The structure of glibenclamide in the solid state

Article abstract of DOI:10.1002/mrc.2868

The structure of glibenclamide, 5-chloro-N-(2-{4-[(cyclohexylamino) carbonyl] aminosulfonyl}phenyl) ethyl)-2-methoxybenzamide, an important antidiabetic drug, has been studied both in solution and in the solid state by a combination of NMR spectroscopy and theoretical calculations. The possibility that glibenclamide suffers a tautomerization under melting to afford a desmotrope was rejected. Copyright

Full text of DOI:10.1002/mrc.2868

MRC Letter
Received: 23 July 2011
Revised: 26 October 2011
Accepted: 6 November 2011
Published online in Wiley Online Library: 1 March 2012
(wileyonlinelibrary.com) DOI 10.1002/mrc.2868
The structure of glibenclamide in the solid state
a
a
b
b
Dionisia Sanz, * Rosa M. Claramunt, Ibon Alkorta, * Goar Sánchez-Sanz
b
and José Elguero
The structure of glibenclamide, 5-chloro-N-(2-{4-[(cyclohexylamino)carbonyl] aminosulfonyl}phenyl) ethyl)-2-methoxybenzamide,
an important antidiabetic drug, has been studied both in solution and in the solid state by a combination of NMR spectroscopy
and theoretical calculations. The possibility that glibenclamide suffers a tautomerization under melting to afford a desmotrope
was rejected. Copyright © 2012 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article.
Keywords: SSNMR; GIAO; B3LYP/6-311++G(d,p)
[
19]
[20–22]
Both Rades and Wojnarowska
forget to cite a fundamental
Introduction
[
24]
[18]
paper by Byrn et al.
and in seven other papers ) where the X-ray structure (no
H atoms) was reported (Fig. 3). The compound has the refcode
in 1986 (it was cited by Hassan et al.
[
25]
Glibenclamide (glyburide, 1) is an antidiabetic drug belonging to
the class of sulfonylureas;
[
1,2]
it was developed in 1966 in a coop-
[
26]
erative study between Boehringer and Hoechst. Still an important
DUNXAL (glyburide).
Note that even if the H atoms were not
[3]
drug, different aspects of glibenclamide continue to attract a
located, there is a clear N(8)–HꢀꢀꢀOMe hydrogen bond in 1.
[4–9]
[27,28]
[29,30]
wide attention.
Mainly Harris
and also ourselves
have solved some
Glibenclamide present polymorphism, a phenomenon of consid-
erable importance in the pharmaceutical industry because it can
extend patents if some beneficial pharmacokinetic difference could
be demonstrated. It is necessary to distinguish between true
polymorphism (generally because of a conformational change of
the molecule or to packing differences), pseudo-polymorphism
structural problems of drugs using this technique in combination
with theoretical calculations of chemical shifts. Obviously, NMR is
one of the methods of choice to study tautomerism.
In view of these results and considering that solid-state CPMAS
NMR is an instrument of choice to study polymorphism, we
decided to examine the case of glibenclamide.
[
31]
[10]
(
solvates), and desmotropy (crystals of two different tautomers
[
11,12]
of the same compound).
tance of tautomerism in drug discovery should be noted.
The first report of glibenclamide polymorphism was published Experimental
Regarding desmotropy, the impor-
[
13]
[14]
in 1982.
In 1989, Suleiman and Najib reported that glibencla-
Glibenclamide was purchased from Sigma (G0639-5 G), mp
mide crystallized from different organic solvents exists in two
polymorphic forms (I and II) and two pseudo-polymorphic forms
ꢁ
1
73–175 C, >99% HPLC, and was used without further purification.
[
15]
Differential scanning calorimetry thermograms were recorded on a
(
pentanol and toluene solvates). Similar results were described
–1
[16]
Seiko DSC 220 C instrument with a scanning rate of 5º min . The
mass spectra experiments were conducted in a system composed
of a quaternary pump LC-MS Finnigan Surveyor coupled to a mass
spectrometer with source of ionization at atmospheric pressure by
electrospray and analyzer of ion trap Finnigan LCQ Deca (Thermo
Fisher Scientific, San Jose, CA, USA). The samples were brought to
in 1997. In 2000, Malamataris et al. characterized by Differential
Scanning Calorimetry (DSC), IR, Scanning Electron Microscopy (SEM)
[
17]
and X-Ray Diffraction (XRD) a new polymorph of glibenclamide.
In these papers, no hypothesis was made about the structure of
[
18]
the polymorphs, but in 1991, Hassan et al.
glassy form of glibenclamide corresponds to the double enol tauto-
proposed that the
–1
[
19]
a concentration of 0.1mgꢀml , and 10 ml was injected through a
mer 1c (Fig. 1). In 2005, Rades et al. studied the effect of quench
cooling and ball milling on the polymorphism of glibenclamide and
deduced, from the inability of sulfonylureas to tautomerize (see 1a),
that the polymorph has the structure 1b (mono-enol of the amide).
Then, in 2010, Wojnarowska et al. published three papers on
the polymorphism of glibenclamide based on the tautomeric
flow loop in acetonitrile: water (75 : 25). [Milli-Q water (Millipore,
[
20–22]
* Correspondence to: Dionisia Sanz, Departamento de Química Orgánica y
Bio-Orgánica, Facultad de Ciencias, Universidad Nacional de Educación a Distancia
forms 1a and 1b.
