Crystalline products of tolbutamide decomposition in water after microwave treatment

Article abstract of DOI:10.1039/c3ce40145f

Microwave treatment of a hot water-drug suspension has resulted in the partial decomposition of tolbutamide (form I). Two new crystalline phases were isolated from the precipitate: the n-butylammoniun salt of tolbutamide and the novel polymorph of p-toluenesulfonamide. Their crystal structures were determined by single-crystal X-ray diffraction. The n-butylammoniun salt of tolbutamide is unstable in air and after decomposition crystallizes in the starting form I tolbutamide. The novel polymorph (β) of p-toluenesulfonamide differs from the old one (α) in an unusual arrangement of layers.

Full text of DOI:10.1039/c3ce40145f

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Crystalline products of tolbutamide decomposition in
water after microwave treatment3
Cite this: DOI: 10.1039/c3ce40145f
Tatiana N. Drebushchak,*ab Natalia A. Pankrushina,ac Aleksandr N. Mikheevad
and Manfred K. A. Thumma
Microwave treatment of a hot water–drug suspension has resulted in the partial decomposition of
tolbutamide (form I). Two new crystalline phases were isolated from the precipitate: the n-butylammoniun
salt of tolbutamide and the novel polymorph of p-toluenesulfonamide. Their crystal structures were
determined by single-crystal X-ray diffraction. The n-butylammoniun salt of tolbutamide is unstable in air
and after decomposition crystallizes in the starting form I tolbutamide. The novel polymorph (b) of
p-toluenesulfonamide differs from the old one (a) in an unusual arrangement of layers.
Received 23rd January 2013,
Accepted 28th February 2013
DOI: 10.1039/c3ce40145f
www.rsc.org/crystengcomm
Introduction
Results and discussion
Tolbutamide,
N-(butylcarbamoyl)-4-methylbenzenesulfona-
Suspension of tolbutamide in distilled water was heated in a
microwave reactor at 106 uC for several minutes under an
applied power of 200 W. Just after the treatment, the test-tube
contained transparent liquid. After shaking, the liquid became
turbid and precipitated two types of crystals (Fig. 1). The first
type (compound A) comprised rather large well-shaped
transparent crystals, just after being taken out of the liquid.
The second type (compound B) comprised flexible accrete
plates. Exposed to air, crystals of compound A became opaque,
but a soft porous mass of accrete plates of compound B
remained unchanged after drying.
mide, is an antidiabetic drug with low solubility in water. It
is used as the model substance in investigations of the
increasing bioavailability. Under normal conditions, tolbuta-
mide is known to exist in five polymorphs, I–IV,1–5 V.6
Polymorph transitions were investigated and new low- and
high-temperature forms were discovered.5–8 Kimura and co-
authors4 have showed that various forms of tolbutamide have
differing dissolution rates and exhibit different oral bioavail-
ability. Form I with the least dissolution rate was concluded to
possess also the least oral bioavailability. At the same time,
chemical ‘‘tolbutamide’’ can be purchased exactly in form I.
The aim of our work was to change the properties of water
suspension of tolbutamide form I with microwave treatment,
in trying to obtain new polymorphs with improved properties.
The microwave technique for the modification of the drug was
chosen because it was reported to increase the dissolution rate
of organic compounds in water.9
Small crystals were picked up from the precipitate and then
used for the structure determination. The phase unstable
under air exposure was found to be the n-butylammoniun salt
of tolbutamide (compound A). Its crystal structure was
determined at 100
K in a capillary. Results after the
aNovosibirsk State University, Pirogova 2, Novosibirsk, Russian Federation.
E-mail: tanya@xray.nsu.ru
bInstitute of Solid State Chemistry and Mechanochemistry SB RAS, Kutateladze 18,
Novosibirsk, Russian Federation
cVorozhtsov Institute of Organic Chemistry SB RAS, Lavrent’eva 9, Novosibirsk,
Russian Federation
dNikolaev Institute of Inorganic Chemistry SB RAS, Lavrent’eva 3, Novosibirsk,
Russian Federation
Electronic supplementary information (ESI) available: XRPD patterns of the
3
precipitate (Fig. S1 and S2). CCDC 918967 and 918969. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3ce40145f
Fig. 1 Optical image of the precipitate taken out of the liquid (binocular
microscope, magnification y8), A – compound A, B – compound B.
