Sodium-23 Solid-State Nuclear Magnetic Resonance
of Commercial Sodium Naproxen and its Solvates
KEVIN M. N. BURGESS, FRÉDÉRIC A. PERRAS, AURORE LEBRUN, ELISABETH MESSNER-HENNING, ILIA KOROBKOV,
DAVID L. BRYCE
Department of Chemistry and Centre for Catalysis Research and Innovation, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
Received 29 February 2012; revised 10 April 2012; accepted 27 April 2012
Published online 22 May 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23196
ABSTRACT: We report on the investigation of sodium coordination environments with solidstate 23 Na nuclear magnetic resonance (NMR) spectroscopy of various hydrates and solvates of
sodium naproxen (SN), a commercially available anti-inflammatory drug sold over the counter
R
, among other names. The 23 Na quadrupolar coupling constant is found to change
as Aleve
significantly depending on the hydration state, and subtle changes in oxygen coordination
environment about the sodium cations were apparent in the NMR spectra. High-resolution
double-rotation NMR experiments are also performed on powdered samples to obtain solutionlike 23 Na NMR spectra. Our attempts at crystallizing various solvates of SN have led to the
characterization of the first crystal structure for the heminonahydrated form. The composition
R
is composed of approximately
of commercial SN is also investigated and it is shown that Aleve
80% monohydrate solvate. Density-functional theory calculations, using the gauge-including
projector-augmented-wave formalism, allow for the assignment of 23 Na NMR peaks to specific
sodium sites in the reported X-ray crystal structure. © 2012 Wiley Periodicals, Inc. and the
American Pharmacists Association J Pharm Sci 101:2930–2940, 2012
Keywords: sodium naproxen; solvates; hydrates; solid-state 23 Na NMR; quadrupolar nuclei;
R
magic-angle spinning; double rotation; polymorphism; crystal structure; Aleve
INTRODUCTION
The polymorphism phenomenon is the ability of one
chemical species to exist in various crystallographic
forms that all have identical molecular formulas. A
solvate, on the other hand, is identified when a different crystal structure results from hydration or solvation. The study of these is of utmost importance in
the pharmaceutical industry as different polymorphs,
hydrates, and solvates of a certain drug have different pharmaceutical characteristics.1 In fact, acAbbreviations used: NMR, nuclear magnetic resonance;
SSNMR, solid-state nuclear magnetic resonance; SN, sodium
naproxen; DOR, double rotation; MAS, magic-angle spinning;
PXRD, powder X-ray diffraction; CP, cross-polarization; CT, central transition; QI, quadrupolar interaction; EFG, electric field gradient; MQMAS, multiple-quantum magic-angle spinning; GIPAW,
gauge-including projector-augmented wave; DFT, density functional theory; DFS, double frequency sweeps; RH, relative humidity.
Additional Supporting Information may be found in the online
version of this article. Supporting Information
Correspondence to: David L. Bryce (Tel.: +1-613-5625800x2018; Fax: +1-613-562-5170; E-mail: [email protected])
Journal of Pharmaceutical Sciences, Vol. 101, 2930–2940 (2012)
© 2012 Wiley Periodicals, Inc. and the American Pharmacists Association
2930
cording to the United States Federal Drug Administration, a polymorph must be fully characterized
before its release into the market.2 The “gold standard” in identifying the presence of polymorphs and
solvates has been powder X-ray diffraction (PXRD)
and/or solid-state 13 C nuclear magnetic resonance
(SSNMR) spectroscopy.3–5 Under magic-angle spinning (MAS) conditions, SSNMR can provide solutionlike spectra for spin-1/2 nuclei such as 13 C in powdered samples because the orientational dependence
of the chemical shifts (CS) with respect to the magnetic field is averaged, giving clear indications as to
the phase purity of the sample.
In this work, we report on a 23 Na SSNMR study of
different hydrates and solvates of sodium naproxen
(SN; see Scheme 1), which is a nonsteroidal antiinflammatory drug. Previous nuclear magnetic resonance (NMR) studies on this system have used 13 C
cross-polarization (CP) MAS experiments, but these
have yielded ambiguous results due to multiple overlapping resonances.6 23 Na is a quadrupolar nucleus
(i.e., spin quantum number, I = 3/2), which makes
the analysis of the corresponding NMR spectra more
challenging as the observed central transition (CT;
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SODIUM-23 SOLID-STATE NMR OF COMMERCIAL SODIUM NAPROXEN AND ITS SOLVATES
2931
the different Na+ coordination environments in SN
solvates.