2 d,2p) calculations and recognize that the enol forms 1a and
b are much less stable than 1. Bharatam et al. have studied the-
oretically (MP2) the tautomerism of one part of glibenclamide,
The authors carry out B3LYP/6-311++G
(
1
(UNED), Senda del Rey 9, E-28040 Madrid, Spain. E-mail: dsanz@ccia.uned.es
Ibon Alkorta, Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006
Madrid, Spain. E-mail: ibon@iqm.csic.es
[
23]
that of the sulfonylurea using compound 6 as model. Among
the different tautomers (besides 6, only two OH are represented
in Fig. 2), the most stable is tautomer 6a, 25 kJ mol less stable
than 6.
a Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias,
Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
–
1
b Instituto de Química Médica, CSIC, Madrid, Spain
Magn. Reson. Chem. 2012, 50, 246–255
Copyright © 2012 John Wiley & Sons, Ltd.

Tautomerism and thermal studies of glibenclamide
H
H
N
O
O
O
O
S
O
O
O
S
H
H
O
O
N
N
H
MeO
O
O
N
H
Cl
N
H
N
N
1a
1c
5
"
4"
Cl
Me
6"
3"
O O O
6
'
O
O
7
'
9'
2"
5
'
S
S
1' N 8'
N
H
1"
O
MeO
N
H
N
H
6
3
9
8
N
H
Cl5
2'
H
1 7
4'
1
0
3'
4
2
1
1b
O
Me
Δ
Cl
O O
O O
6
'
6'
1'
1'
S
S
5'
OH7'
5'
4'
O 8
O
NH2 7'
6
3
9
9
6
Cl 5
4
1
2
2'
Cl 5
1
2
7
8
N
H
2
'
7
4'
N
H
10
3'
10
3'
4
O
3
O
2
3
Me
Me
H
or
5"
4"
5"
6"
4"
6
"
3"
3"
2"
O 9
N
H
O 9'
'
H
2"
1"
O
8' N 1"
N
H
4
5
H
Figure 1. Glibenclamide (1), tautomerism and decomposition.
O
H
H
N
CH
3
H
CH
3
O
S
O
O
O
S
O
N
N
N
H
CH
3
O S
N
N
H
O
H
O
6a
6a'
6
Figure 2. Tautomers of sulfonylureas.
H-X probe equipped with a z-gradient coil. Chemical shifts
1
(
d in ppm) are given from internal solvent, DMSO-d 2.49 for H
6
13 15
and 39.5 for C, and for N NMR, nitromethane (0.00) was used
as external standard. Coupling constants (J in Hz) are accurate to
1
13
1
0
.2 Hz for H and ꢃ 0.6 Hz for C. Typical parameters for H NMR
spectra were spectral width 5000Hz and pulse width 7.5ms at an
13
attenuation level of 0 dB. Typical parameters for C NMR spectra
were spectral width 20 kHz, pulse width 10.6ms at an attenuation
level of ꢂ6 dB and relaxation delay 4 s; WALTZ-16 was used for
broadband proton decoupling; the Free Induction Decays, FIDs
were multiplied by an exponential weighting (lb = 2 Hz) before
Fourier transformation.
Figure 3. The X-ray structure of glibenclamide 1, DUNXAL.
Two-dimensional (2D) inverse proton-detected heteronuclear
1
13
1
13
shift correlation spectra, ( H– C) gs-HMQC, ( H– C) gs-HMBC,
W
Bedford, USA), acetonitrile (LC ꢂ Chromasolv MS grade, Riedel-
1
15
1
15
( H- N) gs-HMBC and ( H– N) gs-HMQC were acquired and
processed using standard Bruker NMR software and in non-phase
sensitive mode. Gradient selection was achieved through a 5%
sine truncated shaped pulse gradient of 1 ms. Selected para-
de-Haën, Seelze, Germany)]. The conditions of the ion source were
-1
as follows: flow rate, 100 ml min ; spray voltage, 4.5kV; capillary
ꢁ
-1
temperature, 275 C; sheath gas (99.5% N ), 1.05 L min ; and
2
-1
1
13
auxiliary gas (99.5% N ), 6 L min .
meters for ( H– C) gs-HMQC and gs-HMBC spectra were spectral
2
1
13
width 5000 Hz for H and 20 kHz for C, 1024 x 512 data set,
number of scans 2 (gs-HMQC) or 4 (gs-HMBC) and relaxation
delay 1 s. The FIDs were processed using zero filling in the F1
domain, and a sine-bell window function in both dimensions
was applied prior to Fourier transformation. In the gs-HMQC
NMR experimental details
Solution NMR spectra were recorded at 300 K on a Bruker DRX
1
13
4
00 (9.4 Tesla, 400.13 MHz for H, 100.62 MHz for
C and
1
5
13
4
0.56 MHz for N) spectrometer with a 5-mm inverse-detection
experiments, GARP modulation of C was used for decoupling.
Magn. Reson. Chem. 2012, 50, 246–255
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

D. Sanz et al.
1
15
1
15
Selected parameters for ( H- N) gs-HMBC and ( H– N) gs-HMQC
have been used for the calculations of the absolute chemical
1
15
[37]
spectra were spectral width of 5000Hz for H and 20 kHz for N,
shieldings with the GIAO method
and the B3LYP/6-311++G
1
024 x 256 data set, number of scans 32 (gs-HMBC) or 8 (gs-HMQC),
(d,p) computational level. All the calculations have been carried
out with the Gaussian-09 package.
