Neutral and zwitterionic polymorphs of 2-(p-tolylamino)nicotinic acid

Article abstract of DOI:10.1021/cg200853u

2-(p-Tolylamino)nicotinic acid (TNA) was crystallized in three polymorphic forms. The crystal structures of forms I and II are sustained by the neutral O-H???N hydrogen bond from the COOH donor to the pyridine N acceptor, whereas proton transfer occurred

Full text of DOI:10.1021/cg200853u

ARTICLE
pubs.acs.org/crystal
Neutral and Zwitterionic Polymorphs of 2-(p-Tolylamino)nicotinic
Acid
Naba K. Nath, S. Sudalai Kumar, and Ashwini Nangia*
School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road, Gachibowli, Hyderabad 500 046, India
S Supporting Information
b
ABSTRACT:
2-(p-Tolylamino)nicotinic acid (TNA) was crystallized in three polymorphic forms. The crystal structures of forms I and II are
sustained by the neutral OꢀH N hydrogen bond from the COOH donor to the pyridine N acceptor, whereas proton transfer
3 3 3
occurred in form III to give a zwitterionic structure of NꢀH+ Oꢀ hydrogen bond. Form III could be obtained only in the
3 3 3
presence of pyridine-type coformers. The trimorphs were characterized by IR, Raman, and ss-NMR spectroscopy, DSC, and single
crystal X-ray diffraction. The neutral form I and zwitterionic form III are 2D isostructural, whereas form II has a different crystal
packing and molecular conformation. XPac analysis showed the 2D supramolecular construct and similarity in crystal structures of
forms I and III. The difference in hydrogen bonding between the neutral and zwitterionic polymorph is analyzed by Hirshfeld
surfaces. The isolation of zwitterionic TNA as a complex with m-nitrobenzoic acid and a TNA salt with o-aminopyridine provides a
mechanistic rationale for the crystallization of the rare zwitterionic structure of amphoteric TNA molecule.
’ INTRODUCTION
polymorphic sets of neutral and zwitterionic forms among solved
X-ray crystal structures of single-component organic molecules
archived in the CSD. Clonixin5 form II (BIXGIY04) is zwitter-
ionic, whereas the other polymorphs of this tetramorphic
compound are neutral (BIXGIY01, BIXGIY02, BIXGIY03).
The monoclinic polymorph of norfloxacin6 is zwitterionic (VET-
VOG01), whereas the triclinic structure is neutral (VETVOG).
Anthranilic acid7 is trimorphic: neutral monoclinic (AMBA-
CO08), neutral orthorhombic (AMBACO05), and zwitterionic
orthorhombic (AMBACO07). Torasemide8 has a crystal structure
containing one zwitterion and one neutral molecule (TORSEM02),
whereas the second polymorph is completely zwitterionic
(TORSEM04).
Ampholites are amphoteric compounds that contain both
acidic and basic functional groups, and such molecules can exist
as zwitterions in certain pH ranges. Zwitterions contain both
positive and negative charges on different atoms of the same
molecule, but they are electrically neutral through a net cancella-
tion of the positive and negative charge.1 Amino acids are the
commonest example of a zwitterion. Some other zwitterionic
categories are buffers, detergents, dyes, and drugs. Amphoteric
compounds are frequently encountered as drugs in medicinal
chemistry and drug metabolites in biochemistry. Amphoteric
drug molecules predominantly exist as charged species in the
physiological pH range and are therefore able to bind to the
plasma targets in the body.2 The variation of pH in the stomach
and digestive tract (1.2ꢀ6.8)3 can cause changes in the physi-
cochemical properties of neutral/zwitterionic drugs, such as
solubility, stability, and permeability.
Many diarylamines are anti-inflammatory,9 e.g., niflumic acid,
clonixin, mefenamic acid, tolfenamic acid, flufenamic acid me-
clofenamic acid, and diclofenac. Several of these molecules
exhibit polymorphism.10 However, except clonixin,5 none of
these compounds, including the recently reported pentamorphs
of tolfenamic acid,10e fall in the category of zwitterion and neutral
polymorphic structures. Torasemide and anthranilic acid have
’ RESULTS AND DISCUSSION
Background. There are very few molecules that exhibit both
neutral and zwitterionic crystal structures in the Cambridge
Structural Database4 (CSD ver 5.32, November 2010, May
2011 update) (Scheme 1). We were able to extract only four
Received: July 7, 2011
Revised:
August 17, 2011
Published: August 29, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/cg200853u Cryst. Growth Des. 2011, 11, 4594–4605
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Crystal Growth & Design
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Scheme 1. Molecules Exhibiting Zwitterionic and Neutral Polymorphs Extracted from the CSD
Scheme 2. Molecular Structure of 2-(p-Tolylamino)nicotinic
Acid (TNA)
Scheme 3. Diarylamine Carboxylic Acids Recently Reported
by Li’s Group11
both neutral and zwitterionic molecules in the same crystal
structure. We studied the crystal structures of 2-(p-tolylamino)-
nicotinic acid (TNA) (Scheme 2) in the above background to
explore neutral/zwitterion polymorphic behavior. Li11 and co-
workers recently reported polymorphism in some diarylamine
carboxylic acids. Even though these molecules (Scheme 3) are
structurally very similar to TNA, the authors did not disclose any
example of neutral and zwitterionic polymorph sets in their
studies. Both 2-(phenylamino)nicotinic acid and 2-[methyl-
(phenyl)amino]nicotinic acid (molecules a and b) were found
to be tetramorphic in their polymorph hunt.
Our recent studies on synthon competition and cooperation in
cocrystals of carboxylic acids and pyridines suggested that it is
very difficult to predict the status of proton migration based on
pKa values of carboxylic acid and pyridine, especially when extra
functional groups such as amine and hydroxyl are present.12 The
utility of the ΔpKa rule, i.e., proton transfer will occur when the
difference in pKa between the conjugate acid of the base and the
carboxylic acid is >3 and a neutral state will occur when ΔpKa < 3,
is widely accepted in the pharmaceutical literature.13 In our
experience, the neutral and the ionic states can be reliably
predicted when ΔpKa < 0 and ΔpKa > 3, respectively, but the
range 0 < ΔpKa < 3 is somewhat of a gray zone, wherein it is dif-
ficult to know the answer beforehand. Incidentally (phenylamino)
nicotinic acids fall in the gray zone category: the pKa of the
conjugate acid of pyridine is ∼5.3, secondary ammonium is
∼10.7, and carboxylic acid is ∼4.2.14 Despite the high basicity of
the secondary amine, its proton-accepting strength is lowered in
the molecules under study because of adjacent electron-with-
drawing pyridine and carboxylic acid groups, with the result that
the more basic functional group in such molecules is the pyridine
moiety. The calculated pKa values for clonixin are 1.69 and 4.80,
which are comparable to those for the closely related niflumic
acid (1.70 and 4.71).13b We therefore felt that crystallization
under different conditions of solvent, concentration, tempera-
ture, additives, coformers, etc. is a logical way to explore this
system for polymorphism. The conformational flexibility of the
molecule could make it polymorph promiscuous.15 The am-
pholitic nature of the molecule meant that there was likelihood
of obtaining neutral and zwitterionic polymorphs in the supra-
molecular solid-state form space by exhaustive exploration of
experimental conditions. Polymorph screening of TNA was
performed using different crystallization techniques including
cocrystallization with carboxylic acid and pyridine derivatives as
coformers.
