Co-crystals of sulfamethazine with some carboxylic acids and amides: Co-former assisted tautomerism in an active pharmaceutical ingredient and hydrogen bond competition study

Article abstract of DOI:10.1021/cg200334m

Ten new co-crystals of an antibacterial drug sulfamethazine (SFZ) with various carboxylic acid and amide co-formers have been synthesized. These new forms are characterized by single crystal X-ray diffraction, infrared spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Crystal structures with 4-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DHB), 3,4-dichlorobenzoic acid (DCB), sorbic acid (SOR), fumaric acid (FUM), 1-hydroxy-2-naphthoic acid (1HNA), benzamide (BEN), picolinamide (PIC), 4-hydroxybenzamide (HBEN), and 3-hydroxy-2-naphthoic acid (3HNA) are determined. The SFZ molecule displays co-former assisted amidine to imidine tautomerism in the co-crystals in that the sulfonamide NH proton moves to one of the pyrimidine N atoms. In all the cases, the SFZ forms a robust hydrogen bonded synthon with a carboxylic acid (amidine_(SFZ)...acid/ imidine_(SFZ)...acid) or amide (imidine_(SFZ)...amide) group from the co-former. The SFZ molecule, in all the carboxylic amide and carboxylic acids, HBA and 3HNA co-crystals, exists in the imidine tautomeric form while it exists in amidine tautomeric form in the rest of the acid co-crystals. Density functional theory (DFT) calculations revealed that the amidine tautomer in free SFZ is much more stable than its imidine tautomeric form, while when it is hydrogen bonded to the co-formers via acid or amide groups, the difference is greatly minimized. But the synthon formation between the stable amidine_(SFZ) and amide co-former is sterically hindered; hence the SFZ tautomerizes itself to the imidine_(SFZ) form to facilitate the formation of a robust imidine_(SFZ)...amide synthon in all the amide based co-crystals in this study. Solubility properties of some of the new co-crystal forms are also studied. The crystal structures are analyzed in the context of hydrogen bond competition between various acceptors and donors, in the presence of other competing functional groups, in the active pharmaceutical ingredient (API) co-crystals.

Full text of DOI:10.1021/cg200334m

ARTICLE
pubs.acs.org/crystal
Co-Crystals of Sulfamethazine with Some Carboxylic Acids and
Amides: Co-Former Assisted Tautomerism in an Active
Pharmaceutical Ingredient and Hydrogen Bond Competition Study
Published as part of a virtual special issue on Structural Chemistry in India: Emerging Themes
Soumyajit Ghosh, Partha Pratim Bag, and C. Malla Reddy*
Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, West Bengal 741252, India
S Supporting Information
b
ABSTRACT: Ten new co-crystals of an antibacterial drug sulfamethazine
(SFZ) with various carboxylic acid and amide co-formers have been
synthesized. These new forms are characterized by single crystal X-ray
diffraction, infrared spectroscopy, differential scanning calorimetry (DSC),
and thermogravimetric analysis (TGA). Crystal structures with 4-hydro-
xybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DHB), 3,4-dichlorobenzoic
acid (DCB), sorbic acid (SOR), fumaric acid (FUM), 1-hydroxy-2-naphthoic
acid (1HNA), benzamide (BEN), picolinamide (PIC), 4-hydroxybenzamide
(HBEN), and 3-hydroxy-2-naphthoic acid (3HNA) are determined. The
SFZ molecule displays co-former assisted amidine to imidine tautomerism
in the co-crystals in that the sulfonamide NH proton moves to one of
the pyrimidine N atoms. In all the cases, the SFZ forms a robust hydrogen
bonded synthon with a carboxylic acid (amidine(SFZ) acid/imidine-
3 3 3
acid) or amide (imidine(SFZ) amide) group from the co-former. The SFZ molecule, in all the carboxylic amide and
(SFZ)
3 3 3
3 3 3
carboxylic acids, HBA and 3HNA co-crystals, exists in the imidine tautomeric form while it exists in amidine tautomeric form in the
rest of the acid co-crystals. Density functional theory (DFT) calculations revealed that the amidine tautomer in free SFZ is much
more stable than its imidine tautomeric form, while when it is hydrogen bonded to the co-formers via acid or amide groups, the
difference is greatly minimized. But the synthon formation between the stable amidine(SFZ) and amide co-former is sterically
hindered; hence the SFZ tautomerizes itself to the imidine(SFZ) form to facilitate the formation of a robust imidine(SFZ) amide
3 3 3
synthon in all the amide based co-crystals in this study. Solubility properties of some of the new co-crystal forms are also studied. The
crystal structures are analyzed in the context of hydrogen bond competition between various acceptors and donors, in the presence
of other competing functional groups, in the active pharmaceutical ingredient (API) co-crystals.
’ INTRODUCTION
medicine.6 Sulfamethazine is an anti-infective agent that has a
spectrum of antimicrobial actions similar to that of other sulfa-
drugs.7 Sulfamethazine is used for veterinary purposes to treat a
variety of infections, as well as being utilized in the management
of diseases in herds. It is also used to treat urinary tract infection,
chlamydia, rheumatoid fever, toxoplasmosis, and malaria in hu-
mans. Sulfamethazine is primarily used as an antibacterial drug
and growth promoter in food animals, such as cattle, pigs, and
poultry. The usage of SFZ in high dosages has side effects, such as
hypersensitivity, photosensitivity, vomiting, etc.
Sulfamethazine has two types of donors (amine NH2, and a
sulfonamide NH) that in total bear three acidic protons. And,
there are three types of acceptors, namely, two sulfoxy O atoms,
one amine N, and two pyrimidine N atoms that are capable of
forming hydrogen bonds in the co-crystal. Sulfamethazine is
The crystal engineering approach has generally been a suc-
cessful design strategy for obtaining new co-crystal forms of
active pharmaceutical ingredients (APIs) for desired physico-
chemical properties without affecting the pharmacological beha-
vior of the drug.1,2 Inrecenttimes, thishasbeenutilizedsuccessfully
to modify the API stability, solubility, bioavailability, mechanical
properties, etc.3 Particularly, crystal engineering, based on the
synthon approach is an effective route that provides the basis for
the selection of co-formers to achieve predetermined structures,
thus properties, with a higher success rate.4 Hence, it is important
to understand the precise role of functional groups, especially in
the presence of other competing functionalities.5 Sulfa drugs
have been interesting in this context and studied to understand
the hydrogen bond preferences of the strong hydrogen bonding
groups such as SO2, NH(sulfonamide), NH2, etc. present on them.5d
Sulfamethazine (SFZ; Scheme 1) is a sulfonamide drug, some-
times known assulfadimidine or sulfadimethylpyridine, that isused
to treat a variety of bacterial diseases in human and veterinary
Received: March 16, 2011
Revised:
May 7, 2011
Published: June 01, 2011
r
2011 American Chemical Society
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Crystal Growth & Design
ARTICLE
1
known to form co-crystals with aspirin, benzoic acid, 2,4-dini-
trobenzoic acid, trimethoprim, 4-aminosalicylic acid, theophyl-
line, etc.8 In this article, we report a series of new co-crystals of
SFZ with various co-formers achieved by a co-crystal screening
process (Scheme 1). The present series of co-crystals also gave
us a chance to study the hydrogen bonding preferences of the
acceptor and donor groups present on both SFZ and the co-
formers.
NMR. H nuclear magnetic resonance (NMR) analysis of single
crystals (2ꢀ3) was performed on a JEOL 400 MHz NMR in DMSO-d6
at 25 °C to confirm the API to co-former ratio.
Powder X-ray Diffraction (PXRD). The PXRD patterns were
collected on a Rigaku SmartLab with a Cu KR radiation (1.540 Å). The
tube voltage and amperage were set at 40 kV and 50 mA, respectively.
Each sample was scanned between 10 and 90° 2θ with a step size of 0.02°
(Figure S11, Supporting Information). The instrument was previously
calibrated using a silicon standard.