15
[38]
relaxation delay 1 s, 37- to 100-ms delay for the evolution of the
1
N- H long-range coupling. The FIDs were processed using zero
filling in the F1 domain, and a sine-bell window function in both
dimensions was applied prior to Fourier transformation.
Solid-state C (100.73 MHz) and N (40.60 MHz) CPMAS NMR
spectra have been obtained on a Bruker WB 400 spectrometer at
Results and Discussion
1
3
15
Gas phase
3
00 K using a 4 mm DVT probe head. Samples were carefully
We have calculated the relative energies of glibenclamide and its
tautomers at the B3LYP/6-311++G(d,p) level (Fig. 4 and Table 1).
The double OH tautomer 1c is destabilized by about the sum
of the destabilizing effects of the two monohydroxy tautomers 1a
and 1b. According to these calculations, only 1 and 1a have a
probability to exist; moreover, the relative stability of 1 compared
with 1a should increase in condensed phases because of its higher
dipole moment.
packed in a 4-mm-diameter cylindrical zirconia rotor with Kel-F
ꢁ
1
end caps. Operating conditions involved 3.2 ms 90 H pulses
and decoupling field strength of 78.1 kHz by TPPM sequence.
13
C spectra were originally referenced to a glycine sample, and
then, the chemical shifts were recalculated to the Me Si [for the
4
15
15
carbonyl atom d (glycine)= 176.1ppm] and N spectra to NH
and then converted to nitromethane scale using the following rela-
tionship: d N(MeNO
tion parameters for C CPMAS were as follows: spectral width,
4
Cl
1
5
15
) = d N(NH
4
Cl) ꢂ 338.1 ppm. Typical acquisi-
The following equations have been used to transform absolute
shieldings into chemical shifts (Table 2):
2
1
3
4
5
0 kHz; recycle delay, 65 s; acquisition time, 30 ms; contact time,
ms; and spin rate, 12kHz. To distinguish protonated and unpro-
1
1
d H ¼ 31:0 ꢂ 0:97 ꢄ s H
tonated carbon atoms, the non-quaternary suppression experi-
ment by conventional cross-polarization was recorded; before the
acquisition, the decoupler is switched off for a very short time of
[
39]
Eqn 1 (reference TMS, 0.00 ppm)
1
3
13
[32,33]
15
d C ¼ 175:7 ꢂ 0:963 ꢄ s C
[40]
25 ms.
Typical acquisition parameters for N CPMAS were
as follows: spectral width, 40kHz; recycle delay, 65 s; acquisition
time, 30 ms; contact time, 5 ms; and spin rate, 6 kHz.
Eqn 2 (reference TMS, 0.00 ppm)
1
5
15
d N ¼ ꢂ152:0 ꢂ 0:946 ꢄ s N
Computational details
[
40]
Eqn 3 (reference ext. neat MeNO , 0.00 ppm)
2
The geometry of the molecules has been fully optimized with the
[34]
hybrid HF/DFT B3LYP computational method and the 6-31 G(d)
Solution
[35]
basis set. Frequency calculations have been carried out at the
same computational level to verify that the structures obtained
correspond to energetic minima. A further optimization has been
1
13
15
We have recorded the H, C and N spectra of glibenclamide
in DMSO-d (20 mg/0.5 ml), assigned the signals through 2D
experiments (HMQC and HMBC) and reported them in Table 3.
6
[
36]
carried out at the B3LYP/6-311++G(d,p) level. These geometries
1
1a
1
b
1c
Figure 4. Minimum energy conformations of glibenclamide and its tautomers.
wileyonlinelibrary.com/journal/mrc
Copyright © 2012 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2012, 50, 246–255

Tautomerism and thermal studies of glibenclamide
–
1
Table 1. B3LYP/6-311++G(d,p) absolute (hartrees), relative (kJ mol
)
Table 2. Calculated chemical shifts (d, ppm) from GIAO absolute
shieldings (s, ppm)
and relative corrected with zero point energy correction (ZPE) (kJ
mol ) energies of glibenclamide tautomers together with their dipole
moments (D)
–
1
Atom
Tautomer 1 Tautomer 1a Tautomer 1b Tautomer 1c
1
Tautomer
Absolute
Erel Erel + ZPE Dipole
moments
H
2-OMe
CH3
3.80
6.42
7.23
8.62
7.86
—
3.75
6.44
7.19
8.57
7.82
—
3.82
6.50
7.01
8.78
—
3.83
6.45
7.13
8.70
—
Dioxo 1
ꢂ2292.5100
ꢂ2292.5068
0.00
8.23
0.00
8.72
6.80
CH4
Monohydroxy
10.27
CH6
(sulfonylurea) 1a
NH-8
OH-7
Monohydroxy (amide) 1bꢂ2292.4847 66.22
Dihydroxy 1c
ꢂ2292.4811 75.88
63.86
75.82
8.01
9.87
9.20
3.60
2.71
7.39
7.43
7.41
7.76
8.40
8.08
5.44
—
9.09
3.58
2.66
7.48
7.29
7.38
7.82
7.76
7.79
—
CH
CH
2
9
3.33
2.86
7.66
7.25
7.46
8.56
7.72
8.14
5.57
—
3.36
2.86
7.58
7.20
7.39
7.86
7.83
7.84
—
2
10
H3’
H5’
The chemical shifts and assignments agree with those previ-
ously reported both for a 600-MHz instrument, DMSO-d
6
,
Average 3’,5’
H2’
[20]
[24]
2
99 K
and a 470 MHz, DMSO-d
6
, r.t.