TNA Polymorphs. We report zwitterionic and neutral crystal
structures of TNA polymorphs. Forms I and II are sustained by
the neutral OꢀH N hydrogen bond, whereas form III has a
3 3 3
zwitterionic molecule and NꢀH+ Oꢀ hydrogen bond. Inter-
3 3 3
estingly, the zwitterionic structure of TNA could be crystallized
only in cocrystallization experiments when a stoichiometric
amount of o-bromo-m-hydroxypyridine, o-aminopyridine, isoni-
cotinic acid, or nicotinic acid was added as a coformer in separate
experiments. We also report a cocrystal of TNA with m-nitro-
benzoic acid and a salt of o-aminopyridine to understand the
formation of zwitterionic polymorph under the attempted co-
crystallization conditions
TNA was crystallized (preparation is reported in the Experi-
mental Section) by using different techniques, such as solvent
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Crystal Growth & Design
ARTICLE
Table 1. Crystallographic Parameters of TNA Polymorphs and Cocrystals
TNA
empirical formula
form I
C13 H12 N2 O2
form II
C13 H12 N2 O2
form III
C13 H12 N2 O2
form III
C13 H12 N2 O2
NH+ꢀTNAꢀCOOꢀ 2NBA
APꢀNH+ TNAꢀCOOꢀ
3
3
C27H22N4O10
562.49
C18 H18 N4 O2
322.36
formula weight
crystal system
space group
T (K)
228.25
monoclinic
P21/n
228.25
orthorhombic
Pbca
228.25
orthorhombic
Pbca
228.25
orthorhombic
Pbca
triclinic
orthorhombic
P212121
298
P1
100
100
100
298
298
a/Å
11.038(10)
9.067(8)
11.392(10)
90
14.2565(16)
10.7542(15)
14.769(3)
90
9.0787(11)
14.2261(17)
17.154(2)
90
9.250(4)
14.207(4)
17.509(10)
90
7.8000(8)
13.0415(16)
14.0098(15)
64.870(11)
86.132(9)
85.992(9)
1286.0(3)
1.453
6.8022(8)
10.4120(12)
23.206(3)
90
b/Å
c/Å
α/deg
β/deg
101.860(14)
90
90
90
90
90
γ/deg
V/Å3
Dcalcd (g cmꢀ3
90
90
90
90
1115.8(17)
1.359
2264.3(6)
1.339
2215.6(5)
1.369
2301.1(17)
1.318
1643.6(3)
1.303
)
μ (mmꢀ1
Z/Z0
)
0.094
0. 092
0.094
0.091
0.113
0.088
4/1
8/1
8/1
8/1
2/1
4/1
reflns collected
unique reflns
observed reflns
R1 [I > 2 σ(I)]
wR2 (all)
10196
10798
20081
5988
9618
15003
2190
4319
2160
2097
5273
3220
1987
2306
2005
866
3625
3101
0.0598
0.1827
1.188
0.0497
0.1026
0.872
0.0521
0.1475
1.185
0.0646
0.1350
0.929
0.0399
0.0420
0.1033
0.0928
goodness-of-fit
diffractometer
1.039
1.162
SMART APEX
CCD
Xcalibur Gemini
Eos CCD
SMART APEX
CCD
Xcalibur Gemini
Eos CCD
Xcalibur Gemini Eos CCD
SMART APEX CCD
evaporation, melting, sublimation, slow cooling, flash cooling,
and crystallization in the presence of different coformers. Three
polymorphs were crystallized in these manual screen experi-
ments. Forms I and II crystallized concomitantly from several
solvents, such as acetone, methanol, ethanol, ethyl acetate,
acetonitrile, chloroform, and THF. Form II was obtained exclu-
sively by melt crystallization and pure form I was crystallized
from acetone. The polymorph identity was established after each
experiment by powder X-ray diffraction. Zwitterionic form III
was obtained when TNA was cocrystallized with o-bromo-m-
hydroxypyridine, o-aminopyridine, isonicotinic acid, or nicotinic
acid in CH3CN solvent. The experimental conditions could not
be fully optimized even after our best efforts; occasionally these
cocrystallizations also gave form I or II or a salt of TNA with o-
aminopyridine. The particular crystalline form(s) in any batch
were checked by determining the unit cell of a few single crystals.
The presence of the coformer was however important: form
III could not be crystallized from solution crystallization in the
absence of pyridine functional group containing coformers.
Cocrystallization of TNA and o-aminopyridine (AP) in CH3CN
Figure 1. (a) Chains of molecules sustained by the acidꢀpyridine
synthon are connected by CꢀH π interaction to make a 2D sheet in
3 3 3
the crystal structure of form I. (b) CꢀH O and CꢀH π interac-
3 3 3
3 3 3
tions in the interlayer region.
175.6ꢀ and C5ꢀH5 O2, 2.55 Å, 133.1ꢀ) are connected by
3 3 3
CꢀH π interaction (C4ꢀH4 C12, 2.88 Å, 145.8ꢀ) to
3 3 3
3 3 3
make a sheet structure, and such sheets are connected by
CꢀH O (C12ꢀH12 O1, 2.58 Å, 174.7ꢀ) and CꢀH
π
3 3 3
3 3 3
3 3 3
interactions (C9ꢀH9 C3, 2.84 Å, 162.1ꢀ) (Figure 1). Hydro-
3 3 3
gen bonds are listed in Table 2.
Block morphology crystals of form II obtained from methanol
were solved and refined in the orthorhombic space group Pbca
resulted in the corresponding salt (APꢀNH+ TNAꢀCOOꢀ)
3
(Z0 = 1). The acidꢀpyridine synthon (O1ꢀH1 N1, 1.68 Å,
along with forms III and I/II occurring concomitantly. Cocrys-
tallization of TNA with m-nitrobenzoic acid (NBA) resulted in
1:2 stoichiometry of the components, wherein TNA was in its
zwitterionic state and the cofomer was neutral (NH+ꢀTNAꢀ
3 3 3
174.7ꢀ and C5ꢀH5 O2, 2.49 Å, 136.1ꢀ) connects the mo-
3 3 3
lecular chains, and additional CꢀH O interaction (C13ꢀ
3 3 3
H13A O2, 2.59 Å, 150.4ꢀ) assemble the zigzag sheet struc-
3 3 3
COOꢀ 2NBA). The structures of all new compounds were
ture. There is offset π π stacking (3.39 Å) between the pyridyl
3
3 3 3
characterized by single crystal X-ray diffraction (Table 1).
