A 2:1 sulfamethazine-theophylline cocrystal exhibiting two tautomers of sulfamethazine

Article abstract of DOI:10.1107/S0108270111024280

In the title cocrystal, 4-amino-N-(4,6-dimethylpyrimidin-2-yl) benzenesulfonamide-4-amino-N-(4,6-dimethyl-1,2-dihy-dro-pyrimidin-2-ylidene) benzenesulfonamide-1,3-dimethyl-7H-pur-ine-2,6-dione (1/1/1), C ₇H₈N₄O₂·2C₁₂H ₁₄N₄O₂S, two sul-fa-methazine molecules cocrystallize with a single molecule of theophylline. Each molecule of sulfamethazine forms a hydrogen-bonded ribbon along the b axis crosslinked by further hydrogen bonding. The two sulfamethazine molecules exhibit a hydrogen-shift isomerization so that the crystal structure contains both tautomeric forms. Calculation of their relative energies showed that the tautomer protonated at the chain N atom is considerably more stable than the one where an N atom in the aromatic ring is protonated. The latter, here observed for the first time, is stabilized through strong intermolecular interactions with the theophylline molecules.

Full text of DOI:10.1107/S0108270111024280

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
N—H sites in the molecule (Trask et al., 2006). Indeed, Childs
et al. (2007) have summarized the complexes formed between
theophylline and both acids (e.g. oxalic acid, malonic acid,
gentisic acid, sulfathiazole, acetaminophen, etc.) and bases
(e.g. urea, benzylamine, phenobarbital, etc.). Sulfamethazine is
a sulfonamide drug that has been used to treat bacterial
diseases in human and veterinary medicine and to promote
growth in cattle, sheep, pigs and poultry. Sulfamethazine is
known to form cocrystals with aspirin, benzoic acid, trime-
thoprim and 4-aminosalicylic acid, among others (Caira, 1992,
2007; Caira et al., 1995; Zhang et al., 2007).
In this work, sulfamethazine and theophylline have been
cocrystallized in a 2:1 ratio to yield a cocrystal, (I), containing
theophylline (hereafter labelled THEO) and two tautomers of
sulfamethazine (hereafter labelled SLET for the low-energy
tautomer and SHET for the high-energy tautomer). Although
observation of both tautomeric forms of a molecule in the
solid state is still rare, it is more probable if the tautomers have
similar energies. This is highlighted in a paper on tautomers in
the Cambridge Structural Database (Cruz-Cabeza & Groom,
2011). In the case of sulfamethazine, however, this is the first
time the high-energy tautomer has been observed. Sulfa-
methazine has been crystallized as a pure substance (Basak et
al., 1983; Tiwari et al., 1984), as well as cocrystallizing with
carboxylic acids and other solvates, but in every case it was the
low-energy stable tautomer that was observed. The observa-
tion of both forms in the same structure is rare, especially
because of the high energy difference between the two
tautomers (see below).
ISSN 0108-2701
A 2:1 sulfamethazine–theophylline
cocrystal exhibiting two tautomers of
sulfamethazine
Jie Lu,a Aurora J. Cruz-Cabeza,b Sohrab Rohanic and
Michael C. Jenningsd*
aSchool of Chemical and Material Engineering, Jiangnan University, Wuxi 214122,
People’s Republic of China, bCambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, England, cDepartment of Chemical and Biochemical
Engineering, University of Western Ontario, London, Ontario, Canada N6A 5B9, and
d185 Chelsea Avenue, London, Ontario, Canada N6J 3J5
Correspondence e-mail: mjennings@teksavvy.com
Received 24 May 2011
Accepted 21 June 2011
Online 6 July 2011
In the title cocrystal, 4-amino-N-(4,6-dimethylpyrimidin-2-
yl)benzenesulfonamide–4-amino-N-(4,6-dimethyl-1,2-dihydro-
pyrimidin-2-ylidene)benzenesulfonamide–1,3-dimethyl-7H-pur-
ine-2,6-dione (1/1/1), C7H8N4O2ꢀ2C12H14N4O2S, two sulfa-
methazine molecules cocrystallize with a single molecule of
theophylline. Each molecule of sulfamethazine forms a
hydrogen-bonded ribbon along the b axis crosslinked by further
hydrogen bonding. The two sulfamethazine molecules exhibit a
hydrogen-shift isomerization so that the crystal structure
contains both tautomeric forms. Calculation of their relative
energies showed that the tautomer protonated at the chain N
atom is considerably more stable than the one where an N atom
in the aromatic ring is protonated. The latter, here observed for
the first time, is stabilized through strong intermolecular
interactions with the theophylline molecules.
Comment
Cocrystals have been increasingly recognized as an attractive
alternative to solid forms of drug products (Vishweshwar et al.,
2006). The design of cocrystals containing an active pharma-
ceutical ingredient (API) with an excipient (Basavoju et al.,
2008) or another component (Childs & Hardcastle, 2007;
Bucar et al., 2007) can provide an opportunity to design drug-
delivery systems at the molecular level. Further, it can
improve the pharmaceutical properties of the API
(Fernandez-Lopez et al., 2001).
Theophylline is often used in the treatment of respiratory
diseases such as asthma or chronic obstructive pulmonary
disease (COPD) (Van Andel et al., 1999). A derivative of
xanthine, theophylline is both weakly acidic and weakly basic,
with corresponding pKa and pKb values of 8.6 and 11.5,
respectively (Cohen, 1975). Theophylline is expected to have a
high potential for cocrystal formation due to the C O and
The molecular structure of each component in (I) is shown
in Fig. 1. The local structure of the theophylline molecule is
unremarkable, yielding a planar molecule [mean deviation =
˚
0.015 (3) A]. The two sulfamethazine molecules differ in their
geometry and, most importantly, in the position of one of the
H atoms. All H atoms involved in hydrogen bonding were
located in a difference map and allowed to refine. SHET has the
H atom on atom N17 of the ring, whereas SLET has the H atom
on atom N31 in the chain. As expected, this affects the bond
distances (Table 1), most notably that the chain N atom has
shorter bonds to both S and C atoms in SHET. In contrast, the
longer intra-ring bond from the bridgehead C atom C12 to the
H-bearing N atom N17 in SHET should be noted. Literature
data for the structure of sulfamethazine, representative of the
stable tautomer, have been included in the table for compar-
ison. Also reported are the torsion angle and interplanar
o306 # 2011 International Union of Crystallography
doi:10.1107/S0108270111024280
Acta Cryst. (2011). C67, o306–o309

organic compounds
S
LET and SHET) extending along the b axis; SHET tautomers are
linked together by hydrogen bond N1—H1Bꢀ ꢀ ꢀO10i and SLET
are linked together via hydrogen bond N21—H21Aꢀ ꢀ ꢀO30ii
(see Table 2 for symmetry codes). The two ribbons form an
extended chain via a hydrogen bond between the amine and
the sulfoxide of the same sulfamethazine. The theophylline
forms a close interaction with SHET, linked together by two
hydrogen bonds, viz. N17—H17Aꢀ ꢀ ꢀO41 and N52—
H52Aꢀ ꢀ ꢀN11, forming a nine-membered ring. There are three
more hydrogen-bonding interactions, which are shown more
clearly in Fig. 3. In this case, the view is approximately down
the b axis. There are three hydrogen-bonding interactions
involving THEO, the two discussed above forming the inter-
action with SHET, and the other side of the theophylline being
linked to SLET via N31—H31Aꢀ ꢀ ꢀN50iv. The two ribbons are
thus linked to each other through THEO, as well as being
linked directly to each other through two other interactions.
Ribbon SLET connects directly to ribbon SHET via N21—
H21Bꢀ ꢀ ꢀO10iii. The final interaction is the weakest but the
most interesting. Atom H1A does not participate in a
conventional hydrogen bond but points towards the centroid
(Cg) of aromatic ring C22–C27 of SLET (Fig. 3). Thus, the
acceptor is the electron density of an aromatic ring, essentially
a very weak N—Hꢀ ꢀ ꢀꢀ interaction. This link between the two
ribbons, the last in Table 2 (entry N1—H1Aꢀ ꢀ ꢀCgi), is certainly
a long interaction but still a fundamental part of the overall
molecular packing scheme.
Figure 1
The molecular structures of the two interacting sulfamethazine tautomers
(SLET and SHET) and one theophylline (THEO) molecule in the cocrystal,
(I). Displacement ellipsoids are drawn at the 50% probability level.
Disordered H atoms of methyl groups (C38, C44 and C48) have been
omitted for clarity.
spacing but, although they differ between the low- and high-
energy tautomers, no trends are observed compared with the
published structures. The terminal NH2 group also shows
some small differences between the two tautomers of sulfa-
methazine. SHET has a slightly pyramidyl shape at the terminal
atom N1 [sum of internal angles = 347 (1)ꢁ], but SLET is almost
planar, with the sum of the internal angles for atom N21 being
358 (1)ꢁ.
The molecular packing of the cocrystal is presented in Figs. 2
and 3, and the geometry of the hydrogen-bonding interactions
is given in Table 2. Fig. 2 is a view approximately down the c
axis, showing two distinct ribbons of sulfamethazine (labelled
The SLET tautomer (protonated at the chain N atom) was
calculated by density functional theory (DFT) methods to be
33.2 kJ molꢂ1 more stable than the SHET tautomer (proton-
ated at the aromatic ring) at the B3LYP/6-311++G** level of
theory and using a polarizable continuum model (see
Experimental). This large tautomeric energy difference is
probably due to the fact that, by protonating the aromatic N
Figure 2
A molecular packing diagram, viewed approximately down the c axis, showing the ribbons of sulfamethazine (SLET and SHET) along the b axis. Atoms
involved in hydrogen bonding are labelled and hydrogen bonds are indicated by thin lines. Disordered H atoms of methyl groups (C38, C44 and C48)
have been omitted for clarity. [Symmetry codes: (ii) x, y + 1, z; (v) x ꢂ 1, y, z; (vi) x ꢂ 1, y ꢂ 1, z.]
ꢃ
Acta Cryst. (2011). C67, o306–o309
Lu et al. C7H8N4O2ꢀ2C12H14N4O2S o307

organic compounds
ture of (I) play an important role in the stabilization of the
high-energy tautomer of sulfamethazine, reported here for the
first time.
In summary, X-ray diffraction shows that a three-compo-
nent adduct is formed in (I) between sulfamethazine and
theophylline in a 2:1 ratio. In the cocrystal, extensive hydrogen
bonding is observed, most notably involving the theophylline
which forms significant hydrogen-bonding interactions to both
the sulfamethazine tautomers. The strong interaction between
theophylline and the high-energy SHET tautomer of sulfa-
methazine, as verified by PIXEL calculations, has made the
observation of the latter in the crystal structure possible for
the first time.
Experimental
Sulfamethazine, theophylline and methanol were purchased from
Sigma–Aldrich (Milwaukee, Wisconsin, USA) and were used without
further purification. A mixture of sulfamethazine (0.056 g, 0.2 mmol)
and theophylline (0.018 g, 0.1 mmol) was stirred in methanol (50 ml)
with slight warming until dissolution was complete. The filtered
solution was kept in a fume hood at room temperature and after
several days, yellow crystals of (I) were obtained.
Figure 3
A molecular packing diagram, viewed approximately down the b axis,
showing the hydrogen-bonding network linking the two ribbons of
sulfamethazine together. Atoms involved in hydrogen bonding are
labelled and hydrogen bonds are indicated by thin or dotted lines.
Disordered H atoms of methyl groups (C38, C44 and C48) have been
omitted for clarity. [Symmetry codes: (iii) ꢂx + 1, y + 12, ꢂz + 21; (vii) ꢂx + 1,
The relative stability of the two tautomers, SLET and SHET, was
calculated using DFT methods with the program GAUSSIAN03
(Frisch et al., 2003). The X-ray molecular geometries for SLET and
SHET were energy minimized in the gas phase at the B3LYP/6-
311++G** level of theory, with the torsion angles constrained to the
experimental values. The energy-minimized molecular geometries
were then used for a single-point energy calculation at the same level
of theory but using a polarizable continuum model (Cossi et al., 2002)
with a dielectric constant " = 3, typical for organic crystals (Cooper et
al., 2008). With this simple model, we took into account the effect of
the crystalline environment on the relative stability of the two
tautomers.
1
2
1
2
1
2
1
2
y ꢂ , ꢂz + ; (viii) ꢂx, y ꢂ , ꢂz + .]
For the calculation of the intermolecular interactions, we used the
PIXEL method as part of the OPIX program developed by Gavez-
zotti (2003, 2007). We calculated the intermolecular interaction
energies of the THEO–SLET and THEO–SHET dimers, as observed in
the crystal structure (see Fig. 4). The geometry of the heavy atoms in
the two dimers was taken from the crystal structure and H-atom
positions were normalized using the program Mercury (Version 2.2;
Macrae et al., 2008). Electron densities were calculated using
GAUSSIAN03 at the MP2/6-31G** level of theory. The molecular
electron density for each molecule was output in a three-dimensional
Figure 4
The relative molecular energies of the two tautomers (SLET and SHET) and
the interaction energies of the THEO–SLET and THEO–SHET dimers.
˚
grid with steps of 0.08 A.
atom, some aromaticity of the pyrimidine ring is lost. The
observation of pairs of tautomers in the solid state with energy
differences greater than 30 kJ molꢂ1 is still uncommon in
crystal structures (Cruz-Cabeza & Groom, 2011). In fact, there
are 16 crystal structures containing sulfamethazine in the
Cambridge Structural Database (Version 5.32, November
2010; Allen, 2002) and all of them crystallize as the most stable
Crystal data
3
˚
C7H8N4O2ꢀ2C12H14N4O2S
V = 3573.7 (2) A
Z = 4
Mr = 736.84
Monoclinic, P21=c
Mo Kꢂ radiation
ꢃ = 0.21 mmꢂ1
T = 293 K
0.51 ꢄ 0.32 ꢄ 0.21 mm
˚
a = 15.8827 (6) A
˚
b = 8.1004 (3) A
˚
c = 27.7913 (10) A
SLET tautomer. This energy penalty is compensated for by the
ꢁ = 91.835 (2)ꢁ
much better interaction between SHET and THEO (which
involves two strong hydrogen bonds and two weak ones;
Fig. 4). The PIXEL interaction energies for the THEO–SHET
and THEO–SLET dimers were calculated to be ꢂ116.5 and
ꢂ44.2 kJ molꢂ1, respectively. Clearly, the interaction between
SHET and THEO and the extended hydrogen-bonding struc-
Data collection
Bruker APEXII CCD area-detector
diffractometer
Absorption correction: multi-scan
(SADABS; Bruker, 2009)
Tmin = 0.900, Tmax = 0.957
46924 measured reflections
7364 independent reflections
5968 reflections with I > 2ꢄ(I)
Rint = 0.024
ꢃ
o308 Lu et al. C7H8N4O2ꢀ2C12H14N4O2S
Acta Cryst. (2011). C67, o306–o309

organic compounds
Table 1
Selected bond distances and angles (A, ).
Table 2
Hydrogen-bond geometry (A, ).
ꢁ
ꢁ
˚
˚
Cg is the centroid of the C22–C27 aromatic ring.
S—N
N—C
C—Nb
C—S—N—Cc Interplanar
angle
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
SHET
SLET
1.6176 (15) 1.338 (2) 1.366 (2) ꢂ68.34 (17)
62.9 (2)
86.0 (2)
78.1 (2)
N1—H1Bꢀ ꢀ ꢀO10i
N17—H17Aꢀ ꢀ ꢀO41
N21—H21Aꢀ ꢀ ꢀO30ii
N21—H21Bꢀ ꢀ ꢀO10iii
N31—H31Aꢀ ꢀ ꢀN50iv
N52—H52Aꢀ ꢀ ꢀN11
N1—H1Aꢀ ꢀ ꢀCgi
0.87 (2)
0.88 (2)
0.86 (2)
0.87 (2)
0.83 (2)
0.87 (2)
0.88 (2)
2.25 (2)
1.92 (2)
2.31 (2)
2.17 (2)
2.31 (2)
2.09 (2)
2.97 (2)
3.097 (2)
2.780 (2)
3.008 (2)
3.017 (2)
3.131 (2)
2.948 (2)
3.755 (2)
163 (2)
165 (2)
137 (2)
167 (2)
168 (2)
172 (2)
149 (2)
1.6424 (16) 1.401 (2) 1.331 (2)
61.43 (19)
Sulfameth- 1.632 (2)
azinea
1.412 (2) 1.343 (2) ꢂ84.9 (2)
Reference: (a) Tiwari et al. (1984). Notes: (b) C12—N17 and C32—N37; (c) C5—S8—
N11—C12 and C25—S28—N31—C32.
1
1
Symmetry codes: (i) x; y ꢂ 1; z; (ii) x; y þ 1; z; (iii) ꢂx þ 1; y þ ; ꢂz þ ; (iv) x þ 1,
2
2
Refinement
y; z.
R[F2 > 2ꢄ(F2)] = 0.040
wR(F2) = 0.110
S = 1.03
7364 reflections
487 parameters
2 restraints
H atoms treated by a mixture of
independent and constrained
refinement
ꢂ3
˚
Áꢅmax = 0.29 e A
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ꢂ3
˚
Áꢅmin = ꢂ0.41 e A
Aromatic H atoms were positioned geometrically and refined
˚
using a riding model, with C—H = 0.93 A and Uiso(H) = 1.2Ueq(C).
Methyl H atoms were idealized with tetrahedral angles and refined as
˚
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structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine
structure: SHELXL97 (Sheldrick, 2008); molecular graphics:
PLATON (Spek, 2009); software used to prepare material for
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This work was supported by the Self-determined Research
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AJCC thanks the Pfizer Institute for Pharmaceutical Materials
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Lu et al. C7H8N4O2ꢀ2C12H14N4O2S o309