EXPERIMENTAL
Scheme 1. Two-dimensional structural representation
of sodium naproxen ((S)-6-methoxy-α-methyl-2-naphthaleneacetic acid sodium salt).
m = +1/2 ↔ −1/2) is broadened by the quadrupolar interaction (QI) to second order. This interaction stems
from the coupling between the quadrupole moment of
23
Na and the electric field gradient (EFG) at the nucleus. The use of quadrupolar nuclei to probe the EFG
has been demonstrated on many occasions7,8 to be
quite sensitive to different crystallographic environments, thereby making their application useful for the
present study. Some illustrative examples9,10 of the
utility of SSNMR experiments at detecting polymorphic species include that of Schurko and coworkers,11
wherein they demonstrated the use of 35 Cl (I = 3/2)
SSNMR to study various hydrochloride salts of pharmaceuticals. Additionally, Xu and Harris12 have employed 23 Na multiple quantum MAS (MQMAS) NMR
to investigate polymorphism in sodium acetate.
As the QI cannot be completely averaged by MAS
alone, more complex two-dimensional NMR experiments may be advantageous to obtain high resolution,
or the sample can be spun about two angles using
23
Na double rotation (DOR) NMR experiments.13–15
This action more completely averages the broadening
due to the QI, permitting an enhancement in resolution between spectral resonances corresponding to
multiple crystallographically distinct sites, as compared with conventional MAS experiments. The different shifts observed in these spectra are representative of the CSs and EFGs of the different 23 Na sites
present. This method was proven to be quite useful
recently in distinguishing between very similar Na
sites in sodium nucleotides.16
Computational methods continue to emerge as
powerful tools to corroborate SSNMR experiments.
However, more conventional chemical model-based
methods are usually inaccurate in their predictions,
as the EFG is dependent on the long-range charge distributions in the crystallite, which are only modeled
when the repetitive nature of the solid is taken into
account.17 The gauge-including projector-augmented
wave (GIPAW) density functional theory (DFT) approach uses the periodicity of plane waves to consider
these long-range effects and uses pseudopotentials for
speed. This method has been shown previously to effectively reproduce experimental 23 Na EFG parameters for the perovskites NaNbO3 and NaTaO3 .18 In
the present study, our aim with these calculations is
to show how the NMR parameters may be related to
DOI 10.1002/jps
Sample Preparation
Naproxen as well as anhydrous SN were purchased
from Sigma–Aldrich and used without further purifiR
cation. Aleve
was purchased from the campus pharmacy of the University of Ottawa in capsule form. A
saturated solution of SN in methanol was placed under argon, where single crystals of SN monohydrate
(verified by single-crystal XRD) formed within a few
weeks. As for the methanol solvate, this was formed
via slow evaporation of a saturated solution of SN in
methanol in open air. The identity of this sample was
confirmed using PXRD (vide infra). The SN heminonahydrate was synthesized by dissolving a 1:1 molar
ratio of naproxen and sodium hydroxide in 1-butanol.
The solution was left to slowly evaporate for several
weeks until single crystals suitable for X-ray analysis appeared. For SSNMR analysis, all samples were
ground and tightly packed into 4 and 7 mm zirconia
rotors for MAS experiments and 4.3 mm vespel rotors
for DOR experiments.
SSNMR Spectroscopy
23
Na SSNMR experiments were performed at magnetic fields of 4.7 T (Bruker AVANCE III (Bruker
Biospin, Milton, Ontario, Canada), νL (23 Na) =
53.92 MHz) and 9.4 T (Bruker AVANCE III, νL(23Na) =
105.84 MHz) at the University of Ottawa. Setup and
pulse calibrations were carried out with solid NaCl
(resonance set to 7.2 ppm).19 The CT-selective pulse,
or “solid-π/2”, used for the SN samples was calibrated
using NaCl, and scaled by a factor of 1/(I + 1/2) = 1/2.
