Solid-state form screen of cardiosulfa and its analogues

Article abstract of DOI:10.1002/asia.201201162

Cardiosulfa is a biologically active sulfonamide molecule that was recently shown to induce abnormal heart development in zebrafish embryos through activation of the aryl hydrocarbon receptor (AhR). The present report is a systematic study of solid-state forms of cardiosulfa and its biologically active analogues that belong to the N-(9-ethyl-9H-carbazol-3-yl)benzene sulfonamide skeleton. Cardiosulfa (molecule 1; R¹=NO₂, R ²=H, R³=CF₃), molecule 2 (H, H, CF ₃), molecule 3 (CF₃, H, H), molecule 4 (NO₂, H, H), molecule 5 (H, CF₃, H), and molecule 6 (H, H, H) were synthesized and subjected to a polymorph search and solid-state form characterization by X-ray diffraction, differential scanning calorimetry (DSC), variable-temperature powder X-ray diffraction (VT-PXRD), FTIR, and solid-state (ss) NMR spectroscopy. Molecule 1 was obtained in a single-crystalline modification that is sustained by N-H...π and C-H...O interactions but devoid of strong intermolecular N-H...O hydrogen bonds. Molecule 2 displayed a N-H...O catemer C(4) chain in form I, whereas a second polymorph was characterized by PXRD. The dimorphs of molecule 3 contain N-H...π and C-H...O interactions but no N-H...O bonds. Molecule 4 is trimorphic with N-H...O catemer in form I, and N-H...π and C-H...O interactions in form II, and a third polymorph was characterized by PXRD. Both polymorphs of molecule 5 contain the N-H...O catemer C(4) chain, whereas the sulfonamide N-H...O dimer synthon R₂²(8) was observed in polymorphs of 6. Differences in the strong and weak hydrogen-bond motifs were correlated with the substituent groups, and the solubility and dissolution rates were correlated with the conformation in the crystal structure of 1, 2, 3, 4, 5, 6. Higher solubility compounds, such as 2 (10.5 mg mL^-1) and 5 (4.4 mg mL ^-1), adopt a twisted confirmation, whereas less-soluble 1 (0.9 mg mL^-1) is nearly planar. This study provides practical guides for functional-group modification of drug lead compounds for solubility optimization.

Full text of DOI:10.1002/asia.201201162

FULL PAPER
DOI: 10.1002/asia.201201162
Solid-State Form Screen of Cardiosulfa and Its Analogues
S. Sudalai Kumar, Soumendra Rana, and Ashwini Nangia*[a]
Abstract: Cardiosulfa is a biologically
(VT-PXRD), FTIR, and solid-state (ss)
NMR spectroscopy. Molecule 1 was ob-
tained in a single-crystalline modifica-
characterized by PXRD. Both poly-
ꢀ
active sulfonamide molecule that was
recently shown to induce abnormal
heart development in zebrafish em-
bryos through activation of the aryl hy-
drocarbon receptor (AhR). The pres-
ent report is a systematic study of
solid-state forms of cardiosulfa and its
biologically active analogues that
belong to the N-(9-ethyl-9H-carbazol-
3-yl)benzene sulfonamide skeleton.
Cardiosulfa (molecule 1; R1 =NO2,
R2 =H, R3 =CF3), molecule 2 (H, H,
CF3), molecule 3 (CF3, H, H), molecule
4 (NO2, H, H), molecule 5 (H, CF3, H),
and molecule 6 (H, H, H) were synthe-
sized and subjected to a polymorph
search and solid-state form characteri-
zation by X-ray diffraction, differential
scanning calorimetry (DSC), variable-
temperature powder X-ray diffraction
morphs of molecule 5 contain the N
H···O catemer C(4) chain, whereas the
ꢀ
ꢀ
tion that is sustained by N H···p and
sulfonamide N H···O dimer synthon
R2 (8) was observed in polymorphs of
2
ꢀ
C H···O interactions but devoid of
ꢀ
strong intermolecular N H···O hydro-
gen bonds. Molecule 2 displayed a N
H···O catemer C(4) chain in form I,
whereas a second polymorph was char-
acterized by PXRD. The dimorphs of
6. Differences in the strong and weak
hydrogen-bond motifs were correlated
with the substituent groups, and the
solubility and dissolution rates were
correlated with the conformation in
the crystal structure of 1–6. Higher
ꢀ
ꢀ
ꢀ
molecule 3 contain N H···p and C
ꢀ
H···O interactions but no N H···O
solubility compounds, such as
2
bonds. Molecule 4 is trimorphic with
(10.5 mgmLꢀ1) and (4.4 mgmLꢀ1),
5
ꢀ
ꢀ
N H···O catemer in form I, and N
adopt a twisted confirmation, whereas
less-soluble 1 (0.9 mgmLꢀ1) is nearly
planar. This study provides practical
guides for functional-group modifica-
tion of drug lead compounds for solu-
bility optimization.
ꢀ
H···p and C H···O interactions in
form II, and a third polymorph was
Keywords: cardiosulfa
·
drug
delivery · molecular conformation ·
polymorphism · X-ray diffraction
Introduction
nitro-4-(trifluoromethyl)benzenesulfonamide (molecule 1 in
Scheme 1).[5a] Cardiosulfa displays agonist-like properties to-
Sulfa drugs[1a,b] are an important class of molecules that con-
tain the sulfonamide moiety (R-SO2-NH-Ar). They display
a wide range of biological activities and a high success rate
in therapeutic medicines. With a frequency of >50% for
more than one crystalline modification, sulfonamides are
the second-best candidates to display polymorphism, the top
drug category being barbiturates at 70%.[2] The biological
action of a drug molecule can change in different poly-
morphic states from therapeutic to toxic owing to sudden
changes in dissolution rate for the given dose as, for exam-
ple, for mebendazole and chloramphenicol.[3] Thus lead mol-
ecules might be optimized from a larger set of sulfonamides
synthesized by combinatorial technology in medicinal
chemistry programs.[4] Such an approach recently led to the
discovery of cardiosulfa or N-(9-ethyl-9H-carbazol-3-yl)-2-
Scheme 1. Chemical structures of cardiosulfa (molecule 1) and analogues
(molecules 2–6).
wards aryl hydrocarbon receptor[5d] (AhR), a transcription
factor and a member of the nuclear receptor family, the pri-
mary function of which is to regulate xenobiotic metabolism
and mediate the toxic response of dioxin-like environmental
pollutants.[][5c–f] In zebrafish models,[5b] cardiosulfa 1 and its
analogues (molecules 2–6) were able to impair cardiovascu-
lar function by modulating the AhR signaling pathway,
which evoked edema-like responses in pericardial and yolk
sacs.[5c]
[a] S. S. Kumar, Dr. S. Rana, Prof. Dr. A. Nangia
School of Chemistry, University of Hyderabad
Central University PO, Prof. C. R. Rao Road
Gachibowli, Hyderabad 500 046 (India)
E-mail: ashwini.nangia@gmail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201201162.
1
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
By contrast, AhR signaling in humans can be tissue-spe-
cific[6a] depending upon whether it is localized in the liver,
kidney, lungs, ovary, or breast.[6b] Numerous studies have il-
luminated the other side of AhR signaling, thereby eliciting
a more defined cell biological response that ranges from cell
growth, proliferation, and differentiation to apoptosis. For
example, agonistic activation of AhR and downstream sig-
naling in the MCF-7 breast cancer cell line cause DNA
damage and possibly offer an alternative therapy for breast
cancer.[6b] AhR agonists can upregulate caspase-8[6c] and en-
hance apoptosis through receptor signaling. Similarly, it has
been shown that the AhR agonist can inhibit pancreatic
cancer cell growth in a dose-dependent manner.[6d] It is sug-
gested that agonist-dependent AhR activation can regulate
both Treg and Th17 cell differentiation, which plays a key
role in immune response.[6e,f] It is therefore important to
study synthetic agonists of AhR and small-molecule poly-
morphism. From quantitative structure–activity relationship
(QSAR) studies, it is apparent that planar molecules with
dimensions limited to 14 ꢁꢂ12 ꢁꢂ5 ꢁ interact with the
AhR ligand-binding domain, even as the effectiveness of the
binding can be contingent upon certain molecular functiona-
lity.[6g]
The binding of cardiosulfa to AhR triggers cardiovascular
impairment in zebrafish, which suggests that cardiosulfa can
serve as a biological probe in understanding heart growth
and development. On the other side, the role of cardiosulfa
in AhR signaling in human tissues is currently unknown and
it is quite possible that cardiosulfa might display therapeuti-
cally beneficial pharmacology in humans. Exploring the
solid-state forms of AhR binding molecules evokes interest
because AhR is involved in several cell biological responses.