The chemical shifts are
nearly identical, but we had to change some assignments and
H6’
13
attribute some unassigned signals. We report the C chemical
shifts of Ref. 20 with three figures after the point to respect the
original article.
Average 2’,6’
NH 7’
OH 8’
12.15
3.64
3.37
1.36
1.44
1.40
1.49
1.40
1.44
1.30
12.11
3.65
3.33
1.33
1.86
1.60
1.50
1.37
1.44
1.30
1
In H NMR, because we have not assigned the axial and equa-
NH 9’
3.02
3.71
1.28
1.25
1.26
1.53
1.52
1.52
1.23
2.91
3.53
1.34
1.25
1.30
1.58
1.42
1.50
1.41
torial protons of the cyclohexyl residue (2"–6"), the regression
should be limited to the remaining protons. When removing
NH7’ and NH9’ (hydrogen bonded), the best regression is
CH 1"
CH
CH
2
2"
6"
2
1
obtained for tautomer 1: exp. d H = (0.23 ꢃ 0.35) + (0.96 ꢃ 0.06)
Average 2",6"
1
2
calcd. d H, n = 11, R = 0.968, imposing the intercept = 0, the
CH
CH
2
3"
5"
1
1
equation becomes exp. d H = (0.99 ꢃ 0.02) calcd. d H, n = 11,
2
2
R = 0.997. However, with the other tautomers, the correlation
Average 3",5"
coefficients are only slightly worse: 0.957 (1a), 0.963 (1b) and
CH
2
4"
1
3
0
.963 (1c), but the intercepts are larger and the slopes further
C
from 1. Note that other authors prefer to use, instead of the
C1
C2
123.37
156.71
53.44
122.93
156.23
52.95
122.47
155.67
53.48
123.26
155.10
53.93
2
[41]
uncertainties of the coefficients, the reduced w statistic.
13
In C NMR, we have removed the carbon atom bearing the Cl
substituent (C5), as it has been widely demonstrated that large
halogen substituents produce abnormal effects on the carbons.
OMe
C3
108.52
131.19
136.01
134.26
161.00
45.31
108.67
131.77
136.39
134.02
160.26
45.41
108.94
131.51
135.04
132.68
153.92
52.16
108.85
131.07
137.23
132.69
153.35
51.95
C4
[42–47]
For the remaining signals, we obtained the following:
C5 (C-Cl)
C6
1
3
13
2
Tautomer 1: d C=–(3. 3 ꢃ 1. 6) + (1.02 ꢃ 0.02)d C, n = 18, R = 0.997
C7 (CO/COH)
1
3
13
2
Tautomer 1a: d C=–(2. 5 ꢃ 2.0) + (1.01 ꢃ 0.02)d C, n = 18, R = 0.995
C9
1
3
13
2
Tautomer 1b: d C=–(5. 1 ꢃ 2. 3) + (1.04 ꢃ 0.02)d C, n = 18, R = 0.993
C10
39.16
39.13
38.94
39.10
1
3
13
2
Tautomer 1c: d C=–(4. 3 ꢃ 2. 6) + (1.03 ꢃ 0.02)d C, n = 18, R = 0.992
Again, tautomer 1 is the best option, but the correlation coeffi-
C4’
146.21
126.78
129.15
127.96
132.85
126.49
129.67
142.72
147.05
49.66
144.81
128.06
128.94
128.50
127.28
125.78
126.53
146.74
156.48
50.03
147.98
127.66
128.85
128.26
126.18
131.62
128.90
142.65
146.12
50.35
146.09
128.61
128.39
128.50
127.39
124.70
126.04
146.05
156.47
50.05
C3’
C5’
cients do not discriminate between tautomers. For C5 and tauto-
mer 1, the model predicts 136.0 ppm instead of 124.8 measured,
that is, 11.2 ppm, a value similar to those (8–9 ppm) found by
Average 3’,5’
C2’
[42,43]
C6’
regression.
1
5
Average 2’,6’
In N, we have only two values; thus, it is better to put together
all the data (Table 4).
C1’
C8’ (CO/COH)
Assuming that the structure of crystalline glibenclamide (see
later on) is the same as the major tautomer in solution, one
should expect for the missing signal of N7’ in DMSO-d a value
6
of ~245–250 ppm. Only tautomer 1 is consistent with these
values; N7’ in tautomer 1a is at least 40 ppm apart from the
expected experimental value, and N8 in tautomers 1b and 1c
C1"
C2"
34.69
33.67
35.58
33.87
C6"
35.35
36.23
37.31
36.12
Average 2",6"
35.02
34.95
36.44
35.00
C3"
28.74
27.54
27.35
27.63
C5"
26.77
27.23
27.81
27.25
(amide enols) is totally different.