Crystal Structure Analysis. Block morphology crystals of
form I were obtained from acetone and the reflections data were
solved and refined in the monoclinic space group P21/n with one
molecule in the asymmetric unit. Chains of molecules linked by
rings (Figure 2).
Block morphology crystals of form III were obtained in
attempted cocrystallization with o-aminopyridine in acetoni-
trile solvent. The crystal structure was solved and refined in
the orthorhombic space group Pbca. The X-ray crystal struc-
ture and difference electron density maps (100 K data set)
acidꢀpyridine two point synthon (O1ꢀH1 N1, 1.59 Å,
3 3 3
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Crystal Growth & Design
ARTICLE
Table 2. Hydrogen Bonds in Crystal Structures of TNA
interactions
H
A/Å
D
A/Å
—DꢀH A/deg
symmetry code
3 3 3
3 3 3
3 3 3
TNA Form I
N2ꢀH2 O2
1.90
1.59
2.34
2.55
2.58
2.591(4)
2.591(4)
2.672(5)
3.272(5)
3.526(5)
147.3
175.6
99.8
intramolecular
3 3 3
O1ꢀH1 N1
1/2 + x, 1/2 ꢀ y, 1/2 + z
intramolecular
3 3 3
C3ꢀH3 O1
3 3 3
C5 ꢀH5 O2
133.1
174.7
ꢀ1/2 + x, 1/2ꢀ y, ꢀ1/2 + z
3/2 ꢀ x, ꢀ1/2 + y, 1/2 ꢀ z
3 3 3
C12ꢀH12 O1
3 3 3
TNA Form II
O1ꢀH1 N1
1.68
1.94
2.38
2.49
2.58
2.663(1)
2.669(1)
2.704(2)
3.222(2)
3.452(2)
174.7
141.7
100.2
136.1
150.4
ꢀ1/2 + x, 1/2 ꢀ y, 1 ꢀ z
intramolecular
3 3 3
N2ꢀH2 O2
3 3 3
C3ꢀH3 O1
intramolecular
3 3 3
C5ꢀH5 O2
1/2 + x, 1/2 ꢀ y, 1 ꢀ z
1/2 + x, y, 1/2 ꢀ z
3 3 3
C13ꢀH13A O2
3 3 3
TNA Form III at 100 K
2.579(2)
N1ꢀH1 O1
1.59
1.84
2.39
2.55
2.46
2.52
141.6
144.1
100.0
137.0
164.0
172.4
3/2 ꢀ x, 1/2 + y, z
intramolecular
3 3 3
N2ꢀH2 O2
2.630(2)
3 3 3
C3ꢀH3 O1
2.722(3)
intramolecular
3 3 3
C5ꢀH5 O2
3.312(3)
3/2 ꢀ x, 1/2 + y, z
1 ꢀ x, 1/2 + y, 1/2 ꢀ z
ꢀ1/2 + x, 1/2 ꢀ y, ꢀz
3 3 3
C9ꢀH9 O2
3.379(3)
3 3 3
C12ꢀH12 O1
3.463(3)
3 3 3
TNA Form III at 298 K
2.571(4)
N1ꢀH1 O1
1.28
1.91
2.38
2.52
2.57
164.2
137.4
101.0
137.7
166.5
3/2 ꢀ x, ꢀ1/2 + y, z
intramolecular
3 3 3
N2ꢀH2 O2
2.644(4)
3 3 3
C3ꢀH3 O1
2.716(4)
intramolecular
3 3 3
C5ꢀH5 O2
3.273(4)
3/2 ꢀ x, ꢀ1/2 + y, z
1 ꢀ x, ꢀ1/2 + y, 1/2 ꢀ z
3 3 3
C9ꢀH9 O2
3.485(6)
3 3 3
NH+ꢀTNAꢀCOOꢀ 2NBA
3
N1ꢀH1 O6
2.17
1.91
2.49
1.66
2.58
1.63
2.44
2.53
2.33
2.40
2.53
2.51
2.50
2.53
2.962(2)
2.621(2)
3.176(2)
2.568(2)
3.056(2)
2.600(2)
2.763(2)
3.286(2)
3.041(2)
3.316(2)
3.447(2)
3.354(3)
3.431(2)
3.457(2)
152.5
139.1
137.2
170.1
112.7
170.4
100.3
138.8
132.5
168.2
167.5
151.9
177.0
174.0
x, y, z
3 3 3
N2ꢀH2 O2
intramolecular
2 ꢀ x, ꢀy, 1 ꢀ z
ꢀ1 + x, y, ꢀ1 + z
ꢀ1 + x, y, ꢀ1 + z
2 ꢀ x, ꢀy, 1 ꢀ z
intramolecular
x, y, z
3 3 3
N2ꢀH2 O7
3 3 3
O3ꢀH3A O1
3 3 3
O3ꢀH3 O2
3 3 3
O8ꢀH8A O2
3 3 3
C3ꢀH3 O1
3 3 3
C5ꢀH5 O5
3 3 3
C5ꢀH5 O10
1 ꢀ x, 1 ꢀ y, ꢀz
2 ꢀ x, 1 ꢀ y, 1 ꢀ z
x, y, 1 + z
3 3 3
C8ꢀH8 O1
3 3 3
C12ꢀH12 O9
3 3 3
C19ꢀH19 O9
1 ꢀ x, ꢀy, ꢀz
1 ꢀ x, 1 ꢀ y, ꢀz
1 ꢀ x, 1 ꢀ y, ꢀz
3 3 3
C25ꢀH25 O5
3 3 3
C26ꢀH26 O4
3 3 3
APꢀNH+ TNAꢀCOOꢀ
3
N2ꢀH2 O2
1.85
1.92
1.94
1.74
2.626(2)
2.806(2)
2.843(2)
2.657(2)
2.919(2)
146.2
169.5
176.2
177.2
121.7
intramolecular
1/2 + x, 3/2 ꢀ y, 2 ꢀ z
1 + x, y, z
3 3 3
N3ꢀH3A
O1
3 3 3
N3ꢀH3B O1
3 3 3
N4ꢀH4A O2
1 + x, y, z
3 3 3
C8ꢀ H8 N1
2.3217
intramolecular
3 3 3
showed that the carboxylic acid proton had migrated to the
pyridine N and that proton transfer was complete to give
a zwitterion. When reflections on the same crystal were
collected at room temperature (298 K), only partial proton
transfer was observed. There was no bulk phase transition
between 100 and 300 K other than the slight hydrogen atom
shift.
The carboxylateꢀpyridinium heterosynthon via N+ꢀH
3 3 3
Oꢀ hydrogen bond (N1+ꢀH1 O1ꢀ, 1.59 Å, 170.9ꢀ) and
3 3 3
auxiliary CꢀH O hydrogen bond (C5ꢀH5 O2, 2.55 Å,
3 3 3
3 3 3
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Crystal Growth & Design
ARTICLE
Figure 5. NꢀH O synthon in the crystal structure of salt APꢀNH+
3 3 3
3
Figure 2. Zigzag sheets of acidꢀpyridine synthon (a) are connected by
TNAꢀCOOꢀ.