A better understanding of the crystal structures and physico-
chemical properties of cardiosulfa analogues is necessary to
exploit its potential as a bioactive molecule in structure-
based drug design. In this direction, we synthesized cardio-
sulfa analogues 1–6 (Scheme 1) and carried out a systematic
solid form search and characterization by using X-ray dif-
fraction, FTIR, 13C solid-state (ss) NMR spectroscopy, and
solubility experiments.[7] Polymorphic phase transformations
were monitored by differential scanning calorimetry (DSC)
and variable-temperature powder X-ray diffraction (VT-
PXRD) to establish the thermodynamic relationship and
thermal stability of polymorphs.[8]
ing was to explore the polymorphic behavior as well as to
determine the aqueous solubility of molecules 1–6 and their
novel polymorphs. Our previous experience[9c] with sulfona-
ꢀ
mides suggested that N H···O dimer and catemer synthons
2
of graph set notations[10] R2 (8) and C(4) are frequent in
these crystal structures. On the other hand, when the
SO2NH group is flanked by aromatic rings on both sides,
ꢀ
ꢀ
there is a possibility of weak N H···p and C H···O hydro-
gen bonds in the crystal structure[11a] instead of strong N
ꢀ
H···O bonds. Sulfonamides 1–6 are expected to exhibit poly-
morphism because 1) they belong to the polymorph promis-
cuous aromatic sulfonamide class;[11] 2) they can form N
ꢀ
H···O dimers or catemers to give synthon polymorphs;[9d–f,
12e]
3) conformational flexibility in the molecule will increase
the likelihood of polymorphism;[12,13] and 4) the presence of
NO2 and CF3 groups introduces competing hydrogen-bond
motifs in the crystal structures, and consequently poly-
morphism. The sulfa compounds (Scheme 1) were prepared
by the amide coupling of 9-ethyl-9H-carbazol-3-amine with
the appropriate benzenesulfonyl chloride (see the Experi-
mental Section for details). The sulfonamide products were
crystallized from suitable solvents and the bulk purity in the
solid state[14a] was ascertained by powder XRD and 13C ss-
NMR (Figures 1 and 2).[14b,c] The crystallization conditions
for polymorph screening are detailed in the Supporting In-
formation, and the 13C chemical shifts of polymorphs are
also listed in the Supporting Information. The different
chemical environments of the carbon atoms due to different
intermolecular interactions and short-range order resulted
in up-/downfield shifts for the polymorphs. The crystalline
and amorphous phases were differentiated by the broadness
of peaks (typical humps) for the amorphous phase. Chemi-
cal shifts of the terminal ethyl group were used to differenti-
ate polymorphs. For example, in molecule 2, the N-ethyl
group resonates at d=13.2 and 33.7 ppm for form I and at
d=11.8 and 33.2 ppm in form II (see the NMR spectra in
Figure 2). The PXRDs of the amorphous products obtained
in the crystallization experiments are given in the Support-
ing Information. Further characterization was carried out by
FTIR[14d] (see the Supporting Information). Crystal struc-
tures of 1–6 were confirmed by single-crystal X-ray diffrac-
tion (Table 1).
Polymorphic Crystal Structures
Molecule 1
Results and Discussion
Cardiosulfa was crystallized from acetone/methanol (1:1),
and the structure was solved and refined in the monoclinic
space group P21/n. The molecular conformation is locked by
Crystal Structures
Among the six sulfonamides,[5a] cardiosulfa (molecule 1) is
the most active[5c] in zebrafish heart deformation relative to
molecules 2, 3, and 4, whereas molecules 5 and 6 are only
weakly active. The purpose of the present solid form screen-
ꢀ
an intramolecular N H···O hydrogen bond (2.44 ꢁ, 1088) of
ꢀ
an S(7) motif. The N H···p interaction is present instead of
ꢀ
a strong intermolecular N H···O hydrogen bond (hydrogen
Figure 1. Experimental (black) and calculated (gray) PXRD line patterns: a) Form I of molecule 1; b) form I of molecule 2; c) form II of molecule 2;
d) form I of molecule 3; e) form II of molecule 3; f) form I of molecule 4; g) form II of molecule 4; h) form I of molecule 5; i) form II of molecule 5; and
j) form I of molecule 6. The excellent overlay confirms the purity of the bulk phase with the single-crystal X-ray structure. Single-crystal X-ray structures
could not be determined for form II of molecules 2 and 3.
&
&
2
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ashwini Nangia et al.
3
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
Figure 2. 13C ss-NMR spectra of polymorphs of molecules 1–6 shown as stacked overlay plots.
ꢀ
ꢀ
bonds listed in Table 2). An N H···p interaction is quite un-
and C5 H5···p (2.82 ꢁ) are involved in the overall crystal
packing (Figure 3b). The presence of two electron-withdraw-
common in sulfonamides[11] given the opportunity for strong
ꢀ
ꢀ
N H···O hydrogen bonding. The molecular arrays are as-
ing groups, CF3 and NO2, decrease the propensity for N
ꢀ
ꢀ
sembled through N1 H1···p (3.04 ꢁ) and S1 O1···p
H···O hydrogen bonding by weakening the O-acceptor capa-
bility. We noted previously in diaryl urea crystal structur-
es[11e] that the NO2 group can significantly alter the molecu-
(3.06 ꢁ) interactions (Figure 3a). Weak interactions such as
ꢀ
ꢀ
C3 H3···O3 (2.47 ꢁ, 1598), C20 H20A···F2 (2.48 ꢁ, 1328),
&
&
4
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ashwini Nangia et al.
Table 1. Crystallographic details of sulfonamides 1–6.
Compound
Polymorph
1
2
3
4
5
6
Form I
Form I
Form I
Form I
Form II
Form I
Form II
Form I
formula
Mr
crystal system
space group
a [ꢁ]
b [ꢁ]
c [ꢁ]
a [8]
b [8]
C21H16F3N3O4S C21H17F3N2O2S C21H17F3N2O2S C20H17N3O4S
C20H17N3O4S
395.44
C21H17F3N2O2S C21H17F3N2O2S
C20H18N2O2S
350.43
monoclinic
C2/c
20.315(5)
12.318(6)
17.402(4)
90
125.269(15)
90
463.44
monoclinic
P21/n
418.44
monoclinic
P21
418.44
395.44
orthorhombic
Pbca
418.44
418.44
monoclinic
P21/n
triclinic
triclinic
triclinic
¯
¯
¯
P1
P1
P1
15.6328(10)
5.6402(4)
22.2846(14)
90
98.2520(10)
90
13.5320(10)
5.0764(3)
14.7251(12)
90
97.781(7)
90
8.2089(10)
8.3534(10)
13.9725(17)
91.917(2)
106.454(2)
95.941(2)
911.97(19)
1.524
14.5064(18)
9.6887(13)
27.895(4)
90
8.2781(11)
8.3657(13)
13.9362(18)
91.966(12)
106.506(11)
94.686(11)
920.6(2)
1.427
8.8705(4)
13.1489(4)
17.3879(6)
80.262(3)
80.491(3)
74.985(4)
1914.83(13)
1.452
12.0002(10)
9.0708(7)
18.0591(13)
90
94.164(7)
90
90
90
g [8]
V [ꢁ3]
1944.5(2)
1.583
1002.21(12)
1.387
3920.5(9)
1.340
1960.6(3)
1.418
3555(2)
1.309
0.197
Dcalcd [gcmꢀ3
]
m [mmꢀ1
]
0.232
0.208
0.229
0.196
0.209
0.218
0.213
q range [8]
Z/Z’
2.63–26.08
4/1
2.78–26.31
2/1
2.46–26.05
2/1
2.79–24.96
8/1
2.80–26.31
2/1
2.80–26.31
4/2
2.72–26.31
4/1
2.87–28.82
8/1
range h
range k
range l
reflns collect-
ed
ꢀ18 to 18
ꢀ6 to 6
ꢀ26 to 26
16101
ꢀ15 to 16
ꢀ5 to 6
ꢀ12 to 18
4196
ꢀ10 to 10
ꢀ10 to 10
ꢀ17 to 17
9424
ꢀ17 to 14
ꢀ11 to 11
ꢀ33 to 27
9500
ꢀ10 to 10
ꢀ10 to 9
ꢀ17 to 17
7280
ꢀ11 to 11
ꢀ16 to16
ꢀ21 to 21
13126
ꢀ9 to 14
ꢀ11 to 7
ꢀ22 to 20
8269
ꢀ22 to 21
ꢀ13 to 11
ꢀ19 to 19
5370
reflns obsd
total reflns
R1 [I>2s(I)]
wR2 (all)
GOF
3421
3149
0.0578
0.1540
1.053
3459
1952
0.0769
0.1648
0.989
3591
3209
0.0466
0.1104
1.096
3463
2032
0.0464
0.1258
0.910
3762
2558
0.0526
0.1289
1.032
7817
5537
0.0536
0.1721
1.159
3998
2811
0.0628
0.1939
1.069
1832
2468
0.0731
0.2185
1.066
T [K]
100
298
100
298
298
298
298
298
X-ray diffrac-
tometer
Bruker
SMART
APEX
Oxford Xcali-
bur Gemini
Bruker
SMART
APEX
Oxford Xcali-
bur Gemini
Oxford Xcali-
bur Gemini
Oxford Xcali-
bur Gemini
Oxford Xcali-
bur Gemini
Oxford Xcali-
bur Gemini
only one crystal structure (i.e., no polymorphs were found
for 1). Attempts with several different crystallization meth-
ods and conditions, such as solvent evaporation, melting,
sublimation, slow cooling, and flash cooling to obtain
a second polymorph of cardiosulfa were unsuccessful.
Molecule 2
This molecule is dimorphic. Form I crystallized in the chiral
space group P21 as thin, colorless plate-type crystals from
a 1:1 acetone/methanol solution. The sulfonamide catemer
ꢀ
synthon (N1 H1···O2, 2.07 ꢁ, 1448) of the C(4) chain runs
along the b axis (Figure 4a). Layers of molecules are con-
ꢀ
ꢀ
nected by C H···O (2.49 ꢁ, 1228) and C H···p interactions
(2.86 ꢁ; Figure 4b).
A second polymorph (form II) was obtained concomitant-
ly[15] from acetic acid along with form I. The crystal quality
of this minor polymorph was not very good. These hair-mor-
phology crystals (thin fibers) were characterized by powder
XRD (a diffractogram is shown in Figure 1).
ꢀ
ꢀ
Figure 3. a) N H···p and C H···p interactions persist, relative to strong
Molecule 3
ꢀ
N H···O H bonding, in cardiosulfa 1. The intramolecular (sulfonami-
Molecule 3 is also dimorphic. Colorless crystals of plate and
block morphology were obtained from acetone, which
solved in the triclinic space group P1. Similar to cardiosulfa
ꢀ
ꢀ
de)N H···O
(nitro) hydrogen bond S(7) is highlighted by an arrow. b) C
H···OACHTUNGTRENNUNG(nitro) and C H··· p interactions in the crystal structure.
ꢀ
¯
ꢀ
1, molecules of 3 are connected through N H···p (2.76 ꢁ)
and p···p-stacking (3.52 ꢁ) interactions (Figure 5a). Auxili-
lar conformation and the strong hydrogen-bond network.