Average 3",5"
C4"
15
27.76
27.38
27.58
27.44
27.93
27.71
26.62
27.67
Decomposition compound
N
[
20]
According to Wojnarowska et al. , when glibenclamide is
N8
ꢂ267.02
ꢂ230.09
ꢂ279.65
ꢂ266.76
ꢂ201.90
ꢂ277.45
ꢂ141.73
ꢂ230.29
ꢂ279.34
ꢂ140.81
ꢂ201.88
ꢂ277.65
heated at its melting point for 1 h, it is transformed into a
compound where they reported its H and C NMR data in
N7’
N9’
1
13
Magn. Reson. Chem. 2012, 50, 246–255
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

D. Sanz et al.
Table 3. NMR chemical shifts (ppm) and coupling constants (Hz) of glibenclamide in DMSO-d
6
[20]
[24]
Atom
d
J
d (J)
d (J)
1
H
2
-OMe
3.77 (s)
—
—
3.796 (s)
3.790
7.144
7.495
7.634
8.272
3.530
2.927
7.484
7.835
—
3
CH3
CH4
CH6
NH 8
7.13 (d)
7.47 (m)
7.62 (d)
8.24 (t)
J
H4 = 8.9
7.149, J = 8.9
7.497, J = 8.9, J = 2.8
7.637, J = 2.8
8.257 J = 5.6
4
3
JH4 = 2.8
JCH2 = 5.6
CH
CH
2
2
9
3.54 (m)
2.92 (t)
—
3.550, J =7.0, J = 5.6
2.935, J =7.0
7.488, J = 8.4
7.839, J = 8.4
10.296
3
10
J
CH2 = 7.0
H1" = 7.8
H3’, H5’
H2’, H6’
NH 7’
7.47 (m)
7.82 (m)
10.2 (vbr)
6.31 (d)
3.26 (m)
1.03–1.63
1.03–1.63
—
—
—
3
NH 9’
J
6.324, J = 7.8
3.276 (m)
6.344
3.263
1.0–1.7
1.0–1.7
1.0–1.7
CH 1"
—
—
—
—
CH
CH
CH
2
2
2", 6"
3", 5"
4"
1.445–1.681 (m)
1.047–1.262 (m)
1.445–1.681 (m)
a
2
1.46 (m)
1
3
[20]
[24]
C
d
J
3
d (J)
d (J)
C1
124.42
155.76
56.28
114.22
131.62
124.79
129.57
163.76
40.20
34.69
145.29
129.35
127.34
138.22
150.52
48.14
32.31
24.21
25.02
J = 5.7
124.756
155.588
56.116
124.59
155.59
56.08
C2
—
1
1
1
OMe
C3
J = 146.0
J = 163.4
114.057
131.385
124.235
129.393
163.528
40.045
113.98
131.42
124.28
129.48
163.50
40.08
3
C4
J = 167.1, J = 6.1
C5 (C-Cl)
C6
—
3
1
J = 166.5, J = 5.5
C7 (CO)
C9
—
J = 140.1
J = 129.5
—
1
1
C10
34.557
34.58
b
C4’
145.104
145.12
129.17
127.22
138.09
150.35
47.98
1
1
3
3
3
C3’, C5’
C2’, C6’
C1’
J = 162.1, J = JCH2 = 5.7
129.170
127.185
3
J = 166.0, J = 5.7
3
b
J = J = 8.5
138.385
C8’ (CO)
C1"
—
J = 137.8
J = 126.8
J = 127.2
J = 127.2
150.323
47.962
32.158
24.058
24.870
1
1
1
1
C2", C6"
C3", C5"
C4"
32.19
24.08
24.88
1
5
N
1
1
N8
ꢂ261.0
J
NH = 94.3
—
—
—
—
—
—
N7’
N9’
Not observed
ꢂ273.7
—
JNH = 89.3
a
One proton, the other at 1.03–1.23 ppm.
b
These two signals were missassigned in reference 20.
DMSO-d
6
. It is not clear if the compound has the structure 2 or 3
0.9946 for 3) and yield fitted values for C4’ of 147.05 (Δd= 5.02, 2)
and 145.26 ppm (Δd= 3.23, 3) and for C1’ of 141.77 (Δd= 1.76, 2)
and 146.65 ppm (Δd= 3.12, 3). Unfortunately, the authors do not
1
because in the experimental part, they report a H SO
2
2
NH signal
at 7.30 ppm, whereas in the theoretical part, they wrote ‘contains
molecules in which the N–S bonds were broken’. The other
fragments corresponding to 2 and 3 are 4 and 5, respectively.
We have calculated the GIAO chemical shifts and compared
them with the reported data (Table 5).
[
20]
report analytical data.
We have followed the procedures (both very similar) described
[
19]
[20]
by Rades
and Wojnarowska,
where heating is quickly
quenched by cooling. Three experiments were carried out, glib-
1
ꢁ
The effects, Δd, in H NMR are very small (the signals of H atoms
enclamide was melted (mp 169–173 C), and the liquid quenched
linked to heteroatoms cannot be used being too sensitive to
solvent effects). In C NMR, leaving aside the carbon C5 bearing
a Cl substituent, the most affected signals are those of the phenyl
after 10 min (280 mg), 1 h (200 mg) and 2 h (230 mg) (Table 6).
Compound C sublimes, but as its percentages should be
the half of B (see below), we have estimated the decomposi-
tion of glibenclamide from the amounts of B. We have
recorded the NMR spectra of the three compounds in
DMSO-d6 from mixtures rich in each one (those of C from
1
3
ring linked to the SO : C4’ (1.38 ppm) and C1’ (5.20 ppm). The
2
regression equations between experimental values and calculated
2
ones have similar correlation coefficients (R = 0.9943 for 2 and
wileyonlinelibrary.com/journal/mrc
Copyright © 2012 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2012, 50, 246–255

Tautomerism and thermal studies of glibenclamide
1
5
1
13
Table 4.