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experiments at room temperature were not quite accurate,
allowing us only to calculate the unit cell parameters. When
corrected for the thermal expansion, the latter agreed with
those at 100 K.
The crystal structure of compound B was reliably deter-
mined at room temperature and turned out to be a novel
polymorph of p-toluenesulfonamide. The structure of the old
polymorph of p-toluenesulfonamide was published about 20
years ago.10 In order to distinguish the two structures, we will
discuss hereafter the old one as the a-form and our new one as
the b-form.
Thus, microwave treatment has caused partial decomposi-
tion of tolbutamide and the products of the decomposition
interact with water. Thermal decomposition of tolbutamide
was found to occur after long heating in water (dissociation).11
We suppose that the formation of p-toluenesulfonamide (3)
during the microwave heating of a water solution can be
described by the reaction shown in Scheme 1. This reaction
was suggested by Bottari and co-authors11 for one of the
probable ways for thermal dissociation of sulfonylureas in
water, and p-toluenesulfonamide (3) was shown to form only
through an intermediate phase of isocyanate (4). In our work,
the remainder of tolbutamide (1) forms a salt with n-buthy-
lamine (2).
Fig. 2 The asymmetric unit of compound A. Displacement ellipsoids are drawn
at the 30% probability level and H atoms are shown with an arbitrary radius.
Hydrogen bonds are shown by dashed lines.
the neutral molecule (1.637(4) Å, averaged over all found
crystal structures of tolbutamide). The conformations of two
symmetry-independent cations of n-butylammonium are simi-
lar to each other and to that typical of alkyl chains of flat
conformation.
Hydrogen bonds link the molecules into infinite layers.
H-bond layers are parallel to plane (001) (Fig. 3). Geometric
parameters of hydrogen bonds are summarized in Table 1. The
Besides two new phases, X-ray powder diffraction reveals
that the precipitate contains the starting form I tolbutamide.
Compound A also transforms back into form I tolbutamide
which decomposes. It was proven with the X-ray powder
diffraction patterns obtained from the opaque crystals exposed
…
hydrogen bonds N–H O (indicated with numbers 1 and 2 in
Fig. 3b) link neighboring tolbutamide molecules into infinite
chains along the crystallographic axis b. The hydrogen bonds
…
N–H N link tolbutamide anions with n-butylammonium
to air. It is still unclear whether form
I tolbutamide
cations (indicated with numbers 3 and 4 in Fig. 3b). It forms
the unstable salt under ambient conditions. When compound
A decomposes and n-butylamine molecules leave the sample,
the product crystallizes in form I tolbutamide, which is
confirmed by the XRPD patterns.
Tolbutamide molecules in compound A are arranged in a
similar way to that in form I of pure tolbutamide. Aromatic
rings of two neighboring molecules are separated with the
plane of the hydrogen bonding, being on the opposite sides of
the plane (Fig. 3a). The layers attract each other by means of
weak van der Waals interaction.
precipitates immediately from solution or after decomposition
of the salt.
Crystal structure of n-butylammoniun salt of tolbutamide
(compound A)
Compound A crystallizes in the space group P21/n (mono-
clinic). The asymmetric unit contains four molecules (Fig. 2),
two anions of tolbutamide and two cations of n-butylammo-
nium. Tolbutamide molecules are in two different conforma-
tions, which differ from one another in the disordering of their
alkyl tails. The first molecule was refined well with only one
conformation and does not show the disordering in the alkyl
tail. The alkyl tail of the second molecule is disordered over
two positions (Fig. 2), with site-occupancy factors of 0.560(6)
and 0.440(6). The S–N distance in the tolbutamide anion is
shortened (1.588(2) and 1.578(2) Å) as compared with that in
Crystal structure of novel polymorph (b) of
p-toluenesulfonamide (compound B)
Compound B crystallizes in space group P1 (triclinic). The
asymmetric unit contains two molecules of p-toluenesulfona-
mide (Fig. 4). The crystal structure of b-polymorph as a whole
does not possess the inversion centre (triclinic space group
P1). Nevertheless, one of the two molecules in the asymmetric
unit matches almost completely with the other in the inverted
conformation. The molecules of p-toluenesulfonamide are
connected with hydrogen bonds (Table 2, Fig. 5) and form
infinite layers parallel to the plane (001). All aromatic rings in
a layer are located on one side of the hydrogen bond plane
(Fig. 6a).
