Chemistry Reference
In-Depth Information
HMQC experiment to a 50% (w/w) amorphous dispersion of acetaminophen in PVP
demonstrated the effectiveness of this approach [121]. Although a direct, fully resolved
correlation between a nitrogen resonance assigned to acetaminophen and protons
assigned to PVP or vice versa could not be clearly observed because of spectral overlap
in this particular dispersion, strong evidence of such a correlation was obtained by careful
assignment of the
1
H
14
N HMQC spectrum and was further supported by changes in
1
H
and
14
N chemical shifts [121]. As applications of this experiment are developed, the
dipolar correlation information obtained should be augmented by valuable
14
N EFG and
chemical shift parameters, given the sensitivity of nitrogen donors and acceptors to
hydrogen bonding interactions in dispersions.
17
O SSNMR can provide insight into hydrogen bonding interactions in amorphous
solid dispersions, and is particularly valuable in studies of oxygen hydrogen bond donor
and acceptor groups such as carboxylic acids, esters, amides, alcohols, and phenols. In
this role, it is complementary to
14
N and
15
N SSNMR experiments that are well suited to
nitrogen hydrogen bond donors and acceptors. Like
14
N,
17
O is a quadrupolar nucleus
that offers access to both EFG and chemical shift parameters. Unlike the
14
N nucleus,
17
O has a spin of 5/2, allowing direct observation of the quadrupolar central transition
without the need for wide-line experiments or special indirect observation methods such
as the aforementioned
1
H
−
14
N HMQC experiment.
17
O also requires synthetic labeling
at oxygen sites of interest in order to facilitate observation because of its low (0.038%)
natural abundance and the loss of sensitivity resulting from quadrupolar broaden-
ing [105].
17
O SSNMR allows for direct study of hydrogen bonding effects and has
been applied to detect hydrogen bonding differences in dispersions involving oxygen
donor and acceptor sites that were much more dif
−
cult to assess using
1
H and
13
C
17
O CP-HETCOR experiments can also be successfully
performed on dispersions and provide speci
1
H
SSNMR methods [79].
−
c information about proton environments in
proximity to labeled oxygen sites [79].
The SSNMR methods described above have recently been extended to study an
amorphous solid dispersion of ezetimibe in mesoporous silica [122]. Amorphous
dispersions in silica systems can be characterized using a specially adapted set of
SSNMR experiments, including
1
H spin diffusion and
1
H
29
Si CP-HETCOR experi-
ments optimized for detection of interactions between silanol groups and the drug. In the
case of a
−
29
Si
CP can be used to directly detect interactions between the drug and the silica to which it is
adsorbed [122]. Although not commonly thought of as a sensitive technique, the use of
abundant isotopes such as
1
H,
19
F, and
31
P allows for SSNMR to achieve excellent
sensitivity in a wide array of applications.
SSNMR methods that measure
1
H
T
1
relaxation times are useful in studies of
amorphous solid dispersions because of their ability to demonstrate phase dis-
association [119,136]. The saturation recovery pulse sequence (Table 4.1) is commonly
used to perform these measurements, and observation of
1
H
T
1
relaxation via
13
Cor
19
F heteronuclear detection is common [119,136]. This experiment is typically per-
formed as a pseudo-2D experiment with 8
fluorinated drug such as ezetimibe, specialized experiments such as
19
F
−
-
16 time increments, and exponential
fitting,
Laplace transforms or regularization, or other specialized
fitting is used to extract or
assess relaxation times [136]. In addition to measurements of
1
H
T
1
relaxation,
1
H
T
1
ρ