ꢀ
ꢀ
Conformational rigidity due to the intramolecular N H···O
and the lack of strong hydrogen-bonding capability gave
ary C H···O interactions complete the overall packing (Fig-
ure 5b).
5
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
Symmetry code
Table 2. Hydrogen bonds in crystal structures (neutron-normalized distances).
ꢀ
Crystal form
Interaction
H···A [ꢁ]
D···A [ꢁ]
aD H···A [8]
ꢀ
1 Form I
N1 H1···O3
2.44
2.47
2.34
2.48
2.07
2.51
2.49
2.22
2.46
2.32
2.51
2.46
2.01
2.50
2.49
2.39
2.35
2.23
2.36
2.59
2.58
1.97
1.92
2.48
2.48
2.39
2.48
2.44
2.49
1.96
2.43
2.43
2.32
2.08
2.41
2.49
2.920(3)
3.496(3)
2.808(4)
3.302(4)
2.947(7)
2.912(8)
3.199(8)
2.920(2)
3.298(3)
2.792(3)
3.487(3)
3.472(3)
2.955(3)
3.063(3)
3.253(3)
2.830(3)
3.254(4)
2.962(3)
2.807(4)
3.410(4)
3.558(3)
2.971(3)
2.929(3)
2.884(3)
3.136(3)
3.471(2)
2.889(3)
3.077(3)
3.267(3)
2.965(3)
2.852(4)
3.486(3)
3.405(5)
3.046(5)
3.421(8)
2.904(8)
108
159
104
132
144
101
122
125
134
105
150
154
154
113
126
103
139
128
103
132
149
172
179
101
118
173
101
117
127
176
101
165
177
160
155
101
intramolecular
3/2ꢀx, 1/2+y, 1/2ꢀz
intramolecular
1ꢀx, 1ꢀy, ꢀz
ꢀ
C3 H3···O3
ꢀ
C6 H6···O2
ꢀ
C20 H20A···F2
ꢀ
2 Form I
3 Form I
N1 H1···O2
x, ꢀ1+y, z
ꢀ
C2 H2···O1
intramolecular
1ꢀx, ꢀ1/2+y, 1ꢀz
intramolecular
ꢀ1+x, y, z
ꢀ
C2 H2···O1
ꢀ
N1 H1···F1
ꢀ
C5 H5···O2
ꢀ
C6 H6···O1
intramolecular
x, 1+y, z
ꢀ
C20 H20C···O1
ꢀ
C12 H12···F2
x, yꢀ1, +z
ꢀ
4 Form I
N1 H1···O1
1/2ꢀx, ꢀ1/2+y, z
intramolecular
1/2+x, 1/2ꢀy, ꢀz
intramolecular
x, 1/2ꢀy, 1/2+z
intramolecular
intramolecular
x+1, y, z
ꢀ
N1 H1···O4
ꢀ
C3 H3···O2
ꢀ
C6 H6···O1
ꢀ
C17 H17···O3
ꢀ
4 Form II
5 Form I
N1 H1···O3
ꢀ
C7 H7B···O2
ꢀ
C5 H5···O1
ꢀ
C14 H14···O2
ꢀx+1, ꢀy+1, ꢀz+1
ꢀ
N1 H1···O4
x, y, z
ꢀ
N3 H3···O2
ꢀ1+x, y, z
ꢀ
C6 H6···O2
intramolecular
intramolecular
1+x, ꢀ1+y, z
intramolecular
intramolecular
1ꢀx, ꢀy, ꢀz
ꢀ
C8 H8···O2
ꢀ
C17 H17···F6
ꢀ
C27 27···O4
ꢀ
C29 H29···O4
ꢀ
C19 H19B···O3
ꢀ
5 Form II
6 Form I
N1 H1···O2
1/2ꢀx, 1/2+y, 1/2ꢀz
intramolecular
1/2ꢀx, ꢀ1/2+y, 1/2ꢀz
1/2+x, 1/2ꢀy, ꢀ1/2+z
1/2ꢀx, ꢀ1/2ꢀy, ꢀz
1/2ꢀx, ꢀ1/2ꢀy, ꢀz
intramolecular
ꢀ
C6 H6···O2
ꢀ
C8 H8···O1
ꢀ
C17 H17···F2
ꢀ
N1 H1···O2
ꢀ
C2 H2···O2
ꢀ
C6 H6···O1
An amorphous phase of 3 was obtained by melting form I
at 1808C. Crystallization of form II occurred between the re-
crystallization (818C) and melting temperature (1628C) of
this amorphous phase by heating it at 1508C for 20–30 min.
The resulting powdery material was confirmed to be a new
polymorph by PXRD (Figure 1). It was not possible to grow
single crystals of form II by solvent evaporation.[10]
(Figure 7), but there are no strong intermolecular hydrogen
ꢀ
bonds in the crystal structure. An intramolecular N1
H1···O3 (2.23 ꢁ, 1288) is present in form II, which is stron-
ger than that in cardiosulfa. Polymorph II of this molecule is
different from form I in three important aspects: 1) a confor-
mational difference in the C-S-N-C (SO2NH) and C-N-C-C
ꢀ
ꢀ
bond (N-ethyl group) torsions, 2) major N H···O/N H···p
interactions between the molecules, and 3) color differences
in crystals and powdered samples[][15] (see the Supporting In-
formation).
Molecule 4
This trimorphic compound belongs to the category of con-
formational and color polymorphs.[15] Form I crystallized
from acetone as colorless crystals of thin and long plate
morphology. In the crystal structure (space group Pbca),
There is no example of polymorphic sulfonamide X-ray
ꢀ
crystal structures that differ by a N H···O catemer/dimer
ꢀ
synthon in one structure and an N H···p interaction in the
ꢀ
two molecules interact through the N H···O C(4) chain
second polymorph, based on a survey of the Cambridge
(2.01 ꢁ, 1548) along the b axis (Figure 6a). The layers are
Structural Database.[16] The closest example we could find is
ꢀ
cross-linked by weak C H···O hydrogen bonds (Figure 6b).
the p-tosylhydrazone derivative of bisACTHNGUTERNNU(G p-methyl)benzophe-
ꢀ
ꢀ
There is an intramolecular N H···O bond with a nitro O
none, for which polymorph I has an N H···O dimer synthon,
whereas forms II and III have no strong hydrogen bonds
ꢀ
(2.50 ꢁ, 1138) and an N H···p interaction (2.82 ꢁ).
Form II was crystallized from methanol as brown-yellow
crystals of thick, long plate morphology, which solved in the
even though the molecule contains an SO2NH group.[11a]
A
list of hydrogen bonds and synthons in molecules 1–6 is pre-
sented in Tables 2 and 3. Such examples of unconventional
hydrogen bonds in sulfonamides are rare in the CSD.
¯
triclinic space group P1. The molecules are stacked through
ꢀ
ꢀ
N H···p (2.82 ꢁ) and C H···O (2.59 ꢁ, 1328) interactions
&
&
6
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ashwini Nangia et al.
Figure 4. Hydrogen bonds in the crystal structure of molecule 2 form I.
ꢀ
ꢀ
a) Sulfonamide N H···O catemer and b) C H···O interactions.
Crystallization of form III of 4 is detailed in the next sec-
tion on cryogenic conditions.
ꢀ
Figure 5. a) N H···p interactions in crystal structure 3. There were no
ꢀ
ꢀ
strong N H···O hydrogen bonds, similar to cardiosulfa 1. b) N H···p and
ꢀ
C H···p interactions in molecule 3.
Molecule 5
It crystallized as two polymorphs, form I (Z’=2) from nitro-
methane as plate-type crystals and form II (Z’=1) from
methanol as block/plate-type crystals. The crystal structure
cules make intermolecular F···F interactions (2.87, 2.88 ꢁ) in
form I.
A single molecule in form II is similar to conformer B of
¯
of form I solved in space group P1, whereas form II is in the
ꢀ
P21/n space group (Figure 8). A third polymorph (form III)
was identified by DSC and VT-PXRD, and it was repro-
duced by heating form I/II at the transition temperature
(about 1708C). Two symmetry-independent conformers A
and B[17] are present in form I, which interact through the
form I. The catemer synthon (N1 H1···O2, 1.96 ꢁ, 1768)
ꢀ
and weak hydrogen bonds (C17 H17···F2, 2.32 ꢁ, 1778; and
ꢀ
C8 H8···O1, 2.43 ꢁ, 1658) in the crystal structure of form II
are similar to form I. Their 2D similarity was quantified by
XPac[18e,f] (Figure 8, and in the Supporting Information),
which showed that the interlayer packing is different. Two
ꢀ
ꢀ
ꢀ
N H···O catemer synthon (Figure 8a; N1 H1···O4 of mole-
ꢀ
cule A, 1.97 ꢁ, 1728; and N3 H3···O2 of molecule B,
neighboring layers in form I are connected by C H···OACHTUNGTRENNUNG(SO2)
ꢀ
1.92 ꢁ, 1798) in a layer structure. Crystal structures of
form I and II are 2D isostructural (Figure 8).[18a–d] The CF3
group in conformer A is a bystander, but conformer B mole-
hydrogen bonds (black color arrow) and C H···F (gray
ꢀ
color arrow) interactions, whereas in form II only C H···F
interactions (gray color arrow only) are present. The CF3
group is shown as spheres.
The 3D packing is different in molecule 5 polymorphs
(Figure 9a and b) because the CF3 group participates in dif-
ꢀ
ꢀ
Table 3. Catemer/dimer N H···O synthon and weak N H···p interactions
in sulfonamides 1–6.
ꢀ
ferent interactions: F···F in form I but C H···F in form II.