The a-form of p-toluenesulfonamide (space group P21/n) is
also formed with the infinite layers of the molecules, but in
another way.10,12 Aromatic rings of neighboring molecules are
Scheme 1
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Fig. 4 The asymmetric unit of compound B. Displacement ellipsoids are drawn
at the 30% probability level and H atoms are shown with an arbitrary radius.
Hydrogen bonds are shown by dashed lines.
Table 2 Geometric parameters of the hydrogen bonds for compound Ba
…
…
…
D–H
A
d(D–H)/Å
d(H A)/Å
d(D A)/Å
/(DHA)/u
…
N11–H11 O21
0.87(3)
0.87(3)
0.83(3)
0.85(4)
0.90(3)
0.90(3)
2.32(3)
2.63(3)
2.31(3)
2.24(4)
2.21(4)
2.67(3)
3.064(4)
3.293(3)
3.056(4)
2.973(4)
3.025(4)
3.320(3)
144(3)
134(2)
149(3)
145(3)
151(3)
130(3)
i
…
N11–H11 O11
ii
i
…
N11–H12 O22
…
N21–H22 O11
iii
i
…
N21–H21 O12
…
N21–H21 O22
a
Symmetry codes: (i) 21 + x, y, z; (ii) x, 1 + y, z; (iii) 21 + x, 21 + y,
z.
Fig. 3 One layer of molecules in the crystal structure of compound A, viewed
along (a) the b axis and (b) the c axis. Hydrogen bonds are shown in blue lines.
Symmetry-independent molecules are coloured differently: green and dark-blue
for molecules of tolbutamide; red and yellow for molecules of n-butylammo-
mide), isostructural with the a-form of p-toluenesulfonamide,
were also published.12 They all have the centre of symmetry.
Polymorphs similar to the b-form of p-toluenesulfonamide
were not so far found.
…
nium. Hydrogen bonds N–H O between tolbutamide molecules are indicated
…
with numbers 1 and 2, those N–H N between tolbutamide and n-butylam-
monium with 3 and 4.
Molecules of p-toluenesulfonamide in a- and b-polymorphs
differ significantly from one another in the rotation of the
aromatic ring against the rest of the molecule (Fig. 7).
located on the opposite sides of the plane of hydrogen
bonding, thus the molecules are arranged antiparallel
(Fig. 6b). Crystal structures of two related compounds (4-
chloro-benzenesulfonamide and 4-bromo-benzenesulfona-
Table 1 Geometric parameters of the hydrogen bonds for compound Aa
…
…
…
D–H
A
d(D–H)/Å
d(H A)/Å
d(D A)/Å
/(DHA)/u
i
…
…
N12–H12N O12
0.84(3)
0.80(3)
0.93(4)
0.87(3)
0.94(4)
0.94(4)
0.89(4)
0.91(4)
0.95(4)
0.95(4)
2.06(3)
2.14(3)
1.88(4)
2.05(4)
2.29(4)
1.97(4)
2.11(4)
1.88(4)
2.20(4)
2.04(4)
2.908(3)
2.936(3)
2.792(3)
2.908(4)
2.873(3)
2.830(4)
2.993(4)
2.738(3)
2.861(3)
2.881(4)
176(3)
174(3)
164(3)
168(3)
120(3)
152(3)
178(3)
157(3)
126(3)
147(3)
ii
N22–H22N O22
…
N31–H31A O23
iii
…
N31–H31B N11
…
N31–H31C O12
…
N31–H31C O13
iv
…
N41–H41A N21
…
N41–H41B O13
…
N41–H41C O22
…
N41–H41C O23
a
Symmetry codes: (i) 3/2 2 x, 1/2 + y, 1/2 2 z; (ii) 1/2 2 x, 21/2 + y,
1/2 2 z; (iii) 3/2 2 x, 21/2 + y, 1/2 2 z; (iv) 1/2 2 x, 1/2 + y, 1/2 2 z.