N chemical shifts
Predicted
Table 6. H and C chemical shifts of the decomposition product
a
Experimental
DMSO-d CPMAS
Heating time
% A
% B
% C
Unchanged
Decomposed
Atom
1
1a
1b
1c
6
1
0 min
h
60
17
8
27
58
72
13
25
20
52 (A)
13 (A)
6 (A)
48 (B + C)
87 (B + C)
94 (B + C)
1
N8
ꢂ267.0 ꢂ266.8 ꢂ141.7 ꢂ140.8 ꢂ261.0
ꢂ247.5
ꢂ245.2
ꢂ271.2
a
2 h
N7’
N9’
ꢂ230.1 ꢂ201.9 ꢂ230.3 ꢂ201.9
a
ꢂ279.6 ꢂ277.4 ꢂ279.3 ꢂ277.6 ꢂ273.7
A is the starting glibenclamide.
a
Not observed.
According to the decomposition pattern, compound C should be
ꢁ
the walls of the flask). Those of A are identical to those
cyclohexyl carbamic acid (5). Our compound melts at 223–225 C,
+
already reported for glibenclamide (Table 3).
and its mass spectrum shows two intense M + H peaks at
ꢁ
ꢁ
[48]
Compound B (mp 234 C) has almost identical NMR signals
225.2 and 449.4 that do not correspond to 5 (215–217 C,
M = 143.1 daltons) but to N,N’-dicyclohexyl urea [DCU,
[
20]
than those described by Wojnarowska
(Table 5), only that
+
+
now all of them were assigned, agreeing with those calculated
C
13
H
24
N
2
O, M + H = 225.2 (the 449.4 is the dimer + H )], a com-
15
ꢁ
for 3. The observation of the SO
2
NH
2
group in N NMR leaves
mercial product that melts at 232–233 C. In DMSO-d
6
, the NHs
3
no doubt about its structure, and in addition, the mass spectra
are observed at 5.54 ( J = 8.2), and the cyclohexyl protons
appeared at 1.29 (m, 5H), 1.48 (m, 1H), 1.60 (m, 2H) and 1.70
(m, 2H). Besides, the compound shows C and N signals at
+
35
37
shows [M + H] molecular peaks at 369.1 ( Cl) and 371.1 ( Cl)
+
13
15
corresponding to [C16
H
17ClN
2
O
4
S + H] .
1
13
Table 5. H and C chemical shifts of the decomposition product
[20]
d
Atom
Exp.
Calcd. 2
Calcd. 3
Δd(2–3)
This work
1
H
2
-OMe
3.81
7.16
7.50
7.65
8.26
3.54
2.92
7.45
7.77
[7.30]
[7.30]
3.79
3.79
0.00
ꢂ0.01
0.00
3.80
3
H3
6.45
6.46
7.14 ( JH4 = 8.9)
4
H4
7.24
7.24
7.49 ( JH6 = 2.8)
H6
8.56
8.57
ꢂ0.01
0.00
7.64
3
NH-8
7.87
7.87
8.24 ( JCH2 = 5.2)
3
CH
CH
2
2
-9
3.32
3.34
ꢂ0.02
0.03
3.54 ( JCH2 = 7.0)
-10
2.95
2.92
2.90
7.44
7.76
—
H3’,5’
H2’,6’
OH-7’
7.46
7.44
0.02
7.85
7.82
0.03
4.50
—
—
(NH
2
)-7’
—
3.50
—
7.28
—
a
[
H1"]
3.27
—
—
—
1
3
[20]
C
Exp.
Calcd. 2
122.93
156.44
53.13
108.73
131.76
136.26
134.20
160.68
45.21
38.75
147.15
129.06
127.04
141.95
Calcd. 2
ꢂ267.61
—
Calcd. 3
122.98
156.46
53.12
108.75
131.69
136.20
134.19
160.69
45.28
38.61
145.77
129.30
126.00
147.15
Calcd. 3
ꢂ267.36
ꢂ277.67
Δd(2–3)
ꢂ0.05
ꢂ0.02
0.01
This work
b
3
2
C1
C2
124.24
155.59
56.17
124.3 ( J = 10.8, J = 3.4)
155.7
1
2
-OMe
56.2 ( J = 142.2)
1
C3
114.06
131.40
124.76
129.40
163.50
40.25
ꢂ0.02
0.07
114.1 ( J = 163.4)
a
b
a
1
3
C4
131.5 ( J = 167.0, J = 6.0)
3
2
C5 (Cl)
C6
0.06
124.8 ( J = J = 5.9)
1
3
0.01
129.5 ( J = 166.4, J = 5.5)
C7 (CO)
C9
ꢂ0.01
ꢂ0.07
0.14
163.6
1
40.3 ( J = 136.7)
1
C10
C4’
34.50
34.6 ( J = 127.3)
e
142.03
129.07
125.60
143.53
1.38
143.6
c
c
3
3
C3’,5’
C2’,6’
C1’
ꢂ0.24
1.04
129.1 ( J = JCH2 = 5.3)
1
3
125.7 ( J = 164.5, J = 6.1)
142.1
ꢂ5.20
Δd(2–3)
ꢂ0.25
—
1
5
N
This work
1
N8
ꢂ261.0 ( J = 94.5)
1
N7’ (NH
2
)
ꢂ284.4 ( J = 79.5)
a
Probably small amounts of glibenclamide remain.
b
Unassigned pairs (arranged to agree with the calculations).