The selective pulse lengths used varied between 1.5
and 2.0 :s. Spectra were collected under MAS conditions using either a one pulse (anhydrous and monohydrate) or Hahn echo sequence (i.e., π/2 → τ1 →
R
(Bayer
π → τ2 → acq;20 methanol solvate and Aleve
Inc., Toronto) along with proton decoupling during
the acquisition time. A Bruker 7 mm HXY tripleresonance MAS probe was used at 4.7 T (with a spinning frequency of 4 kHz for the monohydrate) and a
Bruker 4 mm HXY triple-resonance probe was used
at 9.4 T (with spinning frequencies of 8 kHz for anhydrous SN and 10 kHz for the monohydrate, the
R
). A recycle delay of 2.0 s
methanol solvate, and Aleve
was used for all experiments with the exception of
R
where this was 4.0 s. Spectra of SN monoAleve
hydrate, anhydrous SN, the methanol solvate of SN,
R
were acquired with 228, 3548, 5120, and
and Aleve
1219 scans, respectively. The 23 Na DOR NMR experiments were performed at 9.4 T and used a Bruker
HP WB 73A DOR probe with a 4.3 mm inner rotor
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 8, AUGUST 2012
2932
BURGESS ET AL.
and a 14 mm outer rotor. The inner rotor spinning
was monitored using an antenna which was attached
to the stator and then connected to an oscilloscope.
The outer rotor spin rates were 1004, 825, and 720
R
Hz for the anhydrous, methanol solvate, and Aleve
samples, respectively. Outer rotor spin rates were stable to within 2 Hz, whereas inner rotor spin rates
were only monitored qualitatively. All DOR experiments used a single pulse with proton decoupling and
outer rotor synchronization to remove the odd ordered
sidebands.21 The CT-selective π/2 pulse lengths were
set to 3.1 :s for all experiments. The numbers of scans
R
), 129 (methanol solvate), and 159
were 100 (Aleve
R
) and
(anhydrous), with recycle delays of 1 (Aleve
2 s (anhydrous and methanol solvate). In the case of
R
, the double frequency sweeps (DFS) technique
Aleve
was used to enhance the signal from the CT.22 The
DFS pulse swept from 900 to 175 kHz over a duration
of 667 :s.
Data Processing and Simulations
All NMR spectra were processed with Bruker TopSpin 3.0 software. The free-induction decays (FIDs)
acquired with a Hahn echo sequence were left-shifted
an appropriate number of points to the top of the CT
echo signal. All MAS NMR spectra were then simulated in the frequency domain using the WSolids
software package (Universitat Tuebingen, Germany,
2001). The DOR NMR spectra were simulated with
a GAMMA23 density matrix simulation program described elsewhere.24 The simulations assumed one or
two (vide infra) crystallographically distinct sites, in
accordance with the single-crystal XRD data for each
system. Stack plots for figures were generated with
DMFit (v. 2011).25
Single-Crystal XRD
A suitable crystal of SN heminonahydrate was selected, mounted on a thin glass fiber using paraffin oil,
and cooled to the data collection temperature of 200 K.
Data were collected on a Bruker AXS SMART singlecrystal diffractometer equipped with a sealed Mo tube
source (wavelength = 0.71073 Å), and an APEX II
CCD detector. Raw data collection and processing
were performed with the APEX II software package
from Bruker AXS.26 Diffraction data were collected
with a sequence of 0.3◦ ω scans at 0◦ , 90◦ , 180◦ , and
270◦ each with 600 frames in ϕ. A fifth batch was run
at 0◦ with 50 frames. Initial unit cell parameters were
determined from 60 data frames and correspond to
different sections of the Ewald sphere. Semi-empirical
absorption corrections based on equivalent reflections
were applied.27 The systematic absences and unit cell
parameters were consistent with the C2 space group.
Solutions yielded chemically reasonable and computationally stable results of refinement. The structure
was solved by direct methods, completed with differJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 8, AUGUST 2012
ence Fourier syntheses, and refined with full-matrix
least-squares procedures based on F2 (square of the
structure factor). Positions of all the hydrogen atoms
were obtained from the Fourier map analysis; however, all hydrogen atoms were added into idealized
positions to satisfy the formula. All scattering factors
are contained in several versions of the SHELXTL
program library, with the latest version used being v.6.12.28 Crystallographic data are reported in
Table 2.