π
π stacking (b) in form II.
3 3 3
N being protonated and TNA existing as a carboxylate; the TNA
pyridine N is free (Figure 5).
The carboxylic acid proton state was verified by the analysis of
CꢀO bond distances, OꢀCꢀO bond angles of carboxylic acid/
carboxylate group, and CꢀNꢀC bond angles of the pyridine ring
in the crystal structures (Table 3). The length of the two CꢀO
bond distances in form I (1.30 and 1.23 Å) and form II (1.32 and
1.22 Å) indicate a neutral COOH group, whereas the near equal
CꢀO bond distances in form III (1.26 Å and 1.25 Å) imply a
COOꢀ group. Similarly, OꢀCꢀO and CꢀNꢀC bond angles
argue in favor of a zwitterionic structure in form III but neutral
structures of forms I and II. There is a slight difference in the
proton state between the crystal structures of form III deter-
mined at 100 and 298 K (referred to as LT and RT). The proton
is fully located on the pyridine N and the carboxylate group is
ionic in the LT crystal structure. The transfer of proton from
COOH to pyridine N is slightly less so at RT. There is partial
proton occupancy near both O and N atoms in the ORTEP
(Figure S1, Supporting Information). This slight drift of the pro-
ton from the ionic to the neutral state with an increase in tem-
perature from 100 to 300 K is reflected in the bond distances and
angles parameters (Table 3). The difference between the CꢀO
values increases slightly and the CꢀNꢀC angle shrinks by 1ꢀ.
Comparison of Forms I and III. Forms I and III exhibit 2D
isostructural sheets, even though they contain different hydrogen
bond synthons (form I, acidꢀpyridine; form III, pyridiniumꢀ
carboxylate). Their space group and unit cell parameters are
different (Table 1), but their molecular conformations are similar
(Figure 6). The main torsion angle is the twist around the
diarylamine group listed in Table 4. The calculated X-ray powder
diffraction lines from the crystal structures of forms I and III
exhibit very close 2θ values (Figure 7). The PXRD pattern of
form II is visibly different, as is its molecular packing in the crystal
structure. The main structural difference between polymorphs I
and III is in the direction of the molecular layers within the
identical 2D sheets. If the direction of TNA molecules con-
nected by carboxylic acidꢀpyridine (in form I) or carboxylateꢀ
pyridinium (in form III) running in one direction (right to left) is
designated as X and the opposite direction as Y, then adjacent
layers contain the motif XYXYXYXY in form I, whereas the
sequence is XXYYXXYY in form III (Figure 8). Thus, the
difference is more than just a shift of the proton; the sequence
arrangement of identical 2D sheets in the third dimension is the
major difference between forms I and III. A similar packing
difference between the polymorphs of the anti-inflammatory
drug nimesulide was noted recently.16
Figure 3. Carboxylateꢀpyridinium heterosynthon (a) and CꢀH
O
3 3 3
interactions (b) in form III.
Figure 4. Hydrogen bonding in TNA 2NBA cocrystal, which has a
3
zwitterionic molecule NH+ꢀTNAꢀCOOꢀ and two neutral NBA
coformers in the crystal structure.
137.0ꢀ) is interlinked by CꢀH π (C4ꢀH4 C12, 2.85 Å,
3 3 3
3 3 3
146.4ꢀ) and CꢀH O interactions (C13ꢀH13A O2, 2.71
3 3 3
3 3 3
Å, 136.9ꢀ) in the 100 K data set structure. There are CꢀH
O
3 3 3
interactions (C9ꢀH9 O2, 2.46 Å, 164.0ꢀ and C12ꢀH12
3 3 3
3 3 3
O1, 2.52 Å, 172.4ꢀ) on either side of the 2D sheets (Figure 3).
The cocrystal of TNA and m-nitrobenzoic acid contains one
zwitterionic molecule of TNA and two NBA molecules
(NH+ꢀTNAꢀCOOꢀ 2NBA). However, the normally ex-
3
pected pyridiniumꢀcarboxylate synthon of strong NꢀH+
3 3 3
Oꢀ hydrogen bond is replaced by pyridiniumꢀnitro group
interactions (N1+ꢀH1 O6, 2.17 Å, 152.5ꢀ; C5ꢀH5 O5,
3 3 3
3 3 3
2.53 Å, 138.8ꢀ). The carboxylic acid donors of two NBA
molecules hydrogen bond to the carboxylate acceptor
(O3ꢀH3A O1, 1.66 Å, 170.1ꢀ; O8ꢀH8A O2, 1.63 Å,
3 3 3
3 3 3
170.4ꢀ), as shown in Figure 4.
The salt of TNA and o-aminopyridine (APꢀNH+ TNAꢀ
3
COOꢀ) has a classical crystal structure sustained by pyridiniumꢀ
In contrast to the crystal structures of related (phenylamino)
nicotinic acids reported recently,11 we neither observed a high Z0
carboxylate hydrogen bonding (N4ꢀH4A+ O2ꢀ, 1.74 Å,
3 3 3
177.3ꢀ; N3ꢀH3B O1ꢀ, 1.95 Å, 176.1ꢀ) with the AP pyridine
crystal structure nor the acid acid homodimer in TNA
3 3 3
3 3 3
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Table 3. CꢀO Bond Distances and OꢀCꢀO and CꢀNꢀC Bond Angles in the Crystal Structures of TNA
bond distances (Å)
angles (deg)
polymorph
form I at 100 K
C1ꢀO1
C1ꢀO2
O1ꢀC1ꢀO2
C5ꢀN1ꢀC6
1.303(4)
1.316(2)
1.261(3)
1.269(5)
1.245(2)
1.252(2)
1.217(3)
1.223(2)
1.249(3)
1.242(5)
1.236(2)
1.266(2)
123.9(3)
123.3(1)
125.9(2)
125.7(3)
125.6(1)
118.2(2)
119.1(3)
118.8(1)
122.7(2)
121.0(3)
123.8(1)
118.2(2)
form II at 100 K
form III at 100 K
form III at 298 K
NH+ꢀTNAꢀCOOꢀ 2NBA at 298 K
3
APꢀNH+ TNAꢀCOOꢀ at 298 K
3
Figure 6. Overlay of all the conformations in TNA crystal structures:
TNA form I (red), TNA form II (magenta), TNA form III (100 K)
(blue), TNA form III (298 K) (green), NH+ꢀTNAꢀCOOꢀ 2NBA
3
(orange), and APꢀNH+ TNAꢀCOOꢀ (brown).
Figure 7. Overlay of calculated PXRD patterns of TNA polymorphs
from the crystal structures: form I, red; form II, blue; and form III, green.
3
Table 4. Torsion Angles for All the Conformations of TNA in
Its Crystal Structures
experimental conditions could be important in the crystallization
of such polymorphs (discussed later).
