miscibility can be
demonstrated using
1
H
19
F CP-HETCOR experiments performed on a dispersion of
−
unisal lacks aliphatic protons, so its
1
H SSNMR spectrum has no
resonances in the region between 1 and 5 ppm [119]. It also contains two
di
unisal in PVP. Di
fluorine atoms,
which are not present in the polymer. A
1
H
19
F CP-HETCOR spectrum obtained with a
−
short contact time of 100
unisal in PVP is shown in
Figure 4.9a. This spectrum shows a correlation between the drug and the polymer that
can arise only if the two are in close proximity, that is, within several Å of each other,
thus con
μ
s of a 1% (w/w) dispersion of di
rming that the two components are miscible at the molecular level [119]. The
sensitivity of
19
F SSNMR allows for this analysis to be performed with only 1% (w/w)
drug present in the sample in an experiment time of less than 2 h. Extending the contact
time to 2ms results in the spectrum shown in Figure 4.9b, which shows even greater
intensity in the key correlation between the drug and the polymer. While this enhanced
intensity could be caused by buildup of the direct dipolar interactions between
1
Hand
19
F nuclei, the bulk of the enhancement is more likely caused by spin diffusion between
1
H nuclei prior to the CP transfer to
19
F nuclei. Spin diffusion results from multiple
dipolar interactions between
1
H nuclei, and in the study of amorphous solid dispersions,
spin diffusion extends the range over which correlations can be observed in 2D
HETCOR and similar spectra [119,128,129].
The range of
1
H spin diffusion effects can be estimated from the maximum
diffusion path length (
L
), which indicates the extent of
1
H
1
H
−
1
H spin diffusion that can
occur within the
1
H spin lock during the contact time of a CP-HETCOR experiment (or
during other periods where spin diffusion can occur). This quantity is related to the spin
diffusion coef
−
cient (
D
) and the time (
t
) over which the spin diffusion takes place (such
as the CP contact time) by the following expression [130,131]:
h
L
2
i
6
Dt
;
(4.8)
where the angle brackets denote an ensemble average. The spin diffusion coef
cient (
D
)
in Equation 4.8 may be estimated as
D
h
l
0
i=
T
2
;
(4.9)
◀
Figure 4.9.
19
F CP-HETCOR spectra of a 1% (w/w) amorphous dispersion of di
unisal in PVP
obtained using contact times of (a) 100 μs and (b) 2ms [86]. The dispersion was prepared by
solvent evaporation. The 1D
19
F CP-MAS spectrum (showing the centerband) is plotted along the
F
2
(horizontal) axes, and a summation of columns is plotted along the F
1
(vertical) axes. The 2D
spectra were obtained at 11.7 T and 273K with
ν
r
=12.5 kHz using a Bruker Biospin Avance II+
spectrometer and a 4mm HFX MAS probe. A total of 32 rows were acquired using 64 scans per
row and a 3 s relaxation delay for a total experiment time of 1.7 h for each experiment.
1
H
−