Fig. 5 Hydrogen bonds within one layer of compound B (blue line). Different
molecules in the asymmetric unit are shown in different colors.
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Conclusions
Microwave heating does not result in a new polymorph of
tolbutamide. Partial decomposition of tolbutamide takes place
instead. The remaining tolbutamide crystallizes together with
n-butylamine, a fragment after decomposition, as a salt. The
salt is unstable in air and decomposes into the gas phase and
crystalline form
I of pure tolbutamide. What is more
interesting is that the other fraction of thermal decomposition
of the tolbutamide molecule, p-toluenesulfonamide, crystal-
lizes in a new polymorph with an unusual arrangement of
layers. The repetition of the experiments with microwave
treatment of water–tolbutamide (form I) suspension always
produces these two new crystalline phases.
Experimental
The experiments of water–tolbutamide suspension were
carried out using microwave synthesis system (reactor)
DiscoverTM System S-Class (CEM corp., USA) equipped with
the controller of temperature, pressure, applied power, and
with the function of stirring treated suspension. Starting
reagent tolbutamide was purchased from SIGMA and, accord-
ing to the X-ray powder diffraction pattern, it was pure
tolbutamide form I. Suspension of poorly wettable tolbuta-
mide (182 mg) in water (2 mL) in a special closed test-tube was
placed into the microwave reactor, stirred for 30 s without
irradiation, and then heated for 1 min at 106 uC with a power
of 200 W. The test-tube was dismounted from the reactor when
cooled down to 60 uC. The content of the tube was a uniform
suspension. Then, 1 mL more of water was added and heated
for 2 min under the same conditions (106 uC, excess pressure
of 0.3 bar, 200 W). Taken off the reactor immediately (without
Fig. 6 Fragment of the crystal structure (a) of b-polymorph of p-toluenesulfo-
namide (compound B) and (b) of a-polymorph.12 Hydrogen bonds are shown by
blue lines.
Table 3 Crystallographic data and structure refinement details
Compound
A
B
Formula
Formula weight
Crystal system
Space group
C4H12N+?C12H17N2O3S2
343.48
Monoclinic
P21/n
C7H9NO2S
171.21
Triclinic
P1
T/K
a/Å
b/Å
c/Å
100
295
13.5031(6)
11.2985(5)
25.4543(12)
90
98.694(4)
90
3838.8(3)
8
1.189
5.1562(2)
8.3250(4)
9.8583(7)
100.801(5)
102.284(4)
90.371(3)
405.68(4)
2
1.402
0.346
3.60–26.37
5004
3302
a/u
b/u
c/u
V/Å3
Z
Dc/g cm23
m (Mo Ka)/mm21
h range/u
0.186
3.02–26.37
18 001
7821
5534
0.049
0.068
0.151
Measured reflections
Independent reflections
Reflections with I . 2s(I)
Rint
2790
0.027
0.042
0.097
R[F2 . 2s(F2)]
wR(F2)
Fig. 7 Overlay of the molecular structures of p-toluenesulfonamide molecules in
two polymorphs: dark violet for a, light blue for b.
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cooling), the content was pure liquid. Being shaken, the
content formed the precipitation that was then analyzed with
powder and single-crystal X-ray diffraction.
X-ray powder diffraction was carried out using a diffract-
ometer Bruker D8 GADDS (Cu Ka radiation, graphite mono-
chromator, two-dimensional Hi-Star detector). A variable-
temperature single-crystal X-ray diffraction study was carried
out using an Oxford Diffraction KM-4 diffractometer with a
two-dimensional detector Ruby CCD (graphite monochroma-
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