XPac Analysis. The XPac method22 is a useful tool to display
packing arrangements in crystal structures and to quantify their
degree of similarity. XPac analysis of TNA structures I and III
produced a 2D supramolecular construct (Figure 10a). The XPac
plot (Figure 10b) of δp vs δa (in degrees) displays the degree of
similarity. Both δp and δa points lie close to the origin, which
implies a similarity of the structures being compared. The XPac
dissimilarity index X is 3.5%, which gives the similarity of the 2D
supramolecular constructs.
crystal structure
C6ꢀN2ꢀC7ꢀC8 torsion angle (deg)
TNA form I
68.0(4)
55.2(2)
66.5(3)
66.8(6)
55.0(2)
11.1(3)
TNA form II
TNA form III (100K)
TNA form III (298K)
NH+ꢀTNAꢀCOOꢀ 2NBA
3
APꢀNH+ TNAꢀCOOꢀ
3
Thermal and Spectroscopic Characterization. The three
polymorphs of TNA exhibited very close melting endotherms in
differential scanning calorimetry (DSC): forms I, II, and III melt
at 205, 207, and 204 ꢀC, respectively (Figure 11). No phase
transition was detected, suggesting a monotropic relationship
among the trimorphs. Even though the melting endotherms are
very close, they were reproducible in multiple batches.
polymorphs. A cocrystal containing acidꢀbase functional groups
was part of the fourth Crystal Structure Prediction blind test
conducted by the CCDC in 2007.17 The crystal structure in that
case, a 1:1 cocrystal of 2-amino-4-methylpyrimidine and 2-
methylbenzoic acid, was correctly predicted by both synthon-
based and purely computational approaches.18 Crystal structures
of salts have also been predicted19 but not of a zwitterionic
molecule to our knowledge. Molecular electrostatic potential is
yet another tool to map hydrogen bond strengths and prefer-
ences. After examining the outcome of crystallization for over a
dozen aminopyridines and carboxylic acids, Aaker€oy20 concluded
that when the calculated electrostatic charge (MEPS in AM1
package) on the pyridine N is between ꢀ220 and ꢀ260 kJ/mol, a
cocrystal is formed, and when the value is between ꢀ275 and
ꢀ290 kJ/mol, the outcome is a salt. The MEP value for pyridine
N in TNA is ꢀ268 kJ/mol (calculated in SPARTAN 10,21
Figure 9), placing this molecule in the gray zone and a difficult
to predict case. The fact that both neutral and ionic polymorphs
of TNA are observed implies that kinetic factors and
The infrared OꢀH and NꢀH stretching frequencies of all the
three polymorphs of TNA are broad and the carbonyl stretching
frequencies are significantly different. The carbonyl stretch for
form III (1635 cmꢀ1) is at a lower wavenumber compared to
form I (1663 cmꢀ1) and form II (1658.7 cmꢀ1), consistent with
the carboxylate group vs carboxylic acid stretching frequency.
The pyridine ring shows four skeletal vibrational bands in the
1600ꢀ1430 cmꢀ1 wavenumber range. The pyridine ring bands
are very close in form I (1602, 1579, 1518, 1459 cmꢀ1) and form
II (1602, 1578, 1518, 1459 cmꢀ1), but they are different for form
III (1604, 1564, 1514 cmꢀ1), and the fourth peak at 1460 cmꢀ1
was not observed (see Figure 12 and Table 5). The appearance of a
broad OꢀH stretch in the IR spectrum (centered at 3428 cmꢀ1
)
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Figure 9. Electrostatic surface potential (ESP) calculated for TNA
molecule in Spartan (AM1). The molecular structure was constructed in
GauessView 3.0 and optimized in Spartan 10.
Hirshfeld Plots. Hirshfeld 2D fingerprint plots25 of the three
polymorphs highlight the differences in their intermolecular
contacts (Figure 15). The sharp spikes for the O H interac-
3 3 3
tions in form IIIat de = di ≈ 1.0 are due to the short NꢀH+ Oꢀ
3 3 3
hydrogen bond, whereas these protrusions are absent in plots of
forms I and II. The complementary situation in forms I and II of
short N H contacts due to a strong OꢀH N hydrogen
Figure 8. Adjacent layer in the crystal structures of TNA polymorphs.
The sequence is XYXYXYXY in form I but XXYYXXYY in form III.
Notice that the tolyl methyl groups are oriented in opposite directions in
the central portion of form I (XY interlayer region), whereas they are
oriented adjacent to each other in form III (YY interlayer region). The
3 3 3
3 3 3
bond is represented by the sharp spikes at de = di ≈ 1.0, whereas
they are absent for form III. The CꢀH O hydrogen bonds
3 3 3
occur at longer distance of de = di ≈ 1.4. These plots are yet
other difference is in the hydrogen bonding: neutral OꢀH N in form
3 3 3
I and ionic NꢀH+ Oꢀ in form III.
another manifestation of the neutral OꢀH N hydrogen bond
3 3 3 ꢀ
3 3 3
in polymorphs I and II and ionic NꢀH+ O hydrogen bond
3 3 3
in form III. The π-stacking of linear hydrogen-bonded tapes in
structures of forms I and III (de = di ≈ 2.5) is less dense in form II.
The major intermolecular interactions in TNA polymorphs are
indicates partial proton transfer in form III at room temperature,
which is consistent with the single crystal X-ray structure analysis at
298 K. The FT-Raman spectra were analyzed for diagnostic peaks
(Figure S2 and Table S1, Supporting Information).
depicted in Figure 16. The contribution from N H interac-
tions to the Hirshfeld surface is higher in form I (7.4%) and form
3 3 3
Solid-state NMR spectroscopy is a useful technique to differ-
entiate polymorphic structures.23 15N and 13C ss-NMR spectra of
TNA polymorphs were recorded. There is an upfield shift ∼1
ppm for pyridine N in the 15N ss-NMR spectrum of form III
(ꢀ146.8 ppm) compared to form I (ꢀ147.5 ppm), whereas the
chemical shift for form II is at ꢀ143.0 ppm. 15N ss-NMR spectra
are displayed in Figure 13 and the chemical shift values are listed
in Table 6. Normally a large upfield chemical shift is expected as
the free pyridine N becomes protonated (about 80ꢀ100 ppm).24
A reason why there is no shift of the 15N nucleus despite a change
in the ionization state of the crystal structures of forms I and III is
explained by the RT crystal structure of polymorph III. The RT
structure of form III depicts an in-between proton situation of
neutral and ionic states. The LT structure is clearly zwitterionic.
Since ss-NMR spectra were recorded at room temperature, the
chemical environment of the pyridine N is more neutral-like than
ionic. An IR spectrum of the ss-NMR sample at the end of the
measurement confirmed that grinding of the solid for NMR sample
preparation had not caused any accidental phase transformation to
form I; form III was present after the NMR measurement.
II (8.6%) than that in form III (2.3%), whereas the contribution
from O H interactions follows the opposite trend (form III
3 3 3
20.6%, form II 14.6%, form I 14.4%).