Unassigned pairs (arranged to agree with the calculations).
c
d
The reciprocal coupling constants are not reported.
e
2
Assigned by correlation with the CH .
Magn. Reson. Chem. 2012, 50, 246–255
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

D. Sanz et al.
Figure 5. X-ray powder diffraction patterns: Wojnarowska’s experimental (top left), Rades’ experimental (top right) and calculated from the crystal
structure (bottom).
1
(
56.6 (C8’), 47.5 (C1"), 33.3 (C2",C6"), 25.3 (C4"), 24.4 (C3",C5"), –283.5
Table 7. Experimental chemical shifts in the solid state
1
1
13
J = 86.7, N9’). H and C chemical shifts coincide with those
1
3
[24]a
C
Crystal
From
Glass
[49]
reported for DCU. Because DCU needs two mols of cyclohexyl
carbamic acid (5) to be formed, this explain the 2 :1 ratio of B/C.
Formation of ureas from carbamic acids, through isocyanates or
C1
120.2
157.4
55.5
—
121.8
156.4
55.5
b
C2
158.0
55.9
[
50–53]
directly, has been reported in the literature.
OMe
C3
Thus, having identified the decomposition products, we can turn
118.0
135.4
124.1
129.5
167.0
41.4
—
113.1
—
b
c
our attention to the behavior of glibenclamide in the solid state.
C4
137.1
126.6
129.9
166.4
41.1
C5 (C-Cl)
C6
—
b
130.3
163.7
41.6
Solid state
C7 (CO)
C9
b
b
c
c
c
c
c
c
Differential Scanning Calorimetry (DSC) and X-ray crystallography
C10
C4’
36.2
36.7
34.1
145.3
126.1
126.1
126.1
126.1
139.6
151.4
50.7
145.8
129.9
129.9
126.6
126.6
140.1
149.4
50.2
145.2
130.3
130.3
126.2
126.2
138.6
151.3
49.7
The DSC spectrum of glibenclamide shows a sharp melting point
at 176.1 C and then a glassy state with no clear fusion. Suleiman
et al. reported the same behavior (mp 174.4 C). Similar results
were reported later on (172.75 C). Other DSC experiments led
ꢁ
C3’
ꢁ
[18]
C5’
ꢁ
[54]
C2’
ꢁ ꢁ ꢁ
[15]
[17]
[55]
C6’
to melting points of 173.1 C, 175 C, and 171.5 C.
[
20]
[19]
C1’
Wojnarowska et al. and Rades et al. reported the powder
C8’ (CO)
C1"
diffractogram of crystalline glibenclamide (Fig. 5). From the X-ray
[
26]
c
c
c
c
c
structure deposited in the CSD (DUNXAL) , it is possible to
generate the powder diffractogram (Fig. 5). The differences are
significant; Wojanowska’s seems to be shifted at least 5º.
C2"
32.9
29.3
34.1
C6"
35.3
29.3
34.1
C3"
23.6
27.3
25.3
C5"
25.9
27.3
25.3
Nuclear magnetic resonance
C4"
26.9
26.6
25.3
1
5
N
The solid-state chemical shifts of glibenclamide are reported in
Table 7.
We have now all the elements to establish the structure of
glibenclamide form: a true polymorph or a desmotrope? We feel
that a figure with the C and N NMR spectra of glibenclamide
in the solid state before and after thermal treatment (10 min)
would be useful (Fig. 6).
In C CPMAS NMR, the mixture of 60% glibenclamide, 27% of
3 and 13% of DCU shows only glibenclamide signals, all of them
but very broad. This broadening prevents to see the signals of 3
N8
ꢂ247.5
ꢂ245.2
ꢂ271.2
—
—
—
ꢂ256.8
ꢂ256.8
ꢂ271.0
N7’
N9’
13
15
a
In this publication, there are several reported signals that do not
seem to belong to glibenclamide: 169.5, 152.9, 136.3, 131.8 (C4?),
5
3.2 (OMe?), 46.9 (C1"?) and 43.8 (C9?).
[24]
13
b
c
Incorrectly assigned
[24]
.
Unassigned
.
wileyonlinelibrary.com/journal/mrc
Copyright © 2012 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2012, 50, 246–255

Tautomerism and thermal studies of glibenclamide
1
3
15
13
Figure 6. Top left: C CPMAS crystalline glibenclamide; top right: N CPMAS crystalline glibenclamide; bottom left: C CPMAS amorphous glibenclamide;
15
bottom right: N CPMAS amorphous glibenclamide.
Table 8. Calculated absolute shielding and chemical shifts of glibenclamide tautomers
Tautomer
OMe 2
CO (COH) 7
SO
SO
CO (COH) 8’
s
d
s
d
s
d
s
d
s
d
1
225.33
225.49
233.12
223.27
47.8
47.6
40.8
49.6
ꢂ51.22
296.0
294.5
103.5
102.5
81.00
86.40
81.50
85.55
177.3
172.5
176.9
173.2
113.74
109.71
112.73
113.79
148.0
151.6
148.8
147.9
11.48
239.7
91.0
1
1
1
a
b
c
ꢂ49.51
163.28
164.38
177.18
17.67
234.2
90.2
178.03
and DCU, smaller and with very similar chemical shifts (compare
Tables 3 and 5).