Surprisingly, form I with F···F interactions and Z’=2 is more
Molecule
Form I
Form II
Remarks
ꢀ
stable than form II, which has Z’=1 and C H···F interac-
ꢀ
1
2
3
4
5
6
N H···p
–
–
–
no polymorphs
two polymorphs
two polymorphs
three polymorphs
three polymorphs
no polymorphs
tion. Cryogenic milling[19e] (milling of materials at low tem-
perature by cooling the metal jar with liquid nitrogen) of
crystalline form II at 200 K transformed it into stable poly-
morph I. Polymorph I has higher crystal density (1.45 versus
1.42 gcmꢀ3) and lower cell volume per molecule (920 versus
ꢀ
N H···O catemer
ꢀ
N H···p
ꢀ
ꢀ
N H···O catemer
N H···O catemer
N H···O dimer
N H···p
N H···O catemer
–
ꢀ
ꢀ
ꢀ
7
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
ꢀ
Figure 6. a) Sulfonamide N H···O catemer synthon in form I of molecule
Figure 7. The main differences in intermolecular interactions between
ꢀ
4, and b) C H···O (to NO2 and SO2 acceptors) interactions.
ꢀ
ꢀ
form I and form II of molecule 4. a) N H···p and C H···O interaction in
ꢀ
form II, b) C H···O
T
NO2 acceptor is not involved in intermolecular hydrogen bonding.
957 ꢁ3). Recent pharmaceutical examples of high-Z’ poly-
morphs in the stable state are discussed elsewhere.[12f,19f,g,17a]
Crystallization of a third form of molecule 5 is detailed in
the next section on VT-PXRD.
form was obtained from several organic solvents; that is,
there were no polymorphs.
The molecular conformation is a subtle yet important pa-
rameter in the organic solid state.[12a–c] Rotations about
single bonds (intramolecular torsions) are worth 1–3 kcal
molꢀ1 but can be as high as 8 kcalmolꢀ1 due to steric fac-
tors.[12d–h] Cardiosulfa showed much greater variation in tor-
sion angles at the sulfonamide N-ethyl group (the most flex-
ible terminal group in the molecule) than the other sulfona-
mides (see the Supporting Information, in which torsion
angles are also listed). The difference in torsion angles be-
tween dimorphs of 4 at the ethyl group was 188 and the sul-
fonyl moiety was 78. Conformer A and B (of form I) differ
from form II by about 88 at the ethyl and sulfonyl groups in
molecule 5 (Figure 10a and b).
Polymorphic Transformations
Molecule 5 under Cryogenic Conditions
Molecule 5 exhibited phase transformations under cryogenic
and high-temperature conditions as summarized in Fig-
ure 12a. A single-crystal-to-single-crystal transition[19] was
observed for form II of molecule 5. The crystal structure of
form II was collected at room temperature, because it trans-
formed into form I at low temperature (100 K). The single
crystal of form II is unstable at 08C. These transformations
were analyzed by collecting X-ray reflections at different
temperatures (Table 4). The peaks extracted from the area
detector frames of the 200 K data set viewed in RLATT
(Bruker-AXS crystallographic software to view the recipro-
cal lattice) did not show a periodic pattern, and so the struc-
ture solution was aborted. Reflections on the same crystal
were recollected at 100 K and the crystal structure solved
satisfactorily (the R factor improved from 0.1354 at 200 K to
Molecule 6
Molecule 6 was crystallized from acetic acid as diamond-
morphology crystals, and the structure was solved in the
monoclinic space group C2/c. This is the only cardiosulfa de-
[9]
ꢀ
rivative to exhibit the sulfonamide N H···O dimer synthon
ꢀ
(N1 H1···O2, 2.08 ꢁ, 1608; Figure 11).The same crystalline
&
&
8
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ashwini Nangia et al.
Figure 9. Differences between form I and II of molecule 5. a) The CF3
group in one layer of form I causes F···F interhalogen interactions, where-
as the CF3 group in the next layer is silent. b) The CF3 group participates
ꢀ
in C H···F interaction only, and F···F contacts are absent in form II.
ꢀ
Figure 8. 2D similarity of form I and form II in molecule 5. The N H···O
ꢀ
catemer synthon is common but weak interactions are different; C H···F
ꢀ
ꢀ
and C H···O interactions in a) form I but only b) C H···F interaction in
form II. Their similarity index of 11.2 in XPac indicates that the two
polymorphs are dissimilar.
R=0.0393 at 100 K and 0.0536 at 298 K). The unit-cell pa-
rameters matched with that of form I, molecule 5. The cryo-
genic transition of form II was studied by variable-tempera-
ture PXRD in the T range 298–173 K (Figure 12b). Cryogen-
ic milling[19e] of form II at liquid N2 temperature and slurry
grinding of form III gave stable form I (Figure 12c).
Figure 10. The differences in conformation of polymorphs at the sufonyl
and N-ethyl fuctionality in molecule a) 4 and b) 5.
Molecule 4 under Cryogenic Conditions
When a crystal of form II of molecule 4 was rapidly cooled
by dipping in liquid nitrogen, it got fractured. Such a break-
age upon sudden cooling was observed for molecule 4 only;
the fractured crystal matched with form II by DSC. The
powder pattern of this broken material is named form III,
which is different from that of form I and II as determined
by PXRD (Figure 13). FTIR analysis showed clear differen-
ꢀ
H···p) or form III of molecule 4 for 30 min gave form I (N
H···O) in independent experiments by a PXRD match
(Figure 14). Even though there was no phase change ob-
served for form I and II in slurry crystallization, form III
transformed into form II upon slurry grinding in 80% etha-
nol/water after 24 h (solubility measurement conditions, see
Figure 14f).
ꢀ
ces between the three polymorphs of molecule 4 in the N
H
stretching frequency region at 3280.2, 3344.7, and
3332.8 cmꢀ1 for forms I, II, and III, respectively (see the
ꢀ
Supporting Information). Neat grinding of form II (N
9
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
ꢀ
Figure 11. Sulfonamide N H···O dimer in molecule 6.
High-Temperature Phase Transitions
All polymorphs and amorphous phases were studied by
DSC.[7] The crystalline form of cardiosulfa 1 exhibited
a melting endotherm at 171.58C (see the Supporting Infor-
mation). The glass-transition temperature of the amorphous
phase (Tg =54.18C) was followed by recrystallization (start-
ing at 104.68C) and then melting of the crystalline phase (at
169.28C).[12] The amorphous form of 6 similarly transformed
to the crystalline phase during the DSC measurement (see
the Supporting Information). Both 1 and 6 exist in a single-
crystalline form. A combination of DSC and VT-PXRD[8]
measurements (Figure 15–18) gave an idea of the thermal
stability of polymorphs (low- and high-temperature phases,
Table 5) and the heat of transition rule[8e] enabled assign-
ment of 2, 3, 4, and 5 as enantiotropic systems. The stable
polymorph in these polymorphic systems was identified by
slurry and neat grinding experiments under ambient condi-
tions (Table 6).[7f,8f]
Dissolution and Solubility
The crystalline phases of molecules 1–6 were subjected to
solubility and dissolution studies[20] to rationalize the rela-
tionship between molecular conformation, crystal structure,
and melting point.[21a] Solubility and dissolution experiments
were performed in 80% ethanol/water mixture (Figure 19a;
values are listed in Table 7). Cardiosulfa has a solubility
(0.96 mgmLꢀ1) and an intrinsic dissolution rate (IDR;
0.14 mgcmꢀ2minꢀ1) in the middle zone of series 1–6. Mole-
cule 2 is highly soluble (10.54 mgmLꢀ1) and fast-dissolving
(0.90 mgcmꢀ2 minꢀ1) relative to cardiosulfa and other mole-
cules. The variation in solubility/dissolution rate was ana-
lyzed from the molecular conformation (twisted and/or pla-
nar)[21b] in the crystal structure. The cardiosulfa molecule is
Figure 12. a) Schematic of solid-to-solid phase transitions in molecule 5.
b) VT-PXRD patterns confirm the transformation of molecule 5, form II
to form I upon cooling from 298 to 173 K. T range of phase transition is
210–250 K. The diagnostic peaks for each polymorph are circled. c) Cryo-
genic milling of form II resulted in form I, as confirmed by the overlay of
the experimental PXRD pattern (black) on the calculated diffraction
lines of form I (gray) to form the X-ray crystal structure.
a twisted confirmation, which will result in less dense pack-
ing (e.g.,
D =
calcd =1.58 gcmꢀ3 (cardiosulfa) and Dcalcd
rigidified owing to the intramolecular N H···O hydrogen
1.38 gcmꢀ3 (molecule 2)). The extreme difference between
the planar to twisted conformation (see Figure 19b) of mole-
cule 1 and 2 could account for the observed difference in
their melting point (1718C cardiosulfa 1, and 1528C mole-
cule 2), density, solubility, and dissolution rates.[21c] Molecule
5 adopts an intermediate molecular conformation and densi-
ty (Dcalcd =1.45 gcmꢀ3) between that of cardiosulfa and mol-
ecule 2 (see torsion angles in the Supporting Information),
ꢀ
bond and maintains pseudoplanarity in the crystal structure.
In contrast, molecule 2 lacks the NO2 group and adopts
a twisted conformation in the crystal structure. The pseudo-
planarity and conformational rigidity in cardiosulfa might
account for the observed difference in solubility and dissolu-
tion rate relative to molecule 2. A planar conformation
favors efficient crystal packing and better stability than
&
&
10
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ashwini Nangia et al.
and dissolution than 6 (R1 =H,
Table 7). However, there are
examples of drug molecules for
which solubility increases upon
perfluorination or CF3 group
Table 4. Single-crystal-to-single-crystal transformations of molecule 5.