GIPAW DFT Computations
GIPAW DFT calculations were performed with version 4.1 of CASTEP-NMR (Accelrys Inc., San Diego,
California) and input files were generated using
the available crystal structure data using Materials Studio version 3.2 (Accelrys Inc.).29 The X-ray
structure of the anhydrous form was used as reported in the literature.30 On-the-fly generation ultrasoft pseudopotentials were used for all atoms in
the lattice and were obtained directly from Accelrys Inc. All calculations used the Perdew, Burke, and
Ernzerhof exchange-correlation functional under the
generalized gradient approximation with both an
ultra-fine energy cut-off, Ecut , and k-point grid (see
Table S1 in the Supporting Information). Sodium
magnetic shielding and EFG tensors were then extracted from the output files using a modified version
of the EFGShield program.31 The isotropic magnetic
shielding from the calculations can be related to the
isotropic CS, δiso , in the following way:
δ iso =
(σ iso,ref − σ iso )
(1 − σ iso,ref )
where σiso,ref is the absolute shielding value for a
reference material. For 23 Na, this shielding value is
576.6 ppm for infinitely dilute sodium cations in D2 O
at 297 K.32
RESULTS AND DISCUSSION
The experimental sodium NMR parameters for the
SN hydrates and solvates studied here may be found
in Table 1, whereas Figures 1 and 2 contain the corresponding MAS and DOR NMR spectra. First, 23 Na
MAS spectra of the CT are acquired and analytically simulated to fully characterize the EFG tensor parameters (i.e., the quadrupolar coupling constant, CQ , and the asymmetry parameter, ηQ ) as well
as the isotropic CS, δiso . These results are then complemented with 23 Na DOR NMR experiments, as the
shifts observed under these conditions are the sum
of δiso and the second-order quadrupole-induced shift,
the latter of which is proportional to CQ and ηQ .33
Density matrix simulations24 are used to corroborate
these shifts and the spinning sideband manifolds
DOI 10.1002/jps
SODIUM-23 SOLID-STATE NMR OF COMMERCIAL SODIUM NAPROXEN AND ITS SOLVATES
Table 1.
2933
Experimental 23 Na Quadrupolar Coupling Data
Sodium Naproxen Sample
Anhydrous
Monohydrate
Methanol solvate
|CQ (23 Na)|c (MHz)
ηQ
δiso (ppm)
2.88(0.03)
3.08(0.03)
1.08(0.03)
3.05(0.02)
∼0d
0.70(0.03)
0.58(0.02)
0.52(0.05)
0.32(0.03)
–d
3.3(0.4)
2.4(0.3)
4.9(0.2)
1.4(0.1)
−1.0(0.1)d
Site 1
Site 2
Site 1
Site 2
a Error
bounds are in parentheses.
EFG may be described as a second rank tensor (V), which can be represented by a 3 × 3 Cartesian matrix.
In its principal axis system (PAS), this matrix is diagonal where the principal components, Vii , are defined such that
|V11 | ≤ |V22 | ≤ |V33 | and V11 + V22 + V33 = 0. These principal components are represented conventionally by the
quadrupolar coupling constant, CQ (eQV33 /h in MHz), and the asymmetry parameter, ηQ ((V11 − V22 )/V33 ranging
between 0 and 1).
c One typically measures the absolute value, |C |.
Q
d No second-order line shape broadening effects were observed, suggesting a negligible EFG at this sodium site.
b The
observed (vide infra). Spectra may also be acquired
under stationary conditions to fully characterize the
remaining CS tensor parameters (i.e., the span, ,
and the skew, κ; see the Supporting Information
for more details). These experiments (not shown)
revealed that broadening of the 23 Na CT due to
anisotropic magnetic shielding is not significant in
this study, as never exceeds 10 ppm. The values
for δiso are seen to vary between −1 (site 2 in the
methanol solvate) and 4.9 ppm (monohydrate), which
is within the range of values observed for sodium
acetate12 and tetrasodium ethylenediaminetetraacetate salts.34 The value of CQ (23 Na) ranges from close
to 0 (site 2 in the methanol solvate) to 3.08 MHz (site
2 in the anhydrous form). This exceeds the upper
limit of all the sodium nucleotides studied to date35
and resembles more the values observed for sodium
metallocenes.36,37 Specific results and highlights will
be addressed below for each of the individual solvates
studied.
Anhydrous and Monohydrate Forms of SN
The crystal structures for the anhydrous and monohydrate forms have been solved previously by singlecrystal XRD and each pack in the P21 space group.30,38
For the monohydrate, the crystals isolated as part of
this study matched what was reported by Kim et al.38
This group has also elucidated the structure of the
anhydrous form, which will be used for our interpretations in the context of the NMR parameters.
The 23 Na MAS NMR spectrum of SN monohydrate
acquired at B0 = 9.4 T may be found in Figure 1b.