Crystallography. Co-crystals of sulfamethazine were individually
mounted on a glass pip. Intensity data were collected on a Brukar’s
KAPPA APEX II CCD Duo system with graphite-monochromatic Mo
KR radiation (λ = 0.71073 Å). The data were collected at 296 K
temperature for all the co-crystals, except SFZ/3HNA, SFZ/1HNA, and
SFZ/FUM/ACN which were collected at 100 K. Data reduction was
performed using Bruker SAINT software.9a Crystal structures were
solved by direct methods using SHELXL-97 and refined by full-matrix
least-squares on F2 with anisotropic displacement parameters for non-H
atoms using SHELXL-97.9b Hydrogen atoms associated with carbon
atoms were fixed in geometrically constrained positions. Hydrogen
atoms associated with oxygen and nitrogen atoms were included in
the located positions. Structure graphics shown in the figures were
created using the X-Seed software package version 2.0.10
’ EXPERIMENTAL SECTION
Materials. Sulfamethazine drug and all co-crystal formers were
purchased from Sigma-Aldrich. Commercially available solvents were
used as received without further purification.
Single Crystal Preparation. Sulfamethazine drug and co-crystal
former in a definite stoichiometric ratio were subjected to grinding with
an addition of a few drops of acetonitrile solvent using an agate mortar
and pestle for about 10 min. After grinding, the mixture was transferred to
a 10 mL conical flask followed by addition of acetonitrile. The suspension
was heated until a clear solution was obtained. The resulting mixture was
boiled for 10 min before being filtered into a fresh conical flask. The
filtrate was left to evaporate slowly at ambient conditions. The single
crystals suitable for X-ray diffraction studies were obtained in 4ꢀ6 days.
Similarly, the co-crystals could also be prepared from acetone, methanol,
and ethanol solvents.
Melting Point. Melting points of co-crystals and the individual co-
formers were measured using a digital melting point apparatus,
SECOR INDIA.
Differential Scanning Calorimetry (DSC). DSC was conducted
on a Mettler-Toledo DSI1 STARe instrument. Accurately weighed
samples (2ꢀ3 mg) were placed in hermetically sealed aluminum
crucibles (40 μL) and scanned from 30 to 300 °C at a heating rate of
5 °C/min under a dry nitrogen atmosphere (flow rate 80 mL/min). The
data were managed by STARe software.
Scheme 1. Molecular Structures of the Compounds Used for
Co-Crystallization in This Study
Thermogravimetric Analysis (TGA). TGA was performed on a
Mettler-Toledo TGA/SDTA 851e instrument. Approximately 10ꢀ15
mg of the sample was added to an aluminum crucible and heated from 30
to 500 °C at a rate of 10 °C/min under continuous nitrogen purge.
IR Spectroscopy. Transmission infrared spectra of the solids were
obtained using a Fourier-transform infrared spectrometer (PerkinElmer
502). KBr samples (2 mg in 20 mg of KBr) were prepared and 10 scans
were collected at 4 cmꢀ1 resolution for each sample. The spectra were
measured over the range of 4000ꢀ400 cmꢀ1
.
Solubility Studies. The solubility studies for powder samples of
single component SFZ and its co-crystals with SOR, FUM, 1HNA, BEN,
PIC, and 3HNA were performed according to the literature procedures.11
Table 1. New Sulfamethazine Co-Crystals with Various Carboxylic Acid and Amide Co-Formers and Corresponding Melting
Points
co-former name
(code)
co-crystal, mp (°C)
Tmax from DSC
co-former,
mp (°C)a
co-crystal structure code
SFZ/HBA
4-hydroxybenzoic acid (HBA)
2,4-dihydroxybenzoic acid (DHB)
3,4-dichlorobenzoic acid (DCB)
sorbic acid (SOR)
220.7
200.7
191.5
169.6
199.0
190.2
185.4
163.7
180.0
175.2
199.2
214ꢀ215
225ꢀ227
206
SFZ/DHB
SFZ/DCB
SFZ/SOR
132ꢀ135
299ꢀ300
195ꢀ200
130ꢀ133
110
SFZ/FUM/ACN
SFZ/1HNA
SFZ/BEN
fumaric acid (FUM)
1-hydroxy-2-naphthoic acid (1HNA)
benzamide (BEN)
SFZ/PIC
picolinamide (PIC)
SFZ/HBEN-Tb
SFZ/HBEN-Mc
SFZ/3HNA
4-hydroxybenzamide (HBEN)
161ꢀ162
3-hydroxy-2-naphthoic acid (3HNA)
218ꢀ221
a Melting point values as reported in Sigma-Aldrich chemical catalog. b T = triclinic. c M = monoclinic.
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Crystal Growth & Design
ARTICLE
Excess amounts (∼ 80 mg) of the samples were suspended in 10 mL of
water in a 25 mL round-bottom flask (rbf) and closed with a glass stopper.
These rbfs were kept in a cupboard for 72 h at ∼23 °C and were stirred at
500 rpm using a magnetic stirrer. After 72 h, the suspensions were
filtered through a filter paper (90 mm). The filtered aliquots were
sufficiently diluted and the absorbance was measured in the range of
200ꢀ800 nm. Finally, the concentration of SFZ after 72 h (apparent
aqueous solubility) in each sample was determined from the previously
made standard graph. A standard graph was made by measuring the
absorbance of varied concentrations of SFZ in water using a UV
spectrophotometer (HITACHI U-4100).
Computational Details. Geometry optimizations were performed
with Gaussian 0312 using the B3LYP method13 with the 6-31G(d) basis
set,14 followed by single point energy calculation at the 6-311þþG (2df, 2p)
level, in a density functional theory (DFT) type calculation. The
initial atomic coordinates for all the molecules were taken from the
crystal structures.
while the second hydrogen of the NH2 group forms N(4)ꢀH
(4A) N(2) (2.59(3) Å, 168(2)°) hydrogen bond with the
3 3 3
pyrimidine ring of SFZ from another adjacent tetramer. The
HBA phenyl rings stack over the SFZ pyrimidine rings from
adjacent ladders. In addition, there are several weak interactions
such as CꢀH O to π π between the ladders. All the good
3 3 3
3 3 3
acceptors and donors are fully utilized in this structure.
Sulfamethazine/2,4-Dihydroxybenzoic acid (1:1), (SFZ/
DHB). The co-crystal, SFZ/DHB, crystallizes in triclinic P1 space
group with one molecule of each SFZ and DHB in the asym-
metric unit. The unit cell parameters of the co-crystal SFZ/DHB
suggest that it is isostructural to SFZ/HBA (Table 1). However,
surprisingly, the SFZ molecule exists in the amidine tautomeric
form but not in the imidine tautomeric form as in SFZ/HBA.
Barring this difference, the rest of the packing is very similar
(Figure 2). In the structure, the extra ortho-OH group on DHB
does not interfere in the overall packing as it primarily involves
an intramolecular hydrogen bond (O(5)ꢀH(5A) O(4);
3 3 3
’ RESULTS AND DISCUSSION
1.68(5) Å, 151(4)°) with the carbonyl O atom.
Sulfamethazine/3,4-Dichlorobenzoic Acid (1:1), (SFZ/DCB).