What is the Role of Pyridine Coformers in Giving a
Zwitterionic Structure of TNA? Our observation that zwitter-
ionic form III could be obtained only in the presence of pyridine-
type coformers is not an isolated occurrence. Several cases are
reported in the literature23d,26 wherein a new polymorph was
discovered during attempted cocrystallization. Even so, this is the
first instance of a zwitterionic polymorph being crystallized in the
presence of coformer additives. Despite the frequent occurrence
of such reports, a plausible explanation for this phenomenon is
still elusive. The crystallization of a salt structure with o-amino-
pyridine wherein TNA exists as a carboxylate anion and AP is a
pyridinium cation could offer an explanation, at least in this
instance. The similarity of the pKa of pyridine base, whether the
moiety is present in TNA or AP, suggested that there could be a
dynamic equilibrium between several species in solution
(Scheme 4), a few neutral ones and others ionic. Depending
on the solvent of cocrystallization, temperature, coformer, ad-
ditive, supersaturation, etc., the concentration of the neutral
adduct, salt, and zwitterion will vary depending on the solubility
of that species in the crystallization medium. The species that is
13C ss-NMR spectra of forms I and III exhibit almost identical
chemical shift values, since they are 2D isostructural, whereas
form II peaks are clearly different (Figure 14 and Table 7).
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Crystal Growth & Design
ARTICLE
Figure 10. (a) 2D supramolecular construct identified by XPac analysis of TNA forms I and III. Molecules in different layers are shaded differently.
(b) Plot of interplanar angular deviation (δp, x-axis) vs angular deviation (δa, y-axis) in degrees.
Figure 11. DSC thermograms of form I (red), form II (black), and form III (blue) of TNA. The endotherms are sharp and the Tpeak values are barely
1 ꢀC apart.
the most supersaturated in a given solvent will precipitate first
and the product of such a cocrystallization experiment will
strongly depend upon the supersaturation conditions and, con-
sequently, on crystallization parameters such as solvent, tem-
perature, concentration, rate of cooling, etc. Because solvent
selection in cocrystallization experiments is usually a trial-and-
error process, by testing the solubility of the components in
different solvents and mixtures, the outcome is often a serendi-
pitous result when a new polymorph of one of the components is
discovered. A possible pathway to zwitterionic polymorph III
under cocrystallization conditions is depicted in Scheme 4.
Could a general recipe to obtain the zwitterionic polymorphs
of acidꢀbase compounds be optimized by using coformers
whose acidic/basic functional groups are of a similar pKa to that
of the molecule? Those solvents in which the ionic form is likely
to supersaturate should be preferable for crystallization. The
selective crystallization of zwitterionic polymorphs for acidꢀbase
drugs will have an immediate application for solubility improve-
ment. Experiments are currently under way to establish a general
protocol along these lines. The design parameters will best
operate in the gray zone of ΔpKa between 0 and 3 when there
is dynamic proton equilibrium between the acid and the base.
When ΔpKa < 0 or > 3, the outcome is a predictable neutral
cocrystal or ionic salt.
’ CONCLUSIONS
TNA is as the third example of a polymorphic molecule
exhibiting neutral and zwitterionic crystal structures with 3D
coordinates determined after clonixin and norfloxacin. Anthra-
nilic acid and torasemide are in a different category in that both
neutral and zwitterionic molecules are present in the same crystal
structure. Crystallization of the zwitterionic polymorph III of
TNA was observed only in the presence of pyridine coformers,
more often with o-bromo-m-hydroxypyridine. Interestingly, a
zwitterionic two-component structure of TNA cocrystallized
with m-nitrobenzoic acid and a salt with o-aminopyridine. These
preliminary observations suggest a role for the coformer in
directing the crystallization toward a polymorph, a cocrystal, or
a salt. Even though zwitterionic structures of acidꢀbase organic
molecules are known, the occurrence of both neutral and
zwitterionic polymorphs for the same compound is as such rare.
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Crystal Growth & Design
ARTICLE
Figure 12. FT-IR comparison of TNA forms IꢀIII.
Table 5. FT-IR (KBr pallet) Spectral Bands of TNA
Polymorphs
Table 6. 15N ss-NMR Chemical Shifts (δ, ppm) of TNA
Polymorphs
OꢀH
stretch
polymorph (br) (cmꢀ1
NꢀH
stretch
(br) (cmꢀ1
CdO
pyridine
polymorph
pyridine N
2ꢀ amine N
stretch
ring stretch
(cmꢀ1
)
form I
ꢀ147.6
ꢀ143.0
ꢀ146.8
ꢀ280.5
ꢀ280.0
ꢀ280.3
)
)
(cmꢀ1
)
form II
form III
form I
3467.3
3464.9
3428.0
3263.1
3249.1
3259.4
1663.3
1602, 1579.4,
1518, 1459
form II
form III
1658.7
1635.0
1602, 1578,
1518, 1459
1604, 1564, 1514
Figure 14. 13C ss-NMR of TNA forms IꢀIII.
Figure 13. 15N ss-NMR for TNA forms IꢀIII.
Synthesis. TNA was synthesized27 by refluxing o-chloronicotinic
acid (315.3 mg, 2 mmol), p-toluidine (214.3 mg, 2 mmol), p-toluene-
sulfonic acid (95.0 mg, 0.5 mmol), and few drops of pyridine in water
and acetone solution (1:4, 10 mL) at 70 ꢀC overnight (about 8 h)
(Scheme 5). The precipitated product was filtered and purified by
crystallization from acetone to obtain pure 2-(p-tolylamino)nicotinic
acid (TNA), which was characterized by 1H NMR, 13C NMR, and IR. 1H
NMR (CDCl3, 400 MHz): δ 9.99 (s, 1H), 8.40 (d, J = 8 Hz, 1H), 8.31
(d, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7.19 (d, J = 8 Hz, 2H), 6.72 (d,
Studies are ongoing to optimize the crystallization of zwitterionic
polymorphs for (aminophenyl)nicotinic acids.
’ EXPERIMENTAL SECTION
General. All solvents, reagents, and coformers were purchased from
commercial sources and used without further purification.
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Crystal Growth & Design
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J = 8 Hz, 2H), 2.33 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 171.35,
156.68, 153.50, 141.53, 136.39, 133.46, 129.51, 122.25, 113.05, 20.90. IR
(KBr, cmꢀ1): 3441.2, 3254.2, 3068.4, 1669.3, 1602.2, 1579.4, 1517.6,
1459.3, 1412.6, 1248.9, 1143.3, 795.5. Mp: 205ꢀ207 ꢀC.
“polymorph”, “modification”, and “phase” in the qualifier, excluding the
entries for which 3D coordinates are not available. These searches
resulted in only four zwitterionic and neutral polymorphic sets for single
component organic molecules with solved X-ray crystal structures.
X-ray Crystallography. X-ray reflections for TNA forms I and III
CSD Search. A search of the CSD (version 5.31, November 2010;
May 2011 update)4 was performed using the following functional groups
as search criteria (Table 8), all organic compounds with the word “form”,
(LT data) and APꢀNH+ TNAꢀCOOꢀ salt were collected on a Bruker
3
SMART APEX CCD diffractometer equipped with a graphite mono-
chromator and Mo Kα fine-focus sealed tube (λ = 0.710 73 Å). Data
integration was done using SAINT.28 Intensities for absorption were
corrected using SADABS.29 Structure solution and refinement were
carried out using Bruker SHELX-TL.30 X-ray reflections for TNA forms
Table 7. 13C ss-NMR Chemical Shifts (δ, ppm) of TNA
Polymorphs
II and III (RT data) and NꢀH+ꢀTNAꢀCOOꢀ 2NBA were collected
3
on an Oxford Xcalibur Gemini Eos CCD diffractometer using Mo Kα,
radiation. Data reduction was performed using CrysAlisPro (version
1.171.33.55). OLEX2-1.031 and SHELX-TL 97 were used to solve and
refine the data. All non-hydrogen atoms were refined anisotropically,
numbering in the above structure
form I
form II
18.7
form III
18.7
C13
C2
18.6
108.2
112.0
108.0 108.3
111.1 112.1
C4
C8, C12
C10
C9, C11
C3
128.1 (merged) 124.9 128.2 (merged)
127.1
134.3
136.2
143.5
150.4
157.1
167.5
129.3 134.3
134.2 136.4
142.0 143.6
151.6 150.6
156.2 157.2
167.6 167.6
C7
C5
C6
Figure 16. Contribution from major interactions to the Hirshfeld
surface.
C1
Figure 15. 2D Hirshfeld fingerprint plot for three TNA polymorphs, forms IꢀIII. Note that the O H and N H plots are different for polymorphs I
3 3 3
3 3 3
and III. The sharp blue spikes occur in the N H plot for form I but in the O H plot for form III.
3 3 3 3 3 3
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Crystal Growth & Design
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Scheme 4. Equilibrium Between Soluble and Supersaturated Components, TNA and AP, in CH3CN Solventa
a This kind of equilibrium situation will most probably be present in solution when 0 < ΔpKa < 3.
Scheme 5. Synthesis of 2(p-Tolylamino)nicotinic Acid
(TNA)
sample pans. The typical sample size was 3ꢀ4 mg, and the temperature
range was 30ꢀ250 ꢀC at heating rate of 5 ꢀC/min. Samples were purged
by a stream of dry nitrogen flowing at 150 mL/min.
’ ASSOCIATED CONTENT
S
Supporting Information. Additional information as
b
noted in the text. This material is available free of charge via
the Internet at http://pubs.acs.org.
Table 8. Functional Groups Used To Search the CSD and the
Number of Hits Retrieved
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: ashwini.nangia@gmail.com.
substructure
no. of hits
substructures
no. of hits
N and COOH
N and SO3H
N and PO4H
N and OH
411
10
NH+ and COOꢀ
407
118
31
NH+ and SO3ꢀ
ꢀ
’ ACKNOWLEDGMENT
31
NH+ and PO4
This research was funded by the DST (SR/S1/OC-67/2006),
CSIR (01-2410/10/EMR-II), a JC Bose Fellowship (SR/S2/
JCB-06/2009), and UGC (PURSE grant). N.K.N. and S.S.K.
thank the UGC and CSIR for fellowships.
1276
166
NH+ and Oꢀ
NH+ and (NHꢀ)C(dO)N
807
3
N and NC(dO)N
and CꢀH hydrogens were fixed. NꢀH and OꢀH hydrogens were
located from difference electron density maps and CꢀH hydrogens
were fixed. Packing diagrams were prepared in X-Seed.32 Crystallo-
graphic .cif files (CCDC Nos. 833063ꢀ833068) are available at www.
ccdc.cam.ac.uk/data_request/cif or as part of the Supporting Informa-
tion.
Vibrational Spectroscopy. Nicolet 6700 FT-IR spectrometer
with an NXR FT-Raman module was used to record IR and Raman
spectra. IR spectra were recorded on samples dispersed in KBr pellets.
Raman spectra were recorded on solid samples contained in standard
NMR diameter tubes or on compressed samples contained in a gold-
coated sample holder.
ss-NMR Spectroscopy. Solid-state NMR spectra were recorded
on a Bruker Avance spectrometer at 400 MHz. ss-NMR spectra were
recorded on a Bruker 4 mm double-resonance 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
’ REFERENCES
(1) Lehninger, A. L.; Nelson, D. L.; Cox, M. M. Principles of
Biochemistry, 2nd ed.; Worth Publishers; New York, 1993; pp 81ꢀ83.
(2) (a) Tam, K. Y.; Avdeef, A.; Tsinman, O.; Sun, N. J. Med. Chem.
2010, 53, 392. (b) Ranney, D. F. Biochem. Pharmacol. 2000, 59, 105.
(c) Marcus, S.; Bernstein, M.; Ziv, G.; Glickman, A.; Gipps, M. Vet. Res.
Commun. 1994, 18, 331.
(3) Tong, W.-Q. In Developing Solid Oral Dosage Forms. Pharmaceu-
tical Theory and Practice; Qiu, Y., Chen, Y., Zhang, G. G. Z., Eds.;
Academic Press: New York, 2009; pp 75ꢀ86.
(4) Cambridge Structural Database, ver. 5.31, ConQuest 1.13,
November 2010 release, Cambridge Crystallographic Data Center;
www.ccdc.cam.ac.uk.
(5) Takasuka, M.; Nakai, H.; Shiro, M. J. Chem. Soc., Perkin Trans. 2
1982, 1061(BIXGIY01, BIXGIY02, BIXGIY03, BIXGIY04).
(6) (a) Basavoju, S.; Bostrom, D.; Velaga, S. P. Cryst. Growth Des.
2006, 6, 2699 (VETVOG). (b) Barbas, R.; Prohens, R.; Puigjaner, C.
J. Thermal Anal. Calorim. 2007, 89, 687 (VETVOG01).
(7) (a) Khan, M. Y.; Srivastava, P. Indian J. Pure Appl. Phys. 1968,
6, 166 (AMBACO). (b) Brown, C. J. Proc. R. Soc. London, Ser. A 1968,
302, 185 (AMBACO01, AMBACO02). (c) Boone, C. D. G.; Derissen,
J. L.; Schoone, J. C. Acta Crystallogr. 1977, B33, 3205(AMBACO03).
(d) Murti, K. Indian J. Phys. 1957, 31, 611(AMBACO04). (e) Hardy,
G. E.; Kaska, W. C.; Chandra, B. P.; Zink, J. I. J. Am. Chem. Soc. 1981,
then the chemical shifts were recalculated to the TMS scale (δglycine
=
43.3 ppm). Likewise, 15N CP-MAS spectra recorded at 40 MHz were
referenced to glycine N and then the chemical shifts were recalculated to
nitromethane (δglycine = ꢀ347.6 ppm).
Thermal Analysis. DSC was performed on Mettler Toledo DSC
822e module. Samples were placed in crimped but vented aluminum
4604
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Crystal Growth & Design
ARTICLE
103, 1074 (AMBACO05, AMBACO06). (f) Brown, C. J.; Ehrenberg, M.
Acta Crystallogr. 1985, C41, 441 (AMBACO07). (g) Takazawa, H.;
Ohba, S.; Saito, Y. Acta Crystallogr. 1986, C42, 1880 (AMBACO08). (h)
Lu, T. H.; Chattopadhyay, P.; Liao, F. L.; Lo, J. M. Anal. Sci. 2001,
17, 905 (AMBACO09).
(8) (a) Dupont, L.; Dive, G. Bull. Soc. R. Sci. Liege 1982, 51, 248
(TORESEM02). (b) Bartolucci, G.; Bruni, B.; Coran, S. A.; Vaira, M. D.
Acta Crystallogr. 2009, E65, o972 (TORESEM04).
(22) (a) Gelbrich, T.; Hursthouse, M. B. CrystEngComm 2005,
7, 324. (b) Gelbrich, T.; Hursthouse, M. B. CrystEngComm 2006,
8, 448. (c) Gelbrich, T.; Hughes, D. S.; Hursthouse, M. B.; Threlfall,
T. L. CrystEngComm 2008, 10, 1328. (d) Fabbiani, F. P. A.; Dittrich, B.;
Florence, A. J.; Gelbrich, T.; Hursthouse, M. B.; Kuhs, W. F.; Shankland,
N.; Sowa, H. CrystEngComm 2009, 11, 1396.
(23) (a) Bugay, D. E. Pharm. Res. 1993, 10, 317. (b) Heider, E. M.;
Harperb, J. K.; Grant, D. M. Phys. Chem. Chem. Phys. 2007, 9, 6083.
(c) Vickery, R. D.; Nemeth, G. A.; Maurin, M. B. J. Pharm. Biomed. Anal.
2002, 30, 125. (d) Sanphui, P.; Goud, N. R.; Khandavilli, U. B. R.;
Bhanothb, S.; Nangia, A. Chem. Commun. 2011, 5013.
(9) Thomas, M. J.; Thomas, J. A. In Modern Pharmacology with
Clinical Applications, 5th ed.; Craig, C. R., Stitzel, R. E., Eds.; Little Brown
& Co.: Boston, 1997.
(10) (a) Lee, E. H; Byrn, S. R.; Carvajal, M. T. Pharm. Res. 2006,
23, 2375. (b) McConnell, J. F.; Company, F. Z. Cryst. Struct. Commun.
1976, 5, 861. (c) Fang, L.; Numajiri, S.; Kobayashi, D.; Ueda, H.;
Nakayama, K.; Miyamae, H.; Morimoto, Y. J. Pharm. Sci. 2004, 93, 144.
(d) Andersen, K. V; Larsen, S.; Alhede, B.; Gelting, N.; Buchardt, O. J.
Chem. Soc., Perkin Trans. 2 1989, 1443. (e) Lopez-Mejias, V.; Kampf,
J. W.; Matzger, A. J. J. Am. Chem. Soc. 2009, 131, 4554. (f) Surov, A. O.;
Szterner, P.; Zielenkiewicz, W.; Perlovich, G. L. J. Pharm. Biomed. Anal.
2009, 50, 831. (g) McConnell, J. F. Cryst. Struct. Commun. 1973, 2, 459.
(h) Murthy, M. H. K.; Bhat, T. N.; Vijayan, M. Acta Crystallogr. 1982,
B38, 315. (i) Lee, E. H.; Boerrigter, S. X. M; Rumondor, A. C. F.;
Chamarthy, S. P.; Byrn, S. R. Cryst. Growth Des. 2008, 8, 91. (j) Eun Hee
Lee, E. H.; Boerrigter, S. X. M.; Byrn, S. R. Cryst. Growth Des. 2010,
10, 518. (k) Moser, P.; Sallmann, A.; Wiesenberg, I. J. Med. Chem. 1990,
33, 2358. (m) Demertzi, D. K.; Mentzafos, D.; Terzis, A. Polyhedron 1993,
12, 1361. (n) Castellari, C.; Ottani, S. Acta Crystallogr. 1997, C53, 794.
(o) Jaiboon, N.; Yos-In, K.; Ruangchaithaweesuk, S.; Chaichit, N.;
Thutivoranath, R.; Siritaedmukul, K.; Hannongbua, S. Anal. Sci. 2001,
17, 1465. (p) Muangsin, N.; Prajuabsook, M.; Chimsook, P.; Chantarasiri,
N.; Siraleartmukul, K.; Chaichit, N.; Hannongbua, S. J. Appl. Crystallogr.
2004, 37, 288. (q) Perlovich, G. L.; Surov, A. O.; Hansen, L. K.; Brandl,
A. B. J. Pharm. Sci. 2007, 96, 1031. (r) Surov, A. O.; Terekhova, I. V.;
Bauer-Brandl, A.; Perlovich, G. L. Cryst. Growth Des. 2009, 9, 3265.
(11) (a) Long., S.; Parkin, S.; Siegler, M. A.; Cammers, A.; Li, T.
Cryst. Growth Des. 2008, 8, 4006. (b) Long, S.; Li, T. Cryst. Growth Des.
2009, 9, 4993. (c) Long, S.; Li, T. Cryst. Growth Des. 2010, 10, 2465.
(d) Long, S.; Parkin, S.; Siegler, M.; Brock, C. P.; Cammers, A.; Li, T.
Cryst. Growth Des. 2008, 8, 3137. (e) Long, S.; Siegler, M. A.; Mattei, A.;
Li, T. Cryst. Growth Des. 2011, 11, 414.
(24) (a) Lorente, P.; Shenderovich, I. G.; Golubev, N. S.; Denisov,
G. S.; Buntkowsky, G.; Limbach, H. H. Magn. Reson. Chem. 2001,
39, S18. (b) Li, Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.; Medek, A.;
Trask, A. V. J. Am. Chem. Soc. 2006, 128, 8199.
(25) (a) Spackman, M. A.; Jayatilaka, D. CrystEngComm 2009,
11, 19. (b) McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Chem.
Commun. 2007, 3814.
(26) (a) Nath, N. K.; Nangia, A. CrystEngComm 2011, 13, 47.
(b) Day, G. M.; Trask, A. V.; Motherwell, W. D. S.; Jones, W. Chem.
Commun. 2006, 54. (c) Rafilovich, M.; Bernstein, J. J. Am. Chem. Soc.
2006, 128, 12185. (d) Vishweshwar, P.; McMahon, J. A.; Oliveira, M.;
Peterson, M. L.; Zaworotko, M. J. J. Am. Chem. Soc. 2005, 127, 16802.
(e) Bond, A. D.; Solanko, K. A.; Parsons, S.; Redder, S.; Boese, R.
CrystEngComm 2011, 13, 399. (f) Wenger, M.; Bernstein, J. Mol.
Pharmaceutics 2007, 4, 355. (g) Lou, B.; Bostr€om, D.; Velaga, S. P.
Cryst. Growth Des. 2009, 9, 1254. (h) Mei, X.; Wolf, C. Cryst. Growth Des.
2004, 4, 1099. (i) