Chemistry Reference
In-Depth Information
suppressing dipolar coupling and thus reduces CP. In Figure 4.11b, the spinning
sidebands are also reduced in intensity compared with those in Figure 4.11a, and the
spectrum is further broadened, which is also consistent with averaging of chemical shift
anisotropy by molecular motion of the drug.
In addition to the SSNMR correlation methods that utilize heteronuclear dipolar
coupling as their correlation mechanism, methods based on homonuclear dipolar coupling
are also of use in some cases although limited
1
H resolution restricts their applicabil-
ity [119,122]. Themethods that have been applied to dispersions to date include
1
H double-
quantum correlation spectroscopy using back-to-back excitation and reconversion pulses
(DQ-BABA) andmethods based on
1
H spin diffusion [119,122,132]. Thesemethods allow
for detection of interactions between the components of a dispersion in some cases and can
be useful for assessment of miscibility. In addition, correlation methods based on through-
bond
J
-coupling can be useful in spectral assignments for individual molecules in a
dispersion, and in some cases may be able to probe strong intermolecular hydrogen
bonding where signi
cant orbital overlap and
J
-coupling occur [133].
2D SSNMR experiments have been applied to probe miscibility in a number of
binary amorphous solid dispersion systems as well as more complex ternary and
quaternary systems of pharmaceutical interest. These include dextran
-
trehalose, indo-
methacin
-
PVP, acetaminophen
-
PVP, acetaminophen with two methacrylate copoly-
mers, telithromycin
-
PVP, voriconazole
-
PVP with sodium lauryl sulfate added as a
surfactant, and tenoxicam:
L
-arginine
PVP wherein the
L
-arginine occurs in both mono-
ionized and zwitterionized forms [25,119]. The SSNMR studies to date have largely
focused on systems that contain modest drug concentrations (e.g., 10
-
50% (w/w)), but
the SSNMR approach using a sensitive nucleus such as
19
F has been used to show
miscibility on dispersions containing as low as 1% (w/w) of drug [86].
A recent addition to the catalog of 2D SSNMR methods useful for study of
molecular association is the
-
14
N heteronuclear multiple-quantum coherence
(HMQC) experiment that performs dipolar transfers using a rotational resonance
approach [121]. This experiment utilizes the
14
N isotope, which has several advantages
relative to the
1
H
−
15
N isotope [105,134]. The
1
H
14
N HMQC experiment generally
−
ν
r
is set to 45 kHz or above because of the need to suppress
1
H
homonuclear coupling, and thus requires the use of MAS probes with rotor outer
diameters in the range of 1.0
performs best when
1.9mm [121,135]. An initial application of the
1
H
14
N
-
−
◀
Figure
19
F CP-HETCOR spectra of 6-(2-(5-chloro-2-(2,4-
di
uorobenyzloxy)phenyl)cyclopent-1-enyl)picolinic acid [86,109] in PVP-VA obtained from
(a) a dispersion prepared by mixing a hot melt of the drug and PVP-VA and (b) a physical mixture
of amorphous drug and polymer. The physical mixture of amorphous drug and polymer shown in
(b) recrystallized rapidly in the rotor after this spectrum was obtained. Spectra were obtained
using a 2ms ramp CP contact time at 11.7 T and 273 K with
ν
r
= 14 kHz. The similarly obtained
19
F
CP-MAS spectrum of each sample (showing the centerband and two sidebands) is plotted along
the horizontal axes. A summation of columns is plotted along the F
1
(vertical) axes; because of
the sensitivity of the physical mixture to recrystallization,
1
H DP-MAS spectra at a higher MAS
rate could not be obtained.
4.11.
Comparison
1
H-
of