The SFZ and DCB molecules co-crystallize in monoclinic P21/n
space group with one molecule of each in the asymmetric unit. The
SFZ molecule adopts an L-shape conformation in that the two
aromatic ring planes are face-to-face. In the co-crystal, the
carboxylic acid group from DCB forms synthon 1 with the SFZ
molecule. The packing in this structure is mostly dominated by
Ten new co-crystals of SFZ with various carboxylic acid and
amide co-formers were synthesized by the slow evaporation
crystallization method (Table 1). These new solid phases were
characterized by PXRD, IR spectroscopy, DSC and TGA. Single
crystal X-ray structures with 4-hydroxybenzoic acid (HBA), 2,4-
dihydroxybenzoic acid (DHB), 3,4-dichlorobenzoic acid (DCB),
sorbic acid (SOR), fumaric acid (FUM), 1-hydroxy-2-naphthoic
acid (1HNA), benzamide (BEN), picolinamide (PIC), 4-hydro-
xybenzamide (HBEN), and 3-hydroxy-2-naphthoic acid (3HNA)
were determined. Crystal structure analysis was done to ratio-
nalize the hydrogen bonding preferences of acceptors and donors
in the presence of other competing functional groups. A com-
parison of experimental PXRD patterns with those calculated
from corresponding single crystal data and DSC established the
phase purity of the solids. The same batches of samples were used
for IR spectroscopy and solubility studies. Crystallographic data
are listed in Table 2. Hydrogen bond table (Table S1, Supporting
Information) and the ORTEP diagrams for all the co-crystals are
included in the Supporting Information (Figures S1ꢀS10).
Sulfamethazine/4-Hydroxybenzoic Acid (1:1), (SFZ/HBA).
The co-crystal SFZ/HBA crystallizes in the triclinic P1 space
group with one molecule of each SFZ and HBA in the asymmetric
unit. The SFZ molecule adopts a V-shape conformation in that the
two aromatic rings are twisted to take a propeller shape. The co-
former, HBA molecule, possesses two strong hydrogen bonding
functional groups: a carboxylic acid and a hydroxyl group at the
para position on its phenyl ring. In the structure, the SFZ
molecule exists in the imidine tautomeric form that results from
the transfer of proton from sulfonamide NH to the pyrimidine ring
N as shown in Scheme 3. Hence, in this case, the SFZ molecule
offers the imidine site for binding with the HBA acid functional
synthon 5 in that the NꢀH O hydrogen bonds are formed
3 3 3
between the SO2 and NH2 groups, both from SFZ, leading to the
formation of a polar two-dimensional (2D) square grid network
parallel to the (010) plane (Figure 3). The pyrimidine rings lie
below and above nearly perpendicular to the plane of the 2D
network. The adjacent polar layers are packed in an antiparallel
fashion so that the π π interactions are optimized by the
3 3 3
stacking of pyrimidine and co-former rings from the opposite
layers.
Sulfamethazine/Sorbic Acid (1:1), (SFZ/SOR). Sorbic acid is
an unsaturated carboxylic acid used as a food preservative. The
co-crystal crystallizes in monoclinic P21/c space group in that the
SOR molecule adopts planar conformation. As expected, the
naturally occurring co-former, SOR, forms synthon 1 with SFZ in
the co-crystal. The amine group uses its two protons to form two
N(4)ꢀH(4A) O(1) (2.29(4) Å, 135(4)°) and N(4)ꢀH-
3 3 3
(5A) O(3) (2.29(4) Å, 164(3)°) hydrogen bonds, one with
3 3 3
SO2 group (synthon 5) and the second with the carbonyl O-atom
of an adjacent SOR molecule. This eventually leads to the
formation of a 2D-sheet parallel to the (100) in that pyrimidine
rings of the alternate SFZ molecules protrude out almost perpen-
dicularly from either side of the 2Dsheet as shownin Figure 4. The
SFZ pyrimidine rings and SOR unsaturated chains (that form
synthon 1) are packed antiparallelly over the other similar pairs
group via synthon 2 (see Scheme 2; O(4)ꢀH(4) N(3); d/Å,
from adjacent 2D sheets to interdigitate the structure via π
interactions.
π
3 3 3
3 3 3
θ/°; 2.01 (4) Å, 169(5)°; N(1)ꢀH(1) O(3); 1.79(3) Å,
3 3 3
177.7(16)°). The robust synthon 2 holds the SFZ pyrimidine
ring and HBA phenyl ring in the same plane, which is also the
case in all the co-crystals in this study. The HBA p-hydroxyl
group interacts with the amine group from an adjacent SFZ
Sulfamethazine/Fumaric Acid/Acetonitrile, (2:1:1) (SFZ/
FUM/ACN). It crystallizes in the orthorhombic Pbcn space group
with two SFZ, one FUM, and a disordered acetonitrile molecule
in the asymmetric unit. This is the only co-crystal solvate in the
present series and is interesting in the context of crystal packing
analysis. In the crystal structure, the dicarboxylic acid, FUM,
binds with two SFZ molecules via synthon 1 to form a trimer. The
molecule via O(5)ꢀH(5) N(4) (synthon 7; 2.13(4) Å,
3 3 3
163(4)°) that eventually leads to a tetramer shown in
Figure 1a. One of the two amine hydrogens forms N(4)ꢀH
(4B) O(1) (2.22(3) Å, 165(3)°) hydrogen bond with the
adjacent trimers are linked via synthon 5 (N(4)ꢀH(4A) O(3);
3 3 3
3 3 3
sulfoxy O-atom to join the adjacent tetramers to form a ladder
2.14(2) Å, 164.6(19)° and N(4)ꢀH(4B) O(2); 2.20(2) Å,
3 3 3
(with steps on either side as seen in Figure 1b) along the a-axis,
156.1(17)°) involving the amine (NH2) and SO2 groups from
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Crystal Growth & Design
ARTICLE
Table 2. Crystallographic Data and Structure Refinement Parameters of SFZ Co-Crystals
SFZ/HBA
SFZ/DHB
SFZ/DCB
SFZ/SOR
SFZ/FUM/ ACN
SFZ/1HNA
chemical formula
C
12H14N4O2 S,
C12H14N4O2S,
C7H6O4
432.45
C12H14N4O2 S,
C7H4Cl2O2
469.33
C12H14N4O2S,
C6H8O2
390.46
2(C12H14N4 O2S),
C4H4O4, C2H3N
713.79
C
12H14N4O2S,
C7H6O3
C11H8O3
formula weight
cryst sys
space group
a (Å)
416.45
466.51
triclinic
P1
triclinic
P1
monoclinic
P21/n
monoclinic
P21/c
orthorhombic
Pbcn
triclinic
P1
8.0060(5)
9.3913(5)
13.4786(8)
74.611(3)
75.053(3)
86.102(3)
944.02(10)
1.465
7.9671(3)
9.4629(4)
13.9432(6)
73.662(2)
74.468(2)
87.240(2)
971.50(7)
1.478
8.1070(4)
17.5194(8)
14.7732(7)
90
8.6932(4)
17.0624(7)
14.2695(6)
90
11.4148(7)
20.1672(12)
14.8653(9)
90
12.1076(8)
13.5903(9)
14.7508(10)
77.756(4)
66.198(4)
85.2370(4)
2170.2(3)
1.428
b (Å)
c (Å)
R (°)
β (°)
γ (°)
vol (Å3)
Dcalcd (g/cm3)
93.767(3)
90
106.554(3)
90
90
90
2093.70(17)
1.489
2028.82(15)
1.278
3422.1(4)
1.385
μ (mmꢀ1
)
0.213
0.213
0.444
0.190
0.218
0.194
θ range (°)
Z
1.62 - 26.99
2
1.58 - 27.0
2
1.81 - 27.0
4
1.91 - 27.0
4
2.05 - 27.00
4
1.54 - 27.0
4
range h
ꢀ9 to þ10
ꢀ11 to þ11
ꢀ17 to þ17
11913
ꢀ10 to þ10
ꢀ12 to þ12
ꢀ17 to þ17
20806
ꢀ9 to þ10
ꢀ21 to þ22
ꢀ18 to þ18
24134
ꢀ10 to þ11
ꢀ21 to þ21
ꢀ18 to þ18
45708
ꢀ13 to þ14
ꢀ25 to þ18
ꢀ18 to þ18
15901
ꢀ15 to þ15
ꢀ17 to þ17
ꢀ18 to þ18
32954
range k
range l
reflns collected
independent reflns
obsd reflns
T (K)
4094
4230
4570
4423
3730
9414
3555
3584
3108
3512
3286
7796
296
296
296
296
100
100
R1
0.0458
0.0395
0.0418
0.0412
0.0349
0.0357
wR2
0.1180
0.1312
0.1025
0.1230
0.0994
0.0990
GOF
1.044
1.176
1.086
0.910
0.812
1.029
CCDC no.