The relatively narrow line shape made the analytical simulation of the spectrum more challenging. As
a result, data were acquired at a second field (B0 =
4.7 T, see Figure 1d) where the typical singularities of
a MAS line shape are more apparent as the broadening from the QI is more pronounced when B0 is decreased. The spectra obtained at both magnetic fields
are representative of one sodium site per asymmetric unit in the crystal structure, which is consistent
DOI 10.1002/jps
with the one reported.38 The line shape is characterized by a relatively small CQ (23 Na) of 1.08(0.03) MHz
and the largest δiso observed in this study of 4.9(0.2)
ppm. The sodium cation does not sit on any rotational
axis; therefore, the EFG tensor is not expected to be
axially symmetric (ηQ = 0). The same can be said for
anhydrous SN, for which the 23 Na MAS and DOR
NMR spectra are shown in Figures 1f and 2b, respectively. Both of these spectra were simulated with two
crystallographically distinct sodium sites, each with
100% occupancy, which is consistent with the reported
crystal structure.30 Both sites have very similar δiso
values, but slight differences in their CQ (23 Na) values [2.88(0.03) and 3.08(0.03) MHz for sites 1 and
2, respectively] allow for their differentiation under
both MAS and DOR conditions. This demonstrates
the power of SSNMR in detecting subtle structural
differences between two seemingly identical sodium
sites. An abstract by Yamamoto and coworkers reported PQ (i.e., CQ (1 + ηQ 2 /3)1/2 ) values of 1.10 and
3.09 MHz for anhydrous SN as a result of 23 Na
MQMAS experiments.39 Although our data for site
2 are consistent with their values, the data for site 1
are not. We speculate that their results may have
been misinterpreted, as both sodium sites from the
crystal structure of anhydrous SN are in very similar coordination environments and our 13 C CP/MAS
spectrum (see Figure S1 in the Supporting Information) is in full agreement with the assignment of Di
Martino et al.6 In addition, we have performed our
own 23 Na MQMAS experiment to corroborate these
findings (see Figure S2 in the Supporting Information). We were unable to resolve both sodium sites
of anhydrous SN using this method at 9.4 T, suggesting that DOR NMR experiments can provide a higher
degree of resolution in a shorter amount of time (experiment times of 20 h and 5 min for the MQMAS and
DOR experiments, respectively). Thus, in this case, a
MQMAS NMR experiment does not aid in our characterization of the EFG tensor parameters.
Interestingly, a threefold increase in the value of
CQ (23 Na) for the anhydrous form with respect to the
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2934
BURGESS ET AL.
Figure 1. 23 Na MAS solid-state NMR spectra of the studied solvates of sodium naproxen. The
spectrum for sodium naproxen monohydrate (b) and (d) were acquired at B0 = 9.4 and 4.7 T
with spinning frequencies of 10 and 4 kHz, respectively. Spectra for both the anhydrous (f) and
the methanol solvate (h) of sodium naproxen were acquired at B0 = 9.4 T with spinning frequencies of 8 and 10 kHz, respectively. The asterisk (∗) denotes the presence of sodium chloride
in the sample. All analytical simulations (a, c, e, and g) were performed using WSolids (data in
Table 1).
monohydrate is noted. This can be explained qualitatively by analyzing the sodium cation’s coordination environments in each species. For SN monohydrate, five oxygen atoms arranged in a distorted
trigonal bipyramidal manner surround a Na+ ,
whereas in anhydrous SN, four oxygen atoms coordinate to each Na+ in a trigonal pyramidal fashion.
The decreased degree of symmetry about the sodium
cation in the latter accounts for the increase in the
value of CQ (23 Na).
The Methanol Solvate of SN
Presented in Figures 1h and 2d are, respectively, the
23
Na MAS and DOR NMR spectra of the methanol
solvate of SN. The resonance marked by an “M” represents the presence of a SN monohydrate impurity
as both its shift in the DOR spectrum and the fitting
parameters are exactly those used for this hydrate.
Furthermore, a 23 Na DOR spectrum acquired several
months later (see Figure S3 in the Supporting Information) suggests that this resonance is from a different species than the other two, which stem from
both crystallographically distinct sodium sites of the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 8, AUGUST 2012
methanol solvate of SN. This conclusion is reached
because the relative intensities of sites 1 and 2 do not
change, whereas a significant decrease in the presence of the SN monohydrate is noted over this period of time. A PXRD experiment (see Figure S4 in
the Supporting Information) was performed on this
sample and it confirms that a methanol solvate of
SN was obtained as the peaks match what was reported by Chavez et al.40–42 in their characterization of various alcohol solvates by PXRD and thermogravimetric analysis. Therefore, we speculate that
the methanol solvate contains two different sodium
cations per asymmetric unit and that these are not
in very similar chemical environments, in contrast to
anhydrous SN. This is because of the large difference
in their CQ (23 Na) values [i.e., 3.05(0.02) MHz for site
1 and ∼0 for site 2]. Attempts at corroborating this
with 13 C CP/MAS NMR were unsuccessful as assignments proved quite difficult with the overlapping signal from the monohydrate impurity (see Figure S5).