In N CPMAS NMR, the same mixture shows three signals attrib-
but we have established with certainty that it is not a desmo-
trope: both the crystalline and the amorphous forms correspond
to tautomer 1.
15
utable to glibenclamide, –271.9 N9’ (crystal ꢂ271.2), –256.8 N8
Remember that ball milling modification of the tautomeric
[
19]
(
ꢂ247.5) and ꢂ238.9 N7’ (ꢂ245.2 ppm). The two other signals at
structure of glibenclamide
was doubted by Gobetto et al.
ꢂ293.0 and ꢂ278.5 ppm can be tentatively assigned to N9’ of DCU
and N7’ of 3 (N8 of 3 is probably masked by the ꢂ256.8 ppm signal).
A second polymorph, distinct from the first one by the packing
or small conformational changes, is difficult to differentiate using
(‘it is not clear if the process should be regarded as a phase
[
56]
conversion or as a tautomeric equilibrium’).
A final point is that the amorphous form, after being triturated
in an agate mortar with a pestle by adding a drop of chloroform,
[
31]
13
CPMAS NMR spectroscopy, especially if the signals are broad.
afforded a well-resolved C CPMAS NMR quite close to that of
Maybe glibenclamide after fusion becomes another polymorph,
crystalline glibenclamide.
Magn. Reson. Chem. 2012, 50, 246–255
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

D. Sanz et al.
1
7
[
[
14] M. Kuhnert-Brandstatter, I. Wurian. Sci. Pharm. 1982, 50, 3.
15] M. S. Suleiman, N. M. Najib. Int. J. Pharm. 1989, 50, 103.
O NMR spectroscopy
Although we do not have experimental data to discuss, we have
[16] M. A. Hassan, M. S. Salem, E. Sallam, M. K. Al-Hindawi. Acta Pharm.
Hung. 1997, 67, 81.
1
7
calculated the O s values that, as expected, show large differ-
ences from one tautomer to another. To transform s into d, we
need to establish an equation similar to Eqns 1–3. In the Support-
ing Information (Table S1), we have reported the calculated and
experimental values of a series of oxygen molecules, and from
those data, we have obtained the following Eqn 4 that allowed
us to obtain the values of Table 8:
[17] A. Panagopoulou-Kaplani, S. Malamataris. Int. J. Pharm. 2000, 195, 239.
[18] M. A. Hassan, N. M. Najib, M. S. Suleiman. Int. J. Pharm. 1991, 67, 131.
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T. Rades. J. Pharm. Sci. 2005, 94, 1998.
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M. Paluch, L. Hawelek, R. Wrzalik, M. Dulski. Mol. Pharmaceutics
2
010, 7, 1692.
[
21] Z. Wojnarowska, P. Wlodarczyk, K. Kaminski, K. Grzybowska, L. Hawelek,
M. Paluch. J. Chem. Phys. 2010, 133, 94507.
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J. Phys. Chem. B 2010, 114, 14815.
1
7
17
d O ¼ 250:0 ꢂ 0:898 ꢄ s O
2
Eqn 4 (reference H
2
O, 0.00 ppm), n = 19, R = 0.986
[23] Y. Kasetti, N. K. Patel, S. Sundriyal, P. V. Bharatam. J. Phys. Chem. B
1
7
2
010, 114, 11603.
24] S. R. Byrn, A. T. McKenzie, M. M. A. Hassan, A. A. Al-Badr. J. Pharm. Sci.
986, 75, 596.
2
If the O signals of the SO group are relatively insensitive to
tautomerism (175 and 149 ppm on average), those of positions 7
and 8’ are very sensitive: oxo tautomers 295 (position 7) and
37 ppm (position 8’) and hydroxy tautomers 103 (position 7) and
1 ppm (position 8’). Thus, the four tautomers are clearly different.
[
[
1
25] (a)D. E. Bugay. Pharm. Res. 1993, 10, 317. (b)V. I. Sorokin, S. N.
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2
9
2
2
001, 48, 43. (d)P. A. Tishmack, D. E. Bugay, S. R. Byrn. J. Pharm. Sci.
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Conclusions
We have demonstrated that the phenomenon observed in glib-
enclamide is not a case of desmotropy (or tautomeric polymor-
phism) but a case of classical polymorphism. Stephenson, Pfeiffer
[
2
002, 58, 380. (b)F. H. Allen, W. D. S. Motherwell. Acta Crystallogr.
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http://www.ccdc.cam.ac.uk
[
57]
and Byrn showed in 1997
that acetohexamide was an exam-
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ple of classical polymorphism (both polymorphs were in the keto
form) and not of desmotropy as it was suggested (keto and enol
forms) by several authors. Thus, because of the combined use of
solid-state NMR and DFT calculations, a long-standing error has
been corrected.
[
[
[
[
[
[
Acknowledgements
This work has been financed by the Spanish MICINN (CTQ2009-
1
3129-C02-02 and CTQ2010-16122) and Comunidad Autónoma
de Madrid (Project MADRISOLAR2, ref S2009/PPQ-1533).
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