Chemistry Reference
In-Depth Information
CP-TOSS spectra of dispersions of the developmental compound 6-(2-(5-chloro-2-(2,4-
di
uorobenyzloxy)phenyl)cyclopent-1-enyl)picolinic acid in three common polymers are
shown [86,109]. The polymers include PVP, HPC, and hydroxypropylmethylcellulose
acetate succinate (HPMCAS). The results illustrate the typical sensitivity achieved using
13
C SSNMRwith acquisition times in the vicinity of 5
-
10 h on dispersions containing 20%
(w/w) of drug, which is suf
cient to allow for detection of the carbon resonances of the
drug. In Figure 4.7, the resonances assigned to the polymer sites are relativelywell resolved
from the resonances assigned to the drug molecule, which highlights a general feature of
13
C SSNMR relative to techniques such as IR and Raman spectroscopy (which can be seen
in comparison with Figure 4.4). Broadened lineshapes are usually observed in the SSNMR
spectra of amorphous solids relative to crystalline phases, as seen in Figure 4.7, because
each nucleus experiences a range of chemical shift environments arising from differences
in molecular conformation and local surroundings.
Conventional 1D CP-MAS and CP-TOSS methods are widely used to obtain basic
characterization data for amorphous solid dispersions, like that shown in Figure 4.7.
For example, 1D
13
C SSNMR methods have been applied to characterize dispersions
such as troglitazone in PVP, tenoxicam
-
L
-arginine complexes in PVP, ibuprofen and
flurbiprofen in poly(methyl methacrylate)-based polymers, ketoprofen in poly(ethyl-
ene oxide), indomethacin
-
cyclodextrin complexes in PEG, and felodipine in PVP
-
VA [25,110
115]. Multivariate analysis methods can be applied to assist in the
analysis of
13
C SSNMR spectra, such as to observe subtle trends that were predictive
of recrystallization [115]. The
13
C chemical shift observed for carbonyl groups in 1D
13
C spectra often contains useful information about hydrogen bonding in amorphous
solid dispersions that can be interpreted in a similar manner to carbonyl band shifts
observed in IR spectra [57].
Experimental approaches that allow for measurement of 1D
1
H SSNMR spectra are
also given in Table 4.1. Because of strong
1
H
-
1
H dipolar coupling, observation of high-
resolution 1D
1
H spectra of amorphous solid dispersions often requires the use of
relatively high
−
ν
r
settings (typically greater than 30 kHz), higher
fields, and homonuclear
decoupling [116,117]. Homonuclear decoupling can be accomplished using a variety of
pulse sequences; for example, a commonly used family of sequences known by the
acronym of DUMBO is highly effective at removing dipolar coupling, but yields a
spectrum containing scaled
1
H chemical shifts and produces artifacts that must be
avoided [116,117]. Unlike in solution, where rapid molecular tumbling averages dipolar
coupling,
1
H SSNMR spectra remain broadened even when fast MAS, DUMBO, and
high
fields are used. However, useful information can still be obtained from the spectra
for amorphous solid dispersions, primarily from the observation of deshielded
1
H
environments (typically in the range of 9
15 ppm) that arise from protons engaged
in hydrogen bonding [57]. The
1
H chemical shift of common hydrogen bonding protons
in drugs, such as carboxylic acid protons, phenolic protons, and amide protons, is highly
sensitive to hydrogen bond geometry. For example, the
1
H chemical shift of hydrogen
bonding protons in carboxylic acids interacting with oxygen acceptors is deshielded by
about 1 ppm with every 0.04 Å decrease in the H
∙∙∙
O interatomic distance [118].
Recently, several studies that utilize
1
H SSNMR have been reported that use this type of
effect to probe hydrogen bonding, generally using DP-MAS, DUMBO, or related
-