This further exemplifies that 23 Na SSNMR can easily
differentiate between solvates in a more straightforward manner than 13 C SSNMR for a more challenging sample of SN that contains impurities from other
DOI 10.1002/jps
SODIUM-23 SOLID-STATE NMR OF COMMERCIAL SODIUM NAPROXEN AND ITS SOLVATES
2935
methanol molecules. Even though our sample corresponds to a different methanol solvate, the calculated
EFG tensor parameters (vide infra) for this are in
agreement with experiment, which supports that the
crystal structure of our sample is probably similar to
the single crystal X-ray structure reported by Chavez.
The Crystal Structure of SN Heminonahydrate
Figure 2. 23 Na DOR solid-state NMR spectra of the solvates of sodium naproxen studied in this work. Both anhydrous (b) and the methanol solvate (d) of sodium naproxen
were acquired at B0 = 9.4 T. Numbers indicate the peak
corresponding to each site, as in Table 1. Density matrix
simulations (a and c) were performed to accurately simulate the experimental spectra.
solvates. In the case of 13 C NMR, for example, the
general carbon framework of the naproxen molecule
does not change significantly when comparing different solvates. On the contrary, the sodium cation coordination environment differs immensely from one
hydrate to another, making it the ideal probe for differentiating between solvates.
A preliminary single-crystal X-ray structure, reported in the doctoral thesis of Chavez, has a 3:2 ratio of methanol to SN.40 However, our PXRD data are
more in agreement with Chavez’s diffractogram obtained from powdered crystals synthesized by slow
evaporation (i.e., our method as well), which is in
slight disagreement with the simulated one from
the reported crystal structure.40 This structure contains two crystallographically distinct sodium sites,
one of which is coordinated to three methanol oxygen atoms and three naproxen carboxylate oxygen
atoms in a near octahedral fashion, whereas the other
sodium site is surrounded by seven oxygen atoms
from three naproxen carboxylate groups and two
DOI 10.1002/jps
The existence of a tetrahydrated form of SN was reported by Di Martino et al.6 They synthesized this
hydrate (among others) by exposing anhydrous SN
to various relative humidities (RH) for several days
and it was found that the tetrahydrated form could
be obtained when the RH exceeded 75%.6,43,44 In fact,
the species obtained were highly dependent upon the
RH. In our laboratory, we recrystallized a mixture of
naproxen and sodium hydroxide in 1-butanol without
particular concern for the ambient RH. According to
the crystal structure determined herein, each asymmetric unit in the single crystal contains one SN and
4.5 water molecules (i.e., it is a heminonahydrate).
This structure is different from the others described
earlier as each sodium cation is coordinated solely by
water molecules and forms a “zig–zag” chain sandwiched between layers of naproxen carboxylate moieties (see Figure 3). Table 2 summarizes both the crystallographic data and collection parameters used to
solve this structure. It should be noted that the crystals obtained diffracted rather poorly at high diffraction angles and the results presented here are the
best out of several attempts. Finally, the simulated
PXRD data from this crystal structure (see Figure S6)
is in full agreement with Di Martino et al.’s6 diffractogram and is thus a further characterization of their
material.
As for 23 Na SSNMR experiments, the MAS spectrum obtained for the heminonahydrate was identical to that of the monohydrate. We speculate that the
sample easily transformed into the monohydrate as
the hydration level is known to depend upon the ambient RH.6 Sample grinding, which is essential for the
types of SSNMR experiments and probes available to
us (as well as for PXRD), may have also contributed
to partial dehydration.
The 23 Na SSNMR Characterization of Commercial SN
With the 23 Na EFG tensor parameters of the different SN solvates in hand, we sought to investigate the
composition of a commercial brand of SN sold “ overR
. In Figures 4b and 4d are the
the-counter”: Aleve
23
experimental Na DOR and MAS NMR spectra, reR
along with
spectively, of a single capsule of Aleve
spectral simulations (Figures 4a and 4c). These simulations were generated using a superposition of simulated spectra generated exclusively from the experiR
mental data in Table 1. We can conclude that Aleve
is mostly composed of the monohydrated form of SN
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2936
BURGESS ET AL.