Crystallographic
parameters
At 298 K
Form II
At 200 K
Form II!I beginning
At 100 K
Form II!I complete
At 100 K
Form I
crystal system
a [ꢁ]
b [ꢁ]
c [ꢁ]
a [8]
monoclinic
12.0002(10)
9.0708(7)
18.0591(13)
90.00
94.164(7)
90.00
1960.6(3)
4/1
triclinic
8.894
12.916
17.091
80.77
81.56
76.57
1872
triclinic
8.747(9)
12.929(13)
17.16(2)
79.69(2)
80.121(16)
75.080(16)
1828(3)
triclinic
8.7343(8)
12.9486(12)
17.1899(15)
79.7680(10)
80.3670(10)
74.9410(10)
1832.4(3)
4/2
addition, and
a
plausible
reason could be the high elec-
tronegativity and strong elec-
tron-withdrawing capability of
the fluorine atom.[21g] This ex-
plains the better aqueous solu-
bility of 3 relative to 4. More-
over, both 2 and 5, which are
high in solubility ranking, have
a CF3 substituent.
b [8]
g [8]
V [ꢁ3]
Z/Z’
–
4/2
ꢀ
ꢀ
ꢀ
space group
R factor
P21/n
0.0628
P1
P1
P1
high
0.1354
0.0393
We next compared the solubility and dissolution proper-
ties of two polymorphs of molecule 4, which exhibit differ-
ent hydrogen-bonding motifs. The secondary amino group
ꢀ
ꢀ
(SO2 NH) in form I participates in the sulfonamide N
ꢀ
H···O catemer synthon, whereas form II has weak N H···p/
ꢀ
C H···O interactions. The strong hydrogen bonds of form I
are able to better interact with the solvent water/ethanol
molecules, and the solubility and dissolution rate of form I
are higher than those of form II (0.62 mgmLꢀ1,
0.05 mgcmꢀ2 minꢀ1 versus 0.43 mgmLꢀ1, 0.04 mgcmꢀ2minꢀ1).
Thus, molecule 4 provides further insight into the structure–
ꢀ
property relationship. Form I with an N H···O hydrogen-
bond catemer has a lower density (Dcalcd =1.34 gcmꢀ3) than
ꢀ3
ꢀ
form II (Dcalcd =1.42 gcm ) with N H···p interaction. We
Figure 13. Overlay of calculated PXRD peaks of form I and form II with
the experimental pattern of form III of molecule 4. New diffraction
peaks are highlighted with arrows.
are not aware of such a study on the influence of strong
versus weak hydrogen bonding in drug polymorphs on solu-
bility and dissolution rate. We confirmed in independent ex-
periments (Figure 14) that there is no interconversion be-
tween polymorphs I and II of 4 during dissolution and solu-
bility measurements (Figure 20), but form III transformed
into form II at the end of the solubility experiment (Fig-
ure 14f). The bent conformation of molecule 4 is similar
(Figure 19b) in both structures, and so their solubility differ-
ence might be attributed to hydrogen bonding. This explana-
tion offers yet another reason for the low solubility of cardi-
osulfa, the only crystal structure in this family without
and its solubility (4.40 mgmLꢀ1) and dissolution rate
(0.44 mgcmꢀ2 minꢀ1) lie between those for molecule 1 and 2.
Molecules 3 (Dcalcd =1.52 gcmꢀ3) and 6 (Dcalcd =1.30 gcmꢀ3)
similarly follow the solubility–conformation trend. Thus
functional-group modification might be used as a handle to
control molecular conformation in the solid state and conse-
quently drug solubility. All solubility and dissolution meas-
urements were performed in triplicate, and the mean of the
best two values is reported in Table 7. A better understand-
ing of the factors that correlate molecular conformation in
the crystal structure to the solubility of pharmaceutical com-
pounds is of current interest.[21] The amorphous phases were
not considered for solubility measurements because they
were found (by PXRD) to transform into the stable crystal-
line form within 1–2 days under ambient conditions and
almost immediately (a few minutes) in the aqueous slurry
medium.
ꢀ
strong N H···O hydrogen bonding. The higher solubility of
form III of molecule 4 (0.56 mgmLꢀ1, 0.06 mgcmꢀ2 minꢀ1) is
difficult to rationalize in the absence of crystal structure de-
tails.
Conclusion
The X-ray crystal structures of a new class of synthetic AhR
agonist molecules based on the cardiosulfa lead were sys-
tematically studied and analyzed for solubility trends. Sever-
al new polymorphs were identified, and their phase transi-
tions and stability order were established. The crystal struc-
Even though molecule
3 (form I) and molecule 4
(form II) are isomorphous, their solubility and dissolution
rates are different. Molecule 3 with a CF3 substituent has
a higher solubility and dissolution rate than 4 with an NO2
group. Normally it is expected that the CF3 group will in-
crease lipophilicity and hence the aqueous solubility should
decrease. In fact, 3 (R1 =CF3) has slightly lower solubility
ꢀ
tures of polymorphs were analyzed in terms of strong N
ꢀ
ꢀ
H···O and weak N H···p, C H···O hydrogen bonds. A rela-
tionship between molecular twist and higher solubility for
11
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
Figure 14. Comparison of experimental calculated PXPD line patterns for molecule 4. a) Form I, neat grinding for 30 min, no change; b) form II, neat
grinding for 30 min, transforms to form I; c) form III, neat grinding for 5 min gave form II; d) form I, slurry grinding for 24 h, no change; e) form II,
slurry grinding for 24 h, no change; and f) form III, slurry grinding for 24 h, transforms to form II.
aryl sulfonamides emerged from this study. Planar molecules
pack more efficiently in the crystal lattice and hence are less
soluble; molecules with a bent molecular conformation were
found to have higher solubility. Thus functional groups
should be loaded onto the drug molecule so that there is an
opportunity for strong hydrogen bonding because crystal
ubility. The CF3 group is preferable in lead optimization be-
cause it offers the added benefit of increased solubility and
a bent molecular conformation owing to the impossibility of
intramolecular hydrogen bonding. Finally, multiple crystal-
line forms can often complicate drug formulation, and in
this sense molecule 1 appears to be the best candidate in the
series, because, despite its lower solubility, there was no evi-
ꢀ
structures sustained by N H···O bonds exhibited higher sol-
&
&
12
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ashwini Nangia et al.
Figure 16. a) Phase transition and melting points of polymorphs for mole-
cule 3 by DSC. b) VT-PXRD of the phase transition from form II to
form I in the range of 150–1658C for molecule 3.
Figure 15. a) The thermal behavior of the polymorphs of molecule 2.
b) VT-PXRD shows the phase transition from form II to form I for mole-
cule 2 in the range 120–1308C.
dence of polymorphism. Given the importance and involve-
ment of the AhR receptor in several biological processes,
we expect that these structure–property trends will offer
a rational strategy for the pharmaceutical development of
cardiosulfa analogues as novel drugs.
Scheme 2. Synthesis of cardiosulfa analogues.
Molecule 1
Experimental Section
Yield: 76%; m.p. 171–1738C; 1H NMR (500 MHz, CDCl3): d=8.13 (s,
1H), 8.03 (d, J=7.5 Hz, 1H), 7.87–7.92 (m, 2H), 7.71 (d, J=9 Hz, 1H),
7.46 (m, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.24–7.31 (m, 4H), 4.33 (q, J=
7.5 Hz, 2H), 1.42 ppm (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d=148.5, 140.5, 138.9, 136.1, 135.7, 135.4, 133.0, 129.1, 126.5, 125.8, 123.4,
123.0, 122.9, 122.3, 120.6, 119.3, 117.3, 109.0, 108.8, 37.2, 13.7 ppm.
Synthesis
The starting materials for sulfonamide synthesis were purchased from
Sigma–Aldrich (Hyderabad, India). Sulfonamides (1–6) were prepared
by mixing 3-amino-9-ethylcarbazole (1.0 equiv) and the appropriate ben-
zenesulfonyl chloride (1.2 equiv) in freshly distilled acetone (20 mL)
under inert N2 atmosphere in a 100 mL round-bottomed flask. Pyridine
(2 mL) was added dropwise, and the reaction mixture was stirred over-
night at RT. The product was washed with water and extracted with ethyl
acetate. The product was purified by recrystallization from methanol
(Scheme 2).
Molecule 2
Yield: 80%; m.p. 127–1298C; 1H NMR (500 MHz, CDCl3): d=8.09 (d,
J=7.5 Hz, 1H), 7.68–7.85 (m, 3H), 7.51 (d, J=7.6 Hz, 2H), 7.49 (m,
1H), 7.41 (d, J=10 Hz, 1H), 7.15 (m, 2H), 7.12 (m, 1H), 6.98 (s, 1H),
13
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
Figure 17. a) The thermal behavior of form I and form II of molecule 4
by DSC. b) VT-PXRD shows the phase transition from form II to form I
in the range 150–1658C for molecule 4.
4.33 (q, J=9 Hz, 2H), 1.41 ppm (t, J=9.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=142.6, 140.4, 138.6, 134.5, 134.2, 127.9, 126.4, 126.3, 126.0,
123.3, 122.3, 121.8, 120.6, 119.2, 117.2, 108.9, 108.7, 37.7, 13.8 ppm.
Molecule 3
Yield: 76%; m.p. 181–1828C; 1H NMR (500 MHz, CDCl3): d=9.06 (s,
1H), 7.78 (d, 2H, J=7.5 Hz), 7.40 (d, 2H, J=8.5 Hz), 7.31 (m, 1H), 7.24
(m, 1H), 7.18 (m, 1H), 6.99 (m, 3H), 4.0 (q, 2H, J=7 Hz), 1.15 ppm (t,
3H, J=7 Hz); 13C NMR (125 MHz, CDCl3): d=140.2, 138.5, 137.8, 132.3,
131.9, 131.6, 127.8,127.6,125.95, 123.9, 122.8, 122.2, 122,0, 121.7, 120.3,
118.7, 115.6, 108.6, 108.5, 30.7, 13.6 ppm.
Molecule 4
Yield: 72%; m.p. 198–2008C; 1H NMR (500 MHz, CDCl3): d=7.71 (d,
J=7.5 Hz, 1H), 7.64 (m, 2H), 7.52 (m, 1H), 7.49 (m, 1H), 7.47 (m, 3H),
7.36 (m, 1H), 7.22 (m, 2H), 4.31 (q, J=9 Hz, 2H), 1.41 ppm (t, J=9 Hz,
3H); 13C NMR (125 MHz, CDCl3): d=148.3, 140.4, 138.7, 133.6, 132.4,
132.4, 132.0,126.5, 126.3, 125.1, 123.3, 123.1, 122.3, 120.6, 119.2, 117.2,
108.8, 108.7, 37.7, 13.8 ppm.
Figure 18. a) The thermal behavior of trimorphs of molecule 5 by DSC.
b) VT-PXRD shows the phase transition from form I to form III in the
range of 100–1208C for molecule 5. c) VT-PXRD shows the phase transi-
tion from form II to form III in the range of 150–1608C for molecule 6.
Molecule 5
Yield; 56%; m.p. 170–1728C; 1H NMR (500 MHz, CDCl3): d=8.07 (d,
J=8.5 Hz, 1H), 7.9 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.83 (d,
&
&
14
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ashwini Nangia et al.
Table 5. Thermal analysis and phase transitions of sulfonamide polymorphs by DSC.[a]
Sulfonamide polymorphs
Melting and phase transition onset [8C]
Amorphous phase of sulfonamide
Glass transition onset [8C] Recrystallization onset [8C] Melting onset [8C]
Form I
Form II
Form III
1
2
3
4
5
6
171.54
–
–
–
–
54.19
38.83
43.23
below RT
below RT
45.66
104.65
96.97
81.70
93.01
76.15
84.67
169.25
152.70
180.33
187.31
173.31
194.63
152.70 (HTP) 123.59 (LTP)
180.08 (HTP) 164.35 (LTP)
193.09 (HTP) 186.91 (LTP) 187.52 (LTP)
147.30 (LTP) 155.98 (LTP) 174.70 (HTP)
194.79
–
–
[a] HTP=high-temperature phase; LTP=low-temperature phase
Table 6. Stability and thermodynamic relationships between polymorphs of 1–6.
Molecules Density [gcmꢀ3
Packing fraction Enthalpy of fusion/Enthalpy Thermodynamic relationship and identification of the stable polymorph
]
[%]
Form I Form II Form I Form II Form I Form II
of transition [kJmolꢀ1
]
by slurry and neat grinding at ambient conditions
Form III
1
2
3
4
5
6
1.58
1.38
1.52
1.34
1.45
1.30
–
–
–
1.42
1.41
–
71.8
64.0
71.5
64.4
67.5
65.7
–
–
–
68.6
65.7
–
42.1
28.5
41.9
34.7
1.6
–
–
–
–
no polymorphs, stable form I
15.3, ꢀ14.5
5.3, ꢀ4.6
36.4
form I and form II are enantiotropic, stable form I
form I and form II are enantiotropic, stable form I
form I and II, I and III are enantiotropic, stable form I
form I and III, II and III are enantiotropic, stable form I
no polymorphs, stable form I
36.2
0.2, ꢀ0.4 33.8
36.7
–
–
Table 7. Solubility and dissolution rate of molecules 1–6 in 80% ethanol/
water system.
Solubility at 378C
(24 h) [mgmLꢀ1
IDR at 378C
Compound
G
]
(up to 4 h) [mgcmꢀ2 minꢀ1
)
1 (cardiosulfa)
0.96(ꢁ0.17)
10.54
(ꢁ0.19)
(ꢁ0.03)
(ꢁ0.12)
(ꢁ0.11)
(ꢁ0.18)
N
0.14
0.90
0.20
0.05
0.44
0.25
ACHTUNGTRENNUNG
2
3
4
5
6
G
ACHTUNGTRENNUNG
1.58
0.62
4.40
1.48
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ꢀ
ꢀ
Figure 20. Dissolution profiles of form I (N H···O), form II (N H···p),
and form III of molecule 4 in 80% ethanol/water. The form III curve is
the highest, but there is no information about hydrogen bonding in this
crystal structure.
Figure 19. a) Dissolution profiles of sulfonamides 1–6 in 80% ethanol/
water mixture at 378C. b) Overlay of molecular conformations of mole-
cules 1–6. A and B are conformers of molecule 5 in form I.
J=2 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.46 (m, 2H), 7.38 (d, J=8 Hz,
1H), 7.21 (m, 2H), 7.12 (dd, J=8, 2 Hz, 1H), 4.27 (q, J=7 Hz, 2H),
1.37 ppm (t, J=7 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=140.6, 140.4,
138.4, 131.5, 131.2, 130.6, 129.4, 129.0, 127.0, 126.2, 124.5, 124.4, 124.3,
123.3, 122.9, 122.4, 122.1, 120.6, 119.0, 117.0, 108.7, 108.6, 30.8, 13.6 ppm.
Molecule 6
Yield: 40%; m.p. 190–1928C; 1H NMR (500 MHz, CDCl3 +[D6]DMSO):
d=9.30 (m, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.67 (m, 3H), 7.30 (m, 5H), 7.0
(m, 3H), 4.19 (q, J=7.5 Hz, 2H), 1.28 ppm (t, J=7 Hz, 3H); 13C NMR
15
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
(125 MHz, CDCl3 +[D6]DMSO): d=140.2, 139.8, 137.8, 132.2, 128.6,
127.1, 125.9, 122.9, 122.4, 122.3, 120.4, 118.7, 115.7, 108.6, 37.5, 13.7 ppm.
flask method. To obtain equilibrium solubility, each solid material
(100 mg) was stirred for 24 h in 80% EtOH/water at 378C (5 mL), and
the absorbance was measured at 237–238 nm. The concentration of the
saturated solution was calculated at 24 h, which is referred to as the equi-
librium solubility of the stable solid form. The dissolution rates are ob-
tained from the IDR experiments.
CSD Search
The CSD[16] was searched using fragments SO2NXH···C (105 hits) and
SO2NXH···Ph (25 hits) in the distance range 2.5–3.5 ꢁ; all organic com-
pounds with the word “form”, “polymorph”, “modification”, and
“phase” in the qualifier; but excluding the entries for which 3D coordi-
nates are not available. These searches did not result in any polymorphic
Powder X-ray Diffraction
PXRD was recorded with a SMART Bruker D8 Advance X-ray diffrac-
tometer (Bruker-AXS, Karlsruhe, Germany) in the Bragg–Brentano ge-
ometry using CuKa radiation (l=1.5406 ꢁ) at 40 kV and 30 mA. Diffrac-
tion patterns were collected over the 2q range of 5–508 at a scan rate of
18minꢀ1. The appearance of polymorphs for all the molecules was moni-
tored by the appearance of new diffraction peaks. Powder Cell 2.359[22e]
was used for overlaying the experimental XRPD pattern on the calculat-
ed lines from the crystal structure. Variable-temperature mode was fixed
on the same instrument and recorded the phase transition with 600–
ꢀ
set for a single-component organic sulfonamide with short contacts (N
ꢀ
H···p) in one crystal structure and a catemer N H···O hydrogen bond in
another crystal structure.
X-ray Crystallography
X-ray reflections for molecule 1, 3, and form I of molecule 5 (LT data)
were collected with
a Bruker SMART APEX CCD diffractometer
equipped with a graphite monochromator and MoKa fine-focus sealed
tube (l=0.71073 ꢁ). Data integration was carried out using SAINT.[22a]
Intensities for absorption were corrected using SADABS. Structure solu-
tion and refinement were carried out using Bruker SHELX-TL.[22b] X-ray
reflections for polymorphs of molecules 2, 4, 5, and 6 were collected with
an Oxford Xcalibur Gemini Eos CCD diffractometer using MoKa radia-
tion. Data reduction was performed using CrysAlisPro (version
1.171.33.55). OLEX2-1.0 and SHELX-TL 97 were used to solve and
refine the data.[22c,d] All non-hydrogen atoms were refined anisotropically,
1200 s delay time at a heating rate of 28Cminꢀ1
.
Ball Mill Grinding
A Retsch MM400 ball mill was used for cryogenic milling of form II of
molecule 5 over 10 min at a frequency of 20 Hz for the complete conver-
sion to form I.
ꢀ
ꢀ
and C H hydrogen atoms were fixed. N H was located from difference
ꢀ
ꢀ
electron-density maps, and C H hydrogen atoms were fixed. N H pro-
tons for molecule 1 and 2 were fixed by DFIX by 0.85 ꢁ to remove some
of the alerts. Packing diagrams were prepared in X-Seed.
Acknowledgements
This research was funded by DST JC Bose Fellowship (SR/S2/JCB-06/
2009), CSIR Pharmaceutical Cocrystals (01-2410/10/EMR-II), DST-
SERB project on Novel Solid-state Forms of APIs (No. SR/S1/OC-37/
2011), and the UGC (PURSE grant). S.S.K and S.R. thank the CSIR for
fellowships and a contingency grant.
CCDC-913656, 913657, 913658, 913659, 913660, 913661, 913662, and
913663 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Vibrational Spectroscopy
A Nicolet 6700 FTIR spectrometer with an NXR FT-Raman module was
used to record IR spectra. IR spectra were recorded on samples dis-
persed in KBr pellets.
[1] a) I. Gardner, R. S. Obach, D. A. Smith, Z. Miao, A. A. Alex, K.
Beaumont, A. Kalgutkar, D. Walker, D. Dalvie, C. Prakash, V. Alf,
Metabolism, Pharmacokinetics and Toxicity of Functional Groups:
Impact of Chemical Building Blocks on ADMET (Ed.: D. A.
Smith), Royal Society of Chemistry, 2010, Chapter 5, pp. 210–274;
b) J. E. Lesch, The First Miracle Drugs: How the Sulfa Drugs Trans-
formed Medicine, Oxford University Press, 2007.