817364
817365
817366
817367
817368
817369
SFZ/BEN
SFZ/PIC
SFZ/HBEN-T
SFZ/HBEN-M
SFZ/3HNA
chemical formula
C12H14N4O2S,
C7H7NO
399.47
C
12H14N4O2S,
C6H6N2O
C
12H14N4O2S,
C12H14N4O2S,
C7H7NO2
415.47
C12H14N4O2S,
C11H8O3
466.51
C7H6NO2
formula weight
cryst sys
space group
a (Å)
400.46
orthorhombic
Pbca
414.46
monoclinic
P21/n
triclinic
P1
monoclinic
P21
orthorhombic
P212121
6.7701(4)
16.6846(11)
18.9656(12)
90
8.4321(7)
12.9690(11)
17.5247(16)
90
9.684(4)
15.716(6)
25.310(9)
90
8.3238(6)
9.5864(8)
14.0808(11)
109.249(2)
95.432(2)
106.165(2)
997.06(14)
1.381
8.5398(4)
18.2753(7)
13.3498(5)
90
b (Å)
c (Å)
R (°)
β (°)
γ (°)
vol (Å3)
Dcalcd (g/cm3)
94.200(6)
90
90
105.792(2)
90
90
90
90
1911.3(3)
1.388
3852(2)
1.381
2004.83(14)
1.376
2142.3(2)
1.446
μ (mmꢀ1
)
0.201
0.201
0.199
0.198
0.196
θ range (°)
Z
2.33ꢀ27.0
4
3.43ꢀ25.80
8
1.57ꢀ27.0
2
1.59ꢀ27.0
4
2.44ꢀ27.0
4
range h
ꢀ10 to þ10
ꢀ16 to þ13
ꢀ21 to þ22
15541
ꢀ11 to þ11
ꢀ12 to þ19
ꢀ30 to þ30
23558
ꢀ10 to þ9
ꢀ12 to þ12
ꢀ17 to þ17
15350
ꢀ10 to þ10
ꢀ23 to þ22
ꢀ17 to þ17
20524
ꢀ8 to þ2
ꢀ21 to þ21
ꢀ23 to þ23
10494
range k
range l
reflns collected
independent reflns
obsd reflns
T (K)
4059
3658
4309
7988
4455
3417
2450
3425
7150
4291
296(2)
296(2)
0.0475
0.1094
296
296
100(2)
R1
0.0860
0.0475
0.0365
0.0273
wR2
0.2174
0.1556
0.0998
0.0805
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Crystal Growth & Design
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Table 2. Continued
SFZ/BEN
1.059
817370
SFZ/PIC
1.075
817371
SFZ/HBEN-T
SFZ/HBEN-M
SFZ/3HNA
GOF
0.79
1.202
0.900
817374
CCDC no.
817372
817373
Scheme 2. Synthons Anticipated and/or Observed in the SFZ Co-Crystalsa
a The hydrogen-bonded synthons 11 and 12 are present in the structure of single component (or free) SFZ crystals.
Scheme 3. Schematic Representation of the Tautomerism in
Sulfamethazine Molecule in Some of Its Co-Crystalsa
the SFZ molecules. As a result, the molecules form a honeycomb
network as shown in Figure 5a,b. Further, the network is doubly
interpenetrated as shown in Figure 5c. The disorder modeling of
the acetonitrile molecule, from the low temperature (100 K)
X-ray data, revealed that the methyl C atom resides on the special
position with 50% occupancy factor, while each of the central C and
N atoms occupy two separate sites with 50% occupancy factors. The
disordered acetonitrile molecule resides between two SFZ pyrimi-
dine rings, resembling a supramolecular cleft (Figure 5d).
Sulfamethazine/1-Hydroxy-2-naphthoic Acid (1:1) (SFZ/
1HNA). The co-crystal SFZ/1HNA crystallizes in the triclinic P1
space group with four molecules in the asymmetric unit. There
are two SFZ and two 1HNA molecules in the asymmetric unit in
that the molecules in each pair are related by pseudo inversion
symmetry. To verify if this occurred due to a wrong unit cell
selection, we attempted to solve the structure with a smaller unit
cell, with half the size, but the solution was not fruitful. A
measurement of the unit cell lengths from the diffraction pattern
also supported the selection of the present unit cell. The overlay
diagram of the two independent SFZ molecules from the present
structure shows that their geometries are slightly different; hence
there is no real crystallographic inversion center between them
(Figure 6a). This is also evident from the Figure 6b, which shows
the mismatch of spatial orientation between the first independent
molecule and the inversion related of the second independent
molecule. However, the hydrogen bonding patterns of both the
independent molecular pairs are very similar. In the crystal
structure there are several types of synthons. The 1HNA uses its
carboxylic acid group to form synthon 1 with the SFZ molecule as
a Notice the perturbation of aromaticity in pyrimidine ring in the
imidine(SFZ) tautomer.
the latter exists in its amidine tautomeric form. The hydroxyl
group of 1HNA donates its proton for the intramolecular
OꢀH OdC, while accepts a hydrogen bond from the SFZ
3 3 3
amine group to form NꢀH O (synthon 8). The second
3 3 3
proton of the SFZ amine links to the sulfoxy group of another
SFZ molecule to form NꢀH O(sulfoxy) (synthon 5). The
3 3 3
combination of the hydrogen bonded synthons 1, 5, and 8
between both the co-former molecules result in a double-
stranded one-dimensional (1D) linear tape (Figure 6). The
adjacent 1D tapes are packed further via weak intermolecular
interactions like CꢀH O(sulfoxy), π π, and CꢀH π.
3 3 3
3 3 3
3 3 3
Sulfamethazine/Benzamide (1:1) (SFZ/BEN). The sulfa-
methazine co-crystallizes with benzamide in monoclinic P21/n
space group with one molecule of each SFZ and BEN in the
asymmetric unit. In the structure, the SFZ molecule exists in the
imidine tautomeric form. Hence, in this case, the SFZ molecule
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Crystal Growth & Design
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Figure 3. Hydrogen bonding pattern in the crystal structure of SFZ/
DCB. Formation of synthon 5 (S5) between two SFZ molecules via
NꢀH OdS hydrogen bonds, leading to the formation of the 2D
3 3 3
square grid network parallel to (010). DCB molecules (that form
synthon 1) and methyl hydrogens on pyrimidine ring are not shown
for clarity.
NꢀH O(sulfoxy) (synthon 5) hydrogen bonds to connect
3 3 3
another two adjacent SFZ molecules; as a result each sulfoxy
O-atom is also linked to an amine proton. The hydrogen bond
leads to a 2D network parallel to the (001) as shown in Figure 7.
Because of the V-shape conformation of the SFZ molecule, the
alternate pyrimidine rings reach out perpendicular to either side
of the 2D sheet. The pyrimidine rings are further stacked with the
Figure 1. (a) A tetramer in the structure of SFZ/HBA formed via
synthons 2 (S2) and 7 (S7) by two pairs of SFZ and HBA molecules.
(b) A representative model for the two-sided-stepladder. (c) The two-
sided stepladder packing of SFZ molecules in the crystal structure where
the tetramers are connected via NꢀH
O(sulfoxy) synthons (S5) along
3 3 3
benzamide aromatic rings to optimize the π π interactions
the a-axis.
3 3 3
along [100].
Sulfamethazine/Picolinamide (1:1) (SFZ/PIC). The SFZ/
PIC crystallizes in orthorhombic Pbca space group with one SFZ
molecule and one PIC molecule in the asymmetric unit. The SFZ
molecule exists in the imidinetautomericform to a hydrogen bond
to PIC via synthon 4. The two amine hydrogens are involved in
two NꢀH O (2.21(3) Å, 159(3)°; 2.31(4) Å, 161(3)°)
3 3 3
interactions with the sulfoxy O atoms (synthon 5) of two adjacent
SFZ molecules that lead to the formation of 2D hydrogen bonded
layers in the (001) as seen in Figure 8b. The packing is further
stabilized by the π π interactions between the aromatic rings
3 3 3
from both the co-former molecules. The second amide NH of
PIC and the second pyrimidine N remain unused in the crystal
structure.
Sulfamethazine/4-Hydroxybenzamide (1:1) (SFZ/HBEN).
The 1:1 co-crystal SFZ/HBEN shows concomitant polymorphism
with a triclinic (SFZ/HBEN-T) and a monoclinic (SFZ/HBEN-M)
form (Figure 9a). In our initial observations, the crystal mor-
phology of both the forms appeared very similar, but a careful
examination revealed that the triclinic crystals are long blocks with
four well grown faces, while the monoclinic crystals are thick
needles with more than four faces. The triclinic form crystallizes in
the P1 space group, while the monoclinic form crystallizes in the
P21 noncentrosymmetric space group. In both forms, the SFZ
molecule exists in the imidine tautomeric form to bind to the
HBEN molecule via synthon 4 to form a dimer.
Figure 2. Crystal packing in SFZ/DHB. Notice the ladder structure
along the a-axis, similar to that is seen in SFZ/HBA. Adjacent ladders are
packed via weak CꢀH O and π π interactions.
3 3 3
3 3 3
offers an imidine site for binding with the BEN amide functional
group via synthon 4 (N(2)ꢀH(2) O(3); 1.93(5) Å, 166(6)°;
3 3 3
N(5)ꢀH(7B) N(3); 2.49(6) Å, 166(5)°). Notably, the
3 3 3
NꢀH(BEN) N(sulfonamide) (2.49(6) Å, 166(5)°) in the synthon
3 3 3
is significantly weaker than the CdO(BEN) HꢀN(pyrimidine)
In the triclinic form, there is one molecule of each co-former in
the asymmetric unit. The SFZ molecule adopts a V-shape
conformation in that the two aromatic rings are edge-to-face.
The HBEN binds to SFZ via synthon 4 to form a dimer. The
3 3 3
(1.93(5) Å, 166(6)°). The second proton on the BEN amide
NH2 forms hydrogen bond with the sulfoxy O atom (synthon 9)
of an adjacent SFZ molecule. On the other hand, both the acidic
amine (NH2) protons of the SFZ molecule involve in two separate
dimers are further linked via NꢀH O(sulfoxy) hydrogen bonds
3 3 3
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Crystal Growth & Design
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Figure 4. Sulfamethazine/sorbic acid (1:1). (a) Packing shows the formation of 2D sheets by SFZ molecules via synthon 5. Notice the interaction of
SOR molecules with the SFZ amidine site via synthon 1. (b) Space fill model shows the packing of adjacent 2D ladders.
Figure 5. Crystal packing in the SFZ/FUM/ACN. (a) The honeycomb network formed by SFZ and FUM molecules via synthons 1 and 4.
(b) Honeycomb network that represents packing in (a). (c) Doubly interpenetrated rings from the honeycomb networks. (d) Packing of the disorderd
acetonitrile molecule between two pyrimidine rings from two SFZ molecules that resemble a supramolecular “cleft”.
(synthon 9) formed by the second proton of the HBEN amide
andSFZ sulfoxygroups to makea tetramer (highlighted molecules,
Figure 9b). As a result, the SFZ amine and the HBEN hydroxyl
groups fall on the same line to involve in a well complemented
amino-phenol hydrogen bonded 1D infinite chains along [010]
(Figure 9b).15 The free lying SFZ amine proton links the sulfoxy
O-atom in the [101] direction.
In the monoclinic form, SFZ/HBEN-M, there are a total of
four molecules, with a pair of each co-former, in the asymmetric
unit, that is, the molecules in each pair are crystallographically
distinct. The two independent SFZ molecules in the structure exist
in the imidine tautomeric form and bind to the HBEN molecules
via synthon 4. The hydroxyl groups from both the independent
HBEN molecules involve in two different hydrogen bond types.
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Figure 6. Sulfamethazine/1-hydroxy-2-naphthoic acid (1:1). (a) Overlay diagram of the two symmetry independent SFZ molecules to show the
conformational differences. (b) The view down along [011] to show the spatial mismatch between two symmetry independent (pseudotranslational
related) SFZ molecules from a unit cell. (c) Crystal packing to show the hydrogen bonded synthons 1, 5, and 8 that form the double-stranded 1D
linear tape.
Figure 7. Sulfamethazine/benzamide (1:1) co-crystal. (a) Dimer for-
mation between the SFZ imidine tautomer and benzamide via synthon
4. (b) 2D network formed by the SFZ molecules in the structure of co-
Figure 8. Crystal packing in sulfamethazine/picolinamide (1:1).
(a) Synthon 4 formation between the SFZ and PIC co-formers and
the hydrogen bonds (only one NꢀH O is shown) connecting SFZ
crystal via NꢀH O (synthon 5) hydrogen bonds between the SFZ
3 3 3
3 3 3
molecules via synthon 5. (b) Formation of a 2D network by SFZ
molecules via synthon 5 involving both the SFZ amine protons and
sulfoxy O atoms.
amine and sulfoxy groups. The co-former BEN is not shown for clarity.
The first hydroxyl of the pair forms OꢀH O hydrogen bond
3 3 3
with the second hydroxyl, while the second hydroxyl links to the
form a 1:1 co-crystal in the orthorhombic P212121 space group.
The asymmetric unit consists of one SFZ and one 3HNA
molecule. In contrast to the SFZ/carboxylic acid co-crystals, in
this structure the SFZ molecule undergoes tautomerism to exist
in SFZ imidine form, which is similar to that seen in amide based
co-crystals. The carboxylic acid group from 3HNA forms hydro-
gen bond synthon 2 with the SFZ imidine site. The 3-hydroxyl
SFZ amine group via OꢀH N hydrogen bond (synthon 7).
3 3 3
And the amine further donates its two protons to form two
NꢀH O(sulfoxy) hydrogen bonds (synthon 5) to link with two
3 3 3
different SFZ molecules, all in a co-operative manner (Figure 10).
As a result, the amine group from one of the crystallographically
independent SFZ is involved in a total of three hydrogen bonds,
while the amine group from the other distinct SFZ molecule uses
group of 3HNA involves in an intramolecular OꢀH O(carbonyl)
its two protons to make two NꢀH O(sulfoxy) hydrogen bonds,
3 3 3
3 3 3
as well as an intermolecular NꢀH O hydrogen bond (synthon 8)
but in this the lone pair of N atom remains unused. Notably, the
amine group that utilizes the lone pair adopts a pyramidal shape,
while the other remains nearly planar. The hydrogen bond
formation among the amine and sulfoxy groups leads to the
formation of a honeycomb 2D network parallel to (010) as shown
Figure 10a.
3 3 3
with the SFZ amine group that results in a wavelike 1D chain
along the crystallographic c-axis (Figure 11). The second amine
hydrogen forms a weak NꢀH
O(sulfoxy) (2.22(2) Å, 167(2)°)
3 3 3
interaction. The adjacent wavelike linear 1D chains pack in a
space fill manner along the b-axis as shown in Figure 11a. The
adjacent layers further pack antiparallelly to optimize π
interactions along the a-axis (Figure 11b).
π
Sulfamethazine/3-Hydroxy-2-naphthoic Acid (1:1) (SFZ/
3HNA). Sulfamethazine and 3-hydroxy-2-naphthoic acid (3HNA)
3 3 3
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Crystal Growth & Design
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Figure 10. Sulfamethazine/4-hydroxybenzamide (1:1) monoclinic
form. (a) Crystal packing to show the 2D honeycomb network formed
by SFZ molecules via NꢀH O (synthon 5). Notice that the alternate
3 3 3
SFZ pyrimidine rings lie above and below perpendicular to the 2D sheet.
(b) Linkages of the two SFZ pyrimidine rings from two different 2D
sheets by two HBEN molecules. Notice the synthon 7 (OꢀH N)
3 3 3
between the HBEN hydroxyl and SFZ amine groups.
Figure 9. Sulfamethazine/4-hydroxybenzamide (1:1). (a) Polymorphic
crystals of the monoclinic form (SFZ/HBEN-M) and triclinic form
(SFZ/HBEN-T). (b) Crystal packing in SFZ/HBEN-T. The tetramer
formation (highlighted molecules) via SdO HꢀN(HBEN) (synthon
3 3 3
9) and the infinite amino-phenol hydrogen bonding pattern (synthons 7
and 8) involving the HBEN hydroxyl and SFZ amine groups (protons on
O and N atoms are not shown as they could not be refined properly in
the structure).
Density Functional Theory Calculations. Tautomerism and
polymorphism are common phenomena in sulfonamide drugs,16ꢀ19
but the sulfamethazine is not known to show any such phenomena
in its single component crystals, in the literature reported thus far.6
But in all the SFZ/amide co-crystals in this study, the SFZ molecule
exists exclusively in the imidine tautomeric form, but never in the
amidine tautomeric form. On the contrary, in the SFZ/acid co-
crystals, the SFZ exists predominantly in amidine (synthon 1)
tautomeric form, except in SFZ/HBA and SFZ/3HNA, where
imidine tautomeric form (synthon 2) is involved. To rationalize
the SFZ tautomerism in co-crystals, we performed DFT calculations
using Gaussian software. The calculations were performed on the
free SFZ (1) amidine(SFZ) and (2) imidine(SFZ) tautomeric forms as
well as the hydrogen bonded pairs of the SFZ molecule with (3)
benzoic acid (BA), linked via synthon 1, (4) BA linked via synthon
2, (5) benzamide (BEN) linked via synthon 3, (6) BEN linked via
synthon 4, (7) 1-hydroxy-2-naphthoic acid (1HNA) linked via
synthon 1, (8) 1HNA linked via synthon 2, (9) 3-hydroxy-2-
naphthoic acid (3HNA) linked via synthon 1, and (10) 3HNA
linked via synthon 2, for estimating the relative energy differences of
the two possible synthons in each case. In all the cases, the molecular
pairs were taken from corresponding crystal structures and per-
formed geometry optimization, followed by the single point energy
Figure 11. Sulfamethazine/3-hydroxy-2-naphthoic acid (1:1), SFZ/
3HNA. (a) Crystal packing (view down the a-axis) shows the wavelike
one-dimensional (1D) chains running along the c-axis. (b) Another view
(down the b-axis) of the 1D chains.
calculations. The energy difference between the amidine and
corresponding imidine tautomeric forms of all the calculated
molecules are given in Table 3. The calculations reveal that the
amidine(SFZ) tautomeric form, irrespective of whether hydrogen
bonded or free, is more stable than the imidine(SFZ) tautomeric
form. In case of the free (without co-former) SFZ, the “amidine”
tautomer is more stable by 11.43 kcal/mol per molecule than its
“imidine” counterpart. The poor stability of the free imidine(SFZ) is
attributable to the distress caused by the loss of aromaticity at the
SFZ pyrimidine ring. However, in the case of the hydrogen bonded
SFZ pairs, the energy gap is greatly minimized. For instance, the
energies of the amidine(SFZ) pairs with both BA (synthon 1) and
BEN (synthon 3) are relatively more stable than the imidine(SFZ)
pairs with BA (synthon 2) and BEN (synthon 4) by 4.39 and
0.63 kcal/mol, respectively. The calculated energies for the amidi-
ne(SFZ) BA and imidine(SFZ) BA pairs show a good
3 3 3
3 3 3
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Crystal Growth & Design
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Table 3. Single Point Energies of the Free Amidine (SFZ),
Imidine (SFZ) Tautomers and the Hydrogen Bonded Pairs of
SFZ with Some Co-Former Molecules, Obtained from the
DFT Calculations
amidine ꢀ imidine = energy
s. no.
molecular unit(s)
difference (kcal/mol)
1
2
amidine(SFZ)
imidine(SFZ)
11.43
4.39
0.63
6.50
1.95
3
amidine(SFZ) BA
3 3 3
4
imidine(SFZ) BA
3 3 3
5
amidine(SFZ) BEN
3 3 3
6
imidine(SFZ) BEN
3 3 3
7
amidine(SFZ) 1HNA
3 3 3
Figure 12. The energy optimized molecular pairs of SFZ and BEN
bonded via (a) synthon 3 and (b) synthon 4, obtained from Gaussian
calculations. (a) The space filling model shows the synthon 3 formation
and the unfavorable secondary interactions (red arrows) due to a tight
packing of amide NH2(BEN) and Me(SFZ), and the SO2(SFZ) and OdC
8
imidine(SFZ) 1HNA
3 3 3
9
amidine(SFZ) 3HNA
3 3 3
10
imidine(SFZ) 3HNA
3 3 3
groups. (b) Synthon 4 formation with favorable secondary
(BEN)
interactions (green arrows) between OdC (BEN) Me(SFZ) and SO2-
3 3 3
agreement with the fact that the synthon 1 is observed in the
previously reported crystal structure of SFZ/BA co-crystal. Similarly,
the majority of the studied SFZ/acid co-crystals adopted the
synthon 1, except SFZ/HBA and SFZ/3HNA (synthon 2). The
contrast behavior of these latter two structures may be understood
from the calculations on the amidine/imidine(SFZ) hydrogen
bonded pairs with 1HNA and 3HNA. In the case of the 1HNA,
the energy difference between the amidine(SFZ) and imidine(SFZ)
hydrogen bonded tautomers is 6.5 kcal/mol, while this is only 1.9
kcal/mol in the case of the 3HNA. Hence, as the energy difference in
the case of 3HNA pairs is only marginal, the formation of synthon 2
in its crystal structure is understandable.
H2N(BEN) groups.
(SFZ)
3 3 3
synthon 1) and 3HNA (imidine(SFZ); synthon 2). In the case of
3HNA, the formation of synthon 1 (amidine(SFZ)) is only less
stable by 1.9 kcal/mol than the synthon 2 (imidine(SFZ)), while
this is 6.5 kcal/mol in the case of 1HNA. Hence, the formation of
synthon 2 in SFZ/3HNA is comprehensible as this leads to
favorable secondary interactions, as is also the case in SFZ/HBA.
Hence, the overall crystal packing and the hydrogen bond pre-
ferences of all the functional groups have to be considered for
understanding such observations. The studies reveal that this is
clearly a case of co-former (or synthon) assisted API tautomer-
ism, where the co-former geometry plays an important role in
prompting the tautomerism.
Observation of the tautomerism in SFZ co-crystals inspired us
to screen for the new polymorphic forms of the single compo-
nent SFZ. But, in our quick screening by solvent drop grinding
and slow evaporation methods, we did not observe any poly-
morphism of SFZ. But, it will be no surprise, if a new form of SFZ
with imidine tautomeric form is found, as it is clear from these co-
crystals that the hydrogen bonding greatly reduces the difference
between the amidine and imidine SFZ tautomeric forms. How-
ever, this will depend on the possibility of SFZ achieving the
stable hydrogen bonded imidine tautomer with minimal steric
effects from the pyrimidine methyl group and the sulfoxy
O atom.
Infrared Spectroscopy. Infrared spectroscopy is a reliable
technique to ascertain the formation of co-crystals. Usually co-
crystals show the stretching frequency (νs) bands of both the co-
formers associated with characteristic shifts.20 For the IR spec-
troscopy of all the SFZ co-crystals (in the region 400ꢀ4000 cmꢀ1),
two to three single crystals were chosen by inspecting them under
an optical microscope. A comparison of the νs shifts gave an
estimate of the relative strengths of the hydrogen bonds formed
between the functional groups in co-crystals.20ꢀ24 The detailed
peak assignment for the free SFZ and each co-crystal is given in
Table 4. In the single component or free SFZ crystals, the
stretching frequency band at 3243 cmꢀ1 is assigned to ami-
dine/imidine NH, while the two bands at 3443 and 3345 cmꢀ1
are assigned to the asym NH2 and sym NH2 stretching frequen-
cies of amine groups respectively. In the free SFZ crystals, the
On the other hand, in all the studied SFZ/amide co-crystals,
only the synthon 4, involving the less stable imidine(SFZ), was
observed. The calculations showed that the imidine(SFZ) BEN
3 3 3
pair is only less stable by 0.6 kcal/mol than the amidine(SFZ) BEN
3 3 3
pair. A careful examination of the geometries of calculated SFZ
3 3
BEN pairs with synthon 3 and 4 provided some insights. In the
amidine(SFZ) BEN pair, the synthon 3 was found twisted with
a clear puckering of the amide NH2(BEN) protons away from the
adjacent Me group on the SFZ pyrimidine ring. This suggests a
possible high steric repulsion effect on the amide NH2 protons
by the adjacent Me(SFZ) group. Hence, the unfavorable second-
3
3 3 3
ary interactions such as NH2(BEN)
Me(SFZ) and
3 3 3
SO2(SFZ) OdC(BEN) seem to deter the formation of synthon
3 3 3
3 in the crystal structures. On the other hand, in the case of
synthon 4, the reversal of the amide group on BEN (∼180°
rotation) leads to favorable SO2(SFZ)
H2N(BEN) and
3 3 3
Me(SFZ) OdC(BEN) secondary interactions (Figure 12). This
3 3 3
was also supported by the presence of stronger hydrogen bonds
(smaller matrices) in the calculated synthon 4 than in synthon 3.
Here it is to be noted that the small difference of 0.6 kcal/mol in
tautomeric SFZ BEN pairs is for the isolated hydrogen
3 3 3
bonded molecular pairs with idealized geometries, whereas, in
the crystalline state, the molecular geometries are bound to
deviate from the idealized positions due to packing constraints;
hence the unfavorable or favorable interactions will have a greater
influence on the stabilities, and hence the reversal of the relative
stabilities for amidine(SFZ) and imidine(SFZ) tautomeric forms is
anticipated. Consideration of similar steric factors is also useful to
understand the formation of distinct synthons in the earlier
discussed co-crystals of crowded acids, 1HNA (amidine(SFZ)
;
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Table 4. Infrared Stretching Frequencies for SFZ Amidine NH and Amine NH2 Groups in Free SFZ and Co-Crystalsa
peak assignment
SFZ
SFZ/HBA
SFZ/DHB
SFZ/DCB
SFZ/SOR
SFZ/FUM/ACN
amine ν(NH2)asym (cmꢀ1
)
3443
3357 (ꢀ86)
3379 (ꢀ64)
3487 (þ44)
3469 (þ26)
3478 (þ35)
(D A distance /Å)
3.124
3.104(2)
3.178(2)
3.223(4)
3.182(4)
3.0137(18)
3 3 3
NH N(Ar)
3 3 3
amine ν(NH2)sym
sulfonamide ν(NH)
3345
3293 (ꢀ52)
3241 (ꢀ2)
2.756(2)
3302 (ꢀ43)
3384 (þ39)
3215 (ꢀ28)
2.839(3)
3370 (þ25)
3384 (þ39)
3250 (þ7)
2.7866(16)
3243
(D A distance /Å)
2.945
2.791(2)
2.830(2)
3 3 3
NH O(SO )
2
3 3 3
peak assignment
SFZ/1HNA
SFZ/BEN
SFZ/PIC
SFZ/HBEN-T
SFZ/HBEN-M
SFZ/ 3HNA
amine ν(NH2)asym
3461 (þ18)
3.0451(18)
3378 (þ33)
3267 (24)
3435 (ꢀ8)
2.950(6)
3464 (þ21)
3.186(4)
3416 (ꢀ27)
3.032(3)
3435 (ꢀ8) 3459 (þ16)
2.938(3)
3426 (ꢀ17)
3.0416(19)
3362 (þ17)
3261 (þ18)
2.7486(18)
(D A distance /Å)
3 3 3
amine ν(NH2)sym
sulfonamide ν(NH)
3352 (þ7)
3241 (ꢀ2)
2.704(5)
3373 (þ28)
3256 (þ13)
2.762(3)
3325 (ꢀ20)
3194 (ꢀ49)
2.722(3)
3332 (ꢀ13) 3363 (þ18)
3194 (ꢀ49)
(D A distance /Å)
2.8770(18)
2.709(2)
3 3 3
a The values given in brackets are the frequency shifts in comparison with the corresponding groups in single component SFZ crystals.
amidine NH involves NꢀH O(sulfoxy) while the amine group
3 3 3
involves two NꢀH N(pyrimidine) hydrogen bonds by utilizing
3 3 3
both the protons, whereas, in the co-crystals, the SFZ exists in
either amidine or imidine tautomeric form to make hydrogen
bonded synthons 1, 2, or 4 with the co-formers; hence the
associated stretching bands appear at different frequencies.
Similarly, the SFZ amine also involves different synthons (5, 7,
8, or 12) in different co-crystals. The infrared stretching frequen-
cies with the associated shifts (in brackets) in comparison with
free SFZ are given in Table 4.
The SFZ/HBA co-crystal shows the stretching frequency
bands for both the co-formers with associated shifts confirming
the formation of a new phase (Figure 13a). In the co-crystal, the
bands for SFZ amine (NH2) group are observed at 3357 cmꢀ1
(asym NH2) and 3293 cmꢀ1 (sym NH2) that have shifts to lower
frequencies (ꢀ86 and ꢀ52 respectively) compared to the free
SFZ molecule in its single component crystals. The amidine NH
stretchingfrequency(νNH) band, inthis case, is notprominent, but
a small attributable band is present at 3241 cmꢀ1 (Figure 13a).
The IR spectra of the polymorphic forms SFZ/HBEN-T and
SFZ/HBEN-M are clearly distinct as the stretching frequencies
for SFZ imidine NH and amine NH2 groups in the latter form are
split due to a doubling of molecules in the asymmetric unit
(Figure 13b). However, the shift of proton from the sulfonamide
NH to pyrimidine N atom in the imidine(SFZ) did not show any
large effect on the stretching frequency of NH compared to the
NH in free SFZ, as both the NꢀH bond distances are close
(amidine NꢀH distance: in free SFZ = 1.069 Å; SFZ/HBEN-T =
0.91(4) Å; SFZ/HBEN-M = 0.91(3) and 0.96(3) Å).
Thermal Analysis. A detailed DSC and TGA experiments
were carried out for each co-crystal to study the thermal behavior
with respect to API. The DSC traces and thermogravimetric data
for the sulfamethazine co-crystals are presented in Figures 14 and
15. The DSC thermograms for all the SFZ co-crystals, except
SFZ/HBEN and SFZ/FUM/ACN, showed a single endothermic
transition corresponding to the melting (Figure 14a). The
melting transition temperature of all the co-crystals was distinct
from either of the individual components confirming the forma-
tion of a new phase. The thermogram in the case of SFZ/HBEN
showed two major endotherms at 175.2 and 180 °C (along with a
small endotherm at 129.5 °C). A careful separation of the
Figure 13. Infrared (IR) spectra of (a) SFZ/HBA and (b) SFZ/HBEN-
T and SFZ/HBEN-M forms. Note the splitting of amidine NH and
amine NH2 frequency stretching bands in the SFZ/HBEN-M form due
to a pair of symmetry independent SFZ molecules in the asymmetric
unit, in (b).
polymorphic crystals using optical microscopy, followed by unit
cell determination by SCXRD (using a crystal from each batch)
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Figure 14. Thermal analysis plots of SFZ co-crystals. (a) DSC of the free SFZ and some SFZ co-crystals, and (b) the SFZ/HBEN polymorphs. Panels
(c) and (d) show the TGA plots of all the co-crystals, except SFZ/FUM/ACN.
and then DSC (∼2 mg) revealed that the first major endotherm
corresponds to the monoclinic form while the second endotherm
corresponds to the triclinic form. But the small endotherm at
129.5 °C was not observed in either case, possibly due to the low
amount of samples used for the DSC. But the large amounts
(∼10 mg) of samples taken from two different batches showed a
clear proportionate relationship of the small peak to the melting
endotherm of the triclinic form. Although it is not a conclusive
proof, this suggests to a possible phase transition of the triclinic
form to a more stable unknown third form. Further confirmation
was not possible as growing triclinic crystals with good yields was
difficult.
The co-crystal solvate, SFZ/FUM/ACN, showed three com-
plicated endotherms, with signs of recrystallization, as indicated
by the shapes of the last two endotherms in the thermogram
(Figure 15a). The TGA experiments confirmed that the first
broad endotherm correspond to a loss of solvent (∼6.2% of the
total weight) that matched approximately to one molecule of
acetonitrile in the asymmetric unit (Figure 15b). To explicate the
second and third endotherms, we carried out DSC and TGA on a
sample, which was treated at ∼175 °C for 20 min under vacuum
followed by cooling to room temperature. The DSC of the resulted
solid showed only a single and sharp endotherm exactly at the
place of the third endotherm (199 °C), which is also same as the
mp of the single component SFZ crystalline solid form. The
PXRD of the resulted solid confirmed that this is in fact the single
component SFZ form. Hence, the other endotherm at 185 °C
should correspond to the melting of the co-crystal that is formed/
remained after the solvent loss (Figure 15c). Analysis of the
melting endotherms of all the co-crystals reveals that the SFZ/
HBA displays an improved thermal stability over the free SFZ
crystals, while the DHB and 3HNA co-crystals remain nearly the
same and all the remaining co-crystals display decreased thermal
stability compared to the API.
Solubility Studies. Although we attempted the solubility
studies on several co-crystal samples, it was not possible to obtain
the estimated values for SFZ co-crystals with SOR, 1HNA, 3HNA,
and PIC as both the co-former absorption bands appeared at the
same region. In the case of SFZ/BEN (0.683 mg/mL) and SFZ/
FUM (0.753 mg/mL), the solubility could be estimated and both
showed slightly improved solubility when compared to the free
SFZ crystals (0.556 mg/mL).
Hydrogen Bond Competition. In the SFZ molecule, there
are two types of acceptors and two types of donors with varied
strengths. The slightly stronger acceptor, O(sulfoxy), and the weaker
acceptors, aromatic ring N(pyrimidine) atoms, compete for the
strongest amidine donor (NH). In this, the former successfully
forms synthon 11, leaving the latter to settle with the next
strongest donor, amine (NH2) to form NꢀH N synthon 12.
3 3 3
Notably, the geometrical placementof the amine(para-position) is
also a favorable factor for its easy reach to the N(pyrimidine) than the
sulfonamide NH group. There are no other notable hydrogen
bond synthons in the free SFZ structure. But, in the co-crystals,
the synthon 11 was never found while synthon 12 was found in
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Figure 15. (a) DSC plots of the co-crystal solvate, SFZ/FUM/ACN (red) and an another batch of sample after treating at 175 °C under a vacuum, and
(b) the corresponding TGA plots. (c) The experimental PXRD pattern of the sample treated at 175 °C (red) and the simulated PXRD pattern of the free
SFZ (black). Notice the perfect match between the red and black lines.
both SFZ/HBA and SFZ/DHB. The observations are consistent
with the fact that a strong donor binds to a strong acceptor and a
weak donor to a weak acceptor.25 In all the co-crystals, the dominant
co-former carboxylic acid or amide group primarily binds to the
amidine/imidine(SFZ) site via synthon 1, 2, or 4. All the amide co-
formers interacted with the imidine(SFZ) tautomer via synthon 4,
but never with amidine(SFZ) tautomer via synthon 3, whereas the
acid co-formers bind preferentially with the amidine(SFZ), except
the HBA and 3HNA which bind by imidine(SFZ) tautomer, due to
the reasons discussed earlier using the Gaussian calculations.
The remaining SFZ amine and sulfoxy groups are left free to
interact either with each other or to compete with the other
available hydrogen bonding functional groups from the co-
former, if any. When there was no strong competing hydrogen
bonding group from the co-former, synthon 5 was always found
between the SFZ amine and sulfoxy groups involving both the
protons of amine and O atoms of sulfoxy group. Not only that,
even when there was a strong competing hydrogen bonding group
like OH from the co-former, at least one amine proton and a
sulfoxy O atom participated in the synthon 5, in all the cases
except in SFZ/HBEN-T. When the co-former had a p-OH group
(HBA, DHB, HBEN-T, and HBEN-M), in all the cases, the SFZ
OH primarily involved in intramolecular OꢀH
O(carbonyl)),
3 3 3
the SFZ amine, instead, formed synthon 8 (NꢀH O). The
3 3 3
exceptional utilization of all the acceptors and donors is seen in
the HBEN-T co-crystal. This could be attributed to the easy
accessibility of the OH(HBEN) group being at the para position. In
the structure, the complementary amino-phenol synthons 7 and
8 are present, alongside the rare synthons 9 and 10 in this study.
Synthon 9 is also found in the SFZ/BEN. Analysis of the other
SFZ co-crystals reported in the literature also showed a very
similar hydrogen bonding pattern.
Conclusion. In conclusion, 10 new SFZ co-crystals with
carboxylic acids and amides are synthesized and characterized
thoroughly by single crystal XRD, DSC, TGA, and infrared
spectroscopy. DSC and TGA was used to confirm the relative
stabilities of the new solid forms compared to the free SFZ.
Sulfamethazine shows co-former induced amidine-imidine tau-
tomerism in co-crystals. The acid co-crystals bind to the SFZ via
synthon 1 or 2, while the amides bind via synthon 4, but never via
synthon 3. This is because the formation of synthon 3 is sterically
hindered due to repulsion between the pyrimidine methyl group
of SFZ and the co-former amide NH2 group, as well as the
unfavorable repulsion between the sulfoxy O atoms and the
amide carbonyl O atom from the co-former, whereas such steric
hindrance is absent in case of synthon 4 formation, though there
amine involved additionally in synthon 7 (OꢀH N), while
3 3 3
when the OHwas ortho- to the carboxylic acid or amide (where the
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is a loss of aromatic energy on the SFZ pyrimidine ring of the
imidine(SFZ), which is again made up by the hydrogen bond
formation energy. The geometry and hydrogen bonding func-
tional groups on the co-formers are shown to influence the type
of synthons formed by the SFZ sulfonamide and amine groups in
the co-crystals. The hydrogen bond synthons observed in the
structures are consistent with the fact that the strong acceptors
prefer strong donors and the weak acceptors prefer the weak donors.
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’ ASSOCIATED CONTENT
S
Supporting Information. Geometrical parameters of sig-
b
nificant hydrogen bonds in all the co-crystals (Table S1); ORTEP
diagrams (Figures S1ꢀS10); powder X-ray diffraction patterns of
bulk co-crystal samples (Figures S11 and S12); IR spectral data of
the co-crystals (Figure S13ꢀS21); Crystallographic information
files (CIFs). This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: cmallareddy@rediffmail.com.
(10) Barbour, L. J. X-Seed, Graphical Interface to SHELX-97 and
POV-Ray; University of Missouri; Columbia: Columbia, MO, 1999.
(11) Basavoju, S.; Bostr€om, D.; Velaga, S. P. Cryst. Growth Des. 2006,
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’ ACKNOWLEDGMENT
S.G. thanks the CSIR (New Delhi) for JRF. P.P.B. thanks the
CSIR for SRF. C.M.R. thanks the DST (SR/FT/CS-074/2009)
for funding. We thank Dr. Sanjio S. Zade (IISER Kolkata) for his
suggestions and help with the DFT calculations.
(12) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
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