Table 2. Crystallographic Data and Data Collection Parameters for Sodium
Naproxen Heminonahydrate
Empirical Formula
mol−1 )
Formula weight (g
Crystal size (mm)
Crystal system
Space group
Z
a (Å)
b (Å)
c (Å)
α (◦ )
β (◦ )
γ (◦ )
Volume (Å3 )
Calculated density (Mg/m3 )
Absorption coefficient (mm−1 )
F(000)
Range for data collection (◦ )
Limiting indices
Reflections collected/unique
R(int)
Completeness to = 28.32 (%)
Max and min transmission
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
Largest diff peak/hole (e Å−3 )
along with a nonnegligible amount of anhydrous SN.
A tentative ratio of 1:0.3 can be assigned on the basis of the relative intensities in the MAS spectrum
of the line shapes of the monohydrate and anhydrous
species. We emphasize here that this quantification is
provisional, as the 23 Na QI in these two species varies
C14 H13 NaO3 ·4.5H2 O
333.31
0.16 × 0.14 × 0.08
Monoclinic
C2
4
40.8732 (18)
5.5741 (3)
7.1037 (3)
90
98.045 (3)
90
1602.52 (13)
1.381
0.133
708
3.69–24.78
h = ±48, k = ±6, l = ±8
13,121/2642
0.0592
94.8
0.9894 and 0.9790
2642/1/229
1.059
R1 = 0.0864, wR2 = 0.2084
R1 = 0.1001, wR2 = 0.2240
0.737/−0.364
significantly (see Table 1). As a result, transverse relaxation (i.e., T2 ) will differ between both solvates
leading to slight differences in their relative spectral intensities. Furthermore, sample grinding and
changes in the ambient RH may have an effect, as was
proposed for the SN heminonahydrate (vide supra).
Figure 3. Depiction of part of the crystal structure determined for sodium naproxen heminonahydrate. Eight unit cells of the crystal structure are seen with the b-axis going into the page.
Hydrogen atoms have been omitted for clarity. The grey wire frame represents the naproxen
carbon scaffold. The red and green spheres represent the oxygen and sodium atoms, respectively.
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SODIUM-23 SOLID-STATE NMR OF COMMERCIAL SODIUM NAPROXEN AND ITS SOLVATES
2937
Figure 4. 23 Na solid-state NMR spectra of commercial sodium naproxen. Both the DOR
R
were acquired at B0 = 9.4 T. A
(b) and MAS (d, spinning frequency of 10 kHz) spectra of Aleve
density matrix simulation was performed for the DOR spectrum (a) and WSolids was used to
simulate the MAS spectrum in (c). The insets of the experimental 23 Na DOR and MAS NMR
R
. A sharp
spectra indicate the nonnegligible presence of anhydrous sodium naproxen in Aleve
peak at about −8 ppm in the DOR spectrum is assigned to a small amount of an unknown
species. The asterisk (∗) denotes the presence of sodium chloride in the sample.
DOI 10.1002/jps
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 8, AUGUST 2012
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BURGESS ET AL.
Figure 5. GIPAW DFT calculated vs. experimental 23 Na
EFG tensor components. The individual components are denoted Vii (where ii = 11, 22, or 33). The anhydrous and
monohydrate pseudopolymorphs are depicted here using
black diamonds. The line of best fit is as follows: Vii (23 Na,
calc.) = 1.13(Vii , 23 Na, expt.), R2 = 0.996. The calculated
EFG tensor components for site A of the methanol solvate
are also shown as empty circles.
GIPAW DFT Calculations
Summarized in Table 3 are the GIPAW DFT calculated values for the 23 Na EFG tensor parameters and
isotropic CSs of the various forms of SN considered in
this study. With respect to the monohydrate and anhydrous SN, the calculated 23 Na EFG tensor components are in excellent agreement with experiment, as
quantified by a Pearson’s correlation coefficient, R2 , of
0.996 (Figure 5). It is noted, however, that these values are consistently slightly overestimated by a factor
of 1.13. It is important to note that these results were
obtained from crystal structures in which the hydrogen positions were not optimized. To evaluate the possible effects this could have on our calculated NMR
parameters, the hydrogen positions were optimized
in the monohydrated form of SN within the CASTEP
program (Accelrys Inc.). This was found to slightly
improve the value of CQ by 6% with respect to the
experimental one. This result suggests that the overestimation of the EFG tensor parameters is partly
inherent to the GIPAW DFT method and not solely
because of the inability of XRD to accurately predict
hydrogen positions. The values of δiso are consistently
overestimated by the calculations by approximately
20 ppm when using the absolute shielding scale for
sodium. Again, this does not stem from our inability to accurately predict the hydrogen positions as
an improvement of only 5% was obtained when these
were optimized in the monohydrate’s crystal structure. The calculations allow us to assign both sodium
sites in the crystal structure of anhydrous SN to experimental 23 Na NMR parameters as, for example,
the calculated trends (higher CQ (23 Na), lower ηQ , and
lower δiso ) for site B (Table 3) are consistent with those
of site 2 in Table 1. The same kind of interpretation
may be made for site A and site 1.
For the methanol solvate, the calculated CQ (23 Na)
values for the two crystallographically distinct
sodium sites are quite different from each other, which
is in agreement with our experimental findings. The
calculated EFG tensor components are plotted in Figure 5 for site 2 of the methanol solvate where it is
evident that these are also well reproduced. However,
an unambiguous assignment of sites to spectral parameters, as was carried out for anhydrous SN, cannot be made in this case as the PXRD data do not
match exactly with the single-crystal XRD structure;
this discrepancy is identical to what was found by
Chavez (vide supra). Nevertheless, it is still possible to speculate that site 1 of the methanol solvate
(Table 1) would be in a similar coordination environment to site A in the crystal structure (Table 3).
CONCLUSION
Magic-angle spinning and DOR solid-state 23 Na NMR
methods were used to characterize various forms of
SN: anhydrous, monohydrate, and methanol solvates.
This permitted us to fully characterize their 23 Na
EFG tensors as well as their isotropic CSs. These results indicate that CQ (23 Na) is a marker for the different hydrates/solvates of SN, as this parameter is
quite sensitive to small differences in crystal packing.
The value of CQ (23 Na) is also quite sensitive to the
local oxygen environment about the sodium cations
because of its rather large range. The NMR methods
used here provide information about the phase purity of SN in a more straightforward manner than
13
C solid-state NMR or PXRD, as exemplified with
the methanol solvate sample. We have also analyzed
R
and found that it is
commercial SN sold as Aleve
composed of both the monohydrate and anhydrous
species in an approximately 1:0.3 ratio. During this
study, we have obtained the first crystal structure of
SN heminonahydrate, but attempts at characterizing
Table 3. Calculated 23 Na Quadrupolar Coupling Data and Isotropic Chemical Shifts
for the Different Sodium Naproxen Solvates with the GIPAW DFT Method
Sodium Naproxen Sample
Anhydrous
Monohydrate
Methanol solvate
Site A
Site B
Site A
Site B
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 8, AUGUST 2012
CQ (23 Na) (MHz)
ηQ
δiso (ppm)
3.20
3.47
1.55
3.92
1.47
0.68
0.54
0.48
0.25
0.94
22.2
20.1
24.5
15.4
19.7
DOI 10.1002/jps
SODIUM-23 SOLID-STATE NMR OF COMMERCIAL SODIUM NAPROXEN AND ITS SOLVATES
it by 23 Na NMR were unsuccessful presumably due to
sample grinding and/or the ambient RH. Valuable information was extracted from the GIPAW DFT quantum chemical calculations. For example, we were able
to assign both sodium sites in the crystalline lattice
to their respective NMR signals in anhydrous SN and
the calculated EFG tensor parameters were found to
be in excellent agreement with experiment where an
adequate X-ray crystal structure is available. We envision that 23 Na SSNMR experiments will be quite
useful to pharmaceutical scientists as the phase purity of a drug sample can be evaluated qualitatively in
a matter of minutes under MAS or DOR NMR conditions. We observed that, because of the sharper lines
obtained under DOR conditions, the sensitivity of the
23
Na DOR experiment is comparable to that of the
standard 23 Na MAS experiment. Future work may
lead to more quantitative results for analyzing phase
purity.
ACKNOWLEDGMENTS
K.M.N.B. and F.A.P. thank the Natural Sciences and
Engineering Research Council (NSERC) of Canada
for graduate scholarships. A.L. thanks Dr. Claudia Gomes de Morais at l’Université de Poitiers in
Poitiers, France for support during her exchange program to Canada. E.M.-H. thanks the COOP program
at the University of Ottawa for financial support.
D.L.B. thanks NSERC, the Canada Foundation for Innovation, and the Ontario Ministry of Research and
Innovation for funding. We thank Dr. Glenn Facey
for technical support. We are grateful to Dr. Henry
J. Stronks and coworkers at Bruker Biospin for their
support of our DOR research program.
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