[2] a) C. P. Price, A. L. Grzesiak, A. J. Matzger, J. Am. Chem. Soc. 2005,
127, 5512–5517; f) S. S. Yang, J. K. Guillory, J. Pharm. Sci. 1972, 61,
26–40; Yang, J. K. Guillory, J. Pharm. Sci. 1972, 61, 26–40;
b) D. J. W. Grant, Theory and Origin of Polymorphism: Polymorph-
ism in Pharmaceutical Solids (Ed.: H. G. Brittain), Marcel Dekker,
1999, pp. 1–33; c) S. R. Bryn, R. R. Pfeiffer, J. G. Stowell, Solid-
State Chemistry of Drugs, SSCI, 1999, pp. 160–180; d) N. Blagden,
R. J. Davey, H. F. Lieberman, L. Williams, R. Payne, R. Roberts, R.
Rowe, R. Docherty, J. Chem. Soc. Faraday Trans. 1998, 94, 1035–
1044; e) D. S. Hughes, M. B. Hursthouse, R. W. Lancaster, S. Taven-
er, T. L. Threlfall, Chem. Commun. 2001, 603–604.
[3] a) J. Bernstein, Polymorphism in Molecular Crystals, Clarendon,
2002; b) Polymorphism in the Pharmaceutical Industry, (Ed.: R. Hil-
fiker), Wiley-VCH, Weinheim, 2006; c) F. T. Martins, P. P. Neves, J.
Ellena, G. E. Cami, E. V. Brusau, G. E. Narda, J. Pharm. Sci. 2009,
98, 2336–2344; d) J. Bauer, S. Spanton, R. Henry, J. Quick, W.
Dziki, W. Porter, J. Morris, Pharm. Res. 2001, 18, 859–866; e) S. R.
Byrn, R. R. Pfeiffer, G. Stephenson, D. J. W. Grant, W. B. Gleason,
Chem. Mater. 1994, 6, 1148–1158; f) J. D. Dunitz, Acta Crystallogr.
Sect. B 1995, 51, 619–631; g) F. Rodriguez-Caabeiro, A. Criado-For-
nelio, A. Jimenez-Gonzalez, L. Guzman, A. Igual, A. Perez, M.
Pujol, Chemotherapy 1987, 33, 266–271; h) M. C. Gamberini, C.
Baraldi, A. Tinti, C. Rustichelli, V. Ferioli, G. Gamberini, J. Mol.
Struct. 2006, 785, 216–224.
13C ss-NMR Spectroscopy
Solid-state NMR spectra were recorded with a Bruker Advance spec-
trometer operating at 400 MHz (100 MHz for 13C nucleus). ss-NMR spec-
tra were recorded with a Bruker 4 mm double resonance cross-polariza-
tion magic angle spinning (CP-MAS) probe in zirconia rotors at 5.0 kHz
spin rate with a cross-polarization contact time of 2.5 ms and a recycle
delay of 8 s. 13C CP-MAS spectra recorded at 100 MHz were referenced
to the methylene carbon of glycine, and then the chemical shifts were re-
calculated to the TMS scale (dglycine =43.3 ppm).
Thermal Analysis
DSC was performed on Mettler Toledo DSC 822e module. Samples were
placed in crimped but vented aluminum sample pans. The typical sample
size was 3–4 mg, and the temperature range was 30–2508C at heating
rate of 5 and 208Cminꢀ1. Samples were purged by a stream of dry nitro-
gen flowing at 150 mLminꢀ1
.
Dissolution and Solubility Measurements
Intrinsic dissolution rate (IDR) and solubility measurements were carried
out on a USP certified Electrolab TDT-08L dissolution tester (Electrolab,
Mumbai, MH, India). A calibration curve was obtained for molecules 1–
6 and polymorphs of molecule 4 by plotting absorbance versus concentra-
tion UV/Vis spectra curves with a Thermo Scientific Evolution EV300
UV/Vis spectrometer (Waltham, MA) for known concentration solutions
in 80% EtOH/water medium. The mixed solvent system (EtOH/water)
was selected for its higher solubility of cardiosulfa molecules in this
medium. The slope of the plot from the standard curve gave the molar
extinction coefficient (e) by applying the Beer–Lambert law. Equilibrium
solubility was determined in 80% EtOH/water medium using the shake-
[4] J. E. Torr, J. M. Large, E. McDonald, Comb. Chem. High Through-
put Screening 2009, 12, 275–284.
&
&
16
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ashwini Nangia et al.
[5] a) S.-K. Ko, H. J. Jin, D.-W. Jung, X. Tian, I. Shin, Angew. Chem.
2009, 121, 7949–7952; Angew. Chem. Int. Ed. 2009, 48, 7809–7812;
b) L. D’amico, C. Li, E. Glaze, M. Davis, W. L. Seng, Zebrafish: A
Predictive Model for Assessing Cancer Drug-Induced Organ Toxicity
(Ed.: P. McGrath), Wiley, 2011; c) S.-K. Ko, I. Shin, ChemBioChem
2012, 13, 1483–1489; d) J. Abel, T. Haarmann-Stemmann, Biol.
Chem. 2010, 391, 1235–1248; e) http://glixxlabs.com/chemical-prod-
ucts/drugsdrug-candidates_p3/cardiosulfa; f) J.-Y. Winum, A. Mares-
ca, F. Carta, A. Scozzafava, C. T. Supuran, Chem. Commun. 2012,
48, 8177–8179.
[6] a) J. P. Whitlock, Jr., Annu. Rev. Pharmacol. Toxicol. 1999, 39, 103–
125; b) M. A. Callero, A. I. Loaiza-Pꢃrez, Int. J. Breast Cancer 2011,
DOI: 10.4061/2011/923250; c) K. Stolpmann, J. Brinkmann, S. Sal-
zmann, D. Genkinger, E. Fritsche, C. Hutzler, H. Wajant, A. Luch,
F. Henkler, Cell Death Dis.3 2012, e388, DOI: 10.1038/
cddis.2012.127; d) A. Koliopanos, J. Kleeff, Y. Xiao, S. Safe, A. Zim-
mermann, M. W. B. Chler, H. Friess, Oncogene 2002, 21, 6059–6070;
e) N. P. Singh, U. P. Singh, B. Singh, R. L. Price, M. N. Nagarkatti,
P. S. Nagarkatti, PLoSOne 2011, 6, e23522; f) E. A. Stevens, J. D.
Mezrich, C. A. Bradfield, Immunology 2009, 127, 299–311; g) M. S.
Denison, A. Pandini, S. R. Nagy, E. P. Baldwin, L. Bonati, Chem.-
Biol. Interact. 2002, 141, 3–24.
[7] a) N. Zencirci, T. Gelbrich, D. C. Apperley, R. K. Harris, V. Kahlen-
berg, U. J. Griesser, Cryst. Growth Des. 2010, 10, 302–313; b) D.
Mangin, F. Puel, S. Veesler, Org. Process Res. Dev. 2009, 13, 1241–
1253; c) J. Li, S. A. Bourne, M. R. Caira, Chem. Commun. 2011, 47,
1530–1532; d) K. Fucke, N. Qureshi, D. S. Yufit, J. A. K. Howard,
J. W. Steed, Cryst. Growth Des. 2010, 10, 880–886; e) P. Sanphui, B.
Sarma, A. Nangia, J. Pharm. Sci. 2011, 100, 2287–2299; f) S. Cheru-
kuvada, R. Thakuria, A. Nangia, Cryst. Growth Des. 2010, 10, 3931–
3941.
[8] a) H. Wu, N. Reeves-McLaren, J. Pokorny, J. Yarwood, A. R. West,
Cryst. Growth Des. 2010, 10, 3141–3148; b) D. Braga, F. Grepioni,
L. Maini, M. Polito, Struct. Bonding 2009, 132, 25–50; c) M. Karja-
lainen, S. Airaksinen, J. Rantanen, J. Aaltonen, J. Yliruusi, J. Pharm.
Biomed. Anal. 2005, 39, 27–32; d) E. V. Boldyreva, T. N. Drebush-
chak, T. P. Shakhtshneider, H. Sowa, H. Ahsbahs, S. V. Goryainov,
S. N. Ivashevskaya, E. N. Kolesnik, V. A. Drebushchak, E. B. Burgi-
na, ARKIVOC 2004, 12, 128–155; e) A. Burger, R. Ramberger,
Mikrochim. Acta II 1979, 72, 273–316; f) A. Trask, N. Shan, W.
Motherwell, W. Jones, S. Feng, R. Tan, K. Carpenter, Chem.
Commun. 2005, 880–882.
[9] a) S. Terada, K. Katagiri, H. Masu, H. Danjo, Y. Sei, M. Kawahata,
M. Tominaga, K. Yamaguchi, I. Azumaya, Cryst. Growth Des. 2012,
12, 2908–2916; b) S. Murugavel, N. Manikandan, D. Kannan, M.
Bakthadoss, Acta Crystallogr. Sect. E 2012, 68, o1009–o1010; c) P.
Sanphui, B. Sarma, A. Nangia, Cryst. Growth Des. 2010, 10, 4550–
4560; d) N. Nagel, H. Bock, P. Eller, Acta Crystallogr. Sect. B 2000,
56, 234–244; e) S. Roy, A. J. Matzger, Angew. Chem. 2009, 121,
8657–8660; Angew. Chem. Int. Ed. 2009, 48, 8505–8508; f) B. R.
Sreekanth, P. Vishweshwar, K. Vyas, Chem. Commun. 2007, 2375–
2377.
[10] a) M. C. Etter, Acc. Chem. Res. 1990, 23, 120–126; b) J. Bernstein,
R. E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem. 1995, 107,
1689–1708; Angew. Chem. Int. Ed. Engl. 1995, 34, 1555–1573;
c) D. A. Adsmond, D. J. W. Grant, J. Pharm. Sci. 2001, 90, 2058–
2077; d) J. D. Dunitz, J. Bernstein, Acc. Chem. Res. 1995, 28, 193–
200.
[11] a) S. Roy, A. Nangia, Cryst. Growth Des. 2007, 7, 2047–2058; b) F.-
E. Shi, Acta Crystallogr. Sect. E 2007, 63, o4372; c) H. V. R. Dias, S.
Singh, Dalton Trans. 2006, 1995–2000; d) S. Tsuzuki, K. Honda, T.
Uchimaru, M. Mikami, K. Tanabe, J. Am. Chem. Soc. 2000, 122,
11450–11458; e) L. S. Reddy, S. K. Chandran, S. George, N. J. Babu,
A. Nangia, Cryst. Growth Des. 2007, 7, 2675–2690.
[12] a) J. Bernstein, Conformational Polymorphism in Organic Solid-
State Chemistry, (Ed.: G. R. Desiraju), Elsevier, 1987, pp. 471–518;
b) A. Nangia, Models, Mysteries and Magic of Molecules (Eds.:
J. C. A. Boeyens, J. F. Ogilvie), Springer, 2008, pp. 63–86; c) A.
Nangia, Acc. Chem. Res. 2008, 41, 595–604; d) S. SeethaLekshmi,
T. N. G. Row, Cryst. Growth Des. 2012, 12, 4283–4289; e) S. Aitipa-
mula, P. S. Chow, R. B. H. Tan, Cryst. Growth Des. 2011, 11, 4101–
4109; f) P. Sanphui, N. R. Goud, U. B. R. Khandavilli, S. Bhanoth,
A. Nangia, Chem. Commun. 2011, 47, 5013–5015; g) R. J. Davey, N.
Blagden, G. D. Potts, R. Docherty, J. Am. Chem. Soc. 1997, 119,
1767–1772; h) L. Yu, S. M. Reutzel-Edens, C. A. Mitchell, Org. Pro-
cess Res. Dev. 2000, 4, 396–402.
[13] a) F. T. Martins, M. D. Bocelli, R. Bonfilio, M. B. de Arauꢄjo, P. V.
de Lima, P. P. Neves, M. P. Veloso, J. Ellena, A. C. Doriguetto, Cryst.
Growth Des. 2009, 9, 3235–3244; b) N. J. Babu, S. Cherukuvada, R.
Thakuria, A. Nangia, Cryst. Growth Des. 2010, 10, 1979–1989; c) S.
Tothadi, B. R. Bhogala, A. R. Gorantla, T. S. Thakur, R. K. Jetti,
G. R. Desiraju, Chem. Asian J. 2012, 7, 330–342; d) N. K. Nath, S.
Nilapwar, A. Nangia, Cryst. Growth Des. 2012, 12, 1613–1625.
[14] a) L. Yu, Adv. Drug Delivery Rev. 2001, 48, 27–48; b) M. R. Chier-
otti, L. Ferrero, N. Garino, R. Gobetto, L. Pellegrino, D. Braga, F.
Grepioni, L. Maini, Chem. Eur. J. 2010, 16, 4347–4358; c) D. E.
Bugay, Pharm. Res. 1993, 10, 317–327; d) U. J. Griesser, A. Burger,
K. Mereiter, J. Pharm. Sci. 1997, 86, 352–358.
[15] a) L. Yu, J. Phys. Chem. A 2002, 106, 544–550; b) S. Chen, H. Xi, L.
Yu, J. Am. Chem. Soc. 2005, 127, 17439–17444; c) K. Johmoto, A.
Sekine, H. Uekusa, Y. Ohashi, Bull. Chem. Soc. Jpn. 2009, 82, 50–
57; d) L. N. Kuleshova, B. B. Averkiev, D. V. Gusev, K. Y. Suponit-
skiꢅ, M. Y. Antipin, Crystallogr. Rep. 2004, 49, 798–806; e) S. Matsu-
moto, Y. Uchida, M. Yanagita, Chem. Lett. 2006, 35, 654–655.
[16] Cambridge Structural Database, ver. 5.33, ConQuest 1.13, May 2012
release, Cambridge Crystallographic Data Center; http://
www.ccdc.cam.ac.uk.
[17] a) J. Bernstein, J. D. Dunitz, A. Gavezzotti, Cryst. Growth Des. 2008,
8, 2011–2018; b) S. Roy, P. M. Bhatt, A. Nangia, G. J. Kruger, Cryst.
Growth Des. 2007, 7, 476–480; c) T. S. Thakur, R. Sathishkumar,
A. G. Dikundwar, T. N. G. Row, G. R. Desiraju, Cryst. Growth Des.
2010, 10, 4246–4249; d) B. Rodrꢆguez-Spong, C. P. Price, A. Jayasan-
kar, A. J. Matzger, N. Rodrꢆguez-Hornedo, Adv. Drug Delivery Rev.
2004, 56, 241–274; e) A. J. Florence, K. Shankland, T. Gelbrich,
M. B. Hursthouse, N. Shankland, A. Johnston, P. Fernandes, C. K.
Leech, CrystEngComm 2008, 10, 26–28.
[18] a) C. M. Reddy, M. T. Kirchner, R. C. Gundakaram, K. A. Padma-
nabhan, G. R. Desiraju, Chem. Eur. J. 2006, 12, 2222–2234; b) D.
ˇ ´
ˇˇ ´
Cincic, T. Friscic, W. Jones, Chem. Mater. 2008, 20, 6623–6626;
c) N. K. Nath, B. K. Saha, A. Nangia, New J. Chem. 2008, 32, 1693–
1701; d) A. Kꢇlmꢇn, Acta Crystallogr. Sect. B 2005, 61, 536–547;
e) F. P. A. Fabbiani, B. Dittrich, A. J. Florence, T. Gelbrich, M. B.
Hursthouse, W. F. Kuhs, N. Shankland, H. Sowa, CrystEngComm
2009, 11, 1396–1406; f) N. K. Nath, S. S. Kumar, A. Nangia, Cryst.
Growth Des. 2011, 11, 4594–4605; g) T. Gelbrich, T. L. Threlfall,
M. B. Hursthouse, CrystEngComm 2012, 14, 5454–5464.
[19] a) D. Das, E. Engel, L. J. Barbour, Chem. Commun. 2010, 46, 1676–
1678; b) M.-L. Cao, H.-J. Mo, J.-J. Liang, B.-H. Ye, CrystEngComm
2009, 11, 784–790; c) S. Takahashi, H. Miura, H. Kasai, S. Okada,
H. Oikawa, H. Nakanishi, J. Am. Chem. Soc. 2002, 124, 10944–
10945; d) Q. Chu, D. C. Swenson, L. R. MacGillivray, Angew. Chem.
2005, 117, 3635–3638; Angew. Chem. Int. Ed. 2005, 44, 3569–3572;
e) T. N. Drebushchak, V. A. Drebushchak, E. V. Boldyreva, Acta
Crystallogr. Sect. B 2011, 67, 163–176; f) T. N. Drebushchak, A. A.
Ogienko, E. V. Boldyreva, CrystEngComm 2011, 13, 4405–4410;
g) J. B. Nanubolu, B. Sridhar, V. S. P. Babu, B. Jagadeesh, K. Raviku-
mar, CrystEngComm 2012, 14, 4677–4685; h) N. Mahꢃ, M.-A.
Perrin, M. Barrio, B. Nicolaꢈ, I. B. Rietveld, J. L. Tamarit, R. Cꢃolin,
J. Pharm. Sci. 2011, 100, 2258–2266.
[20] a) M. R. Yadav, A. R. Shaikh, V. Ganesan, R. Giridhar, R. Chadha,
J. Pharm. Sci. 2008, 97, 2637–2648; b) Y. Qiu, Y. Chen, L. Liu,
G. G. Z. Zhang, Developing Solid Oral Dosage Forms: Pharmaceuti-
cal Theory and Practice, 1st ed., Academic Press, 2009, pp. 75–86;
c) M. McAllister, Mol. Pharmaceutics 2010, 7, 1374–1387; d) J. Ha-
leblian, W. McCrone, J. Pharm. Sci. 1969, 58, 911–929.
[21] a) Y. Fujita, M. Yonehara, K. Kitahara, J. Shimokawa, Y. Hashimo-
to, M. Ishikawa, Heterocycles 2011, 83, 2563–2575; b) Y. Fujita, M.
Yonehara, M. Tetsuhashi, T. Noguchi-Yachide, Y. Hashimoto, M.
17
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ashwini Nangia et al.
Ishikawa, Bioorg. Med. Chem. 2010, 18, 1194–1203; c) M. Ishikawa,
Y. Hashimoto, J. Med. Chem. 2011, 54, 1539–1554; d) J. Kasuga, M.
Ishikawa, M. Yonehara, M. Makishima, Y. Hashimoto, H. Miyachi,
Bioorg. Med. Chem. 2010, 18, 7164–7173; e) B. Kuhn, P. Mohr, M.
Stahl, J. Med. Chem. 2010, 53, 2601–2611; f) G. Lewin, A. Maciuk,
A. Moncomble, J. P. Cornard, Planta Med. 2012, 78, 1080; g) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320–330.
Area Detector Data, University of Gçttingen, Germany, 1997;
c) SMART (Version 5.625) and SHELX-TL (Version 6.12), Bruker-
AXS Inc., 2000; d) G. M. Sheldrick, SHELXS-97 and SHELXL-97,
University of Gçttingen, Germany, 1997; e) Powder Cell, A program
for structure visualization, powder pattern calculation and profile
fitting, www.ccp14.ac.uk.
Received: December 6, 2012
Revised: February 8, 2013
Published online: && &&, 0000
[22] a) SAINT-Plus, version 6.45, Bruker-AXS Inc., 2003; b) G. M. Shel-
drick, SADABS, Program for Empirical Absorption Correction of
&
&
18
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

FULL PAPER
A twist to solubility: A solid form
screen of aryl hydrocarbon receptor
(AhR) modulator molecule cardiosulfa
1 and its analogues 2–6 showed that
cardiosulfa exists in only one crystal-
line form, whereas 2–5 are polymorph-
ic. The more soluble compounds 2 and
5 adopt twisted conformations in the
crystal structure (see figure), unlike
a near-planar conformation of the less
soluble 1.
Polymorphism
S. Sudalai Kumar, Soumendra Rana,
Ashwini Nangia*
&&&& — &&&&
Solid-State Form Screen of Cardiosulfa
and Its Analogues
19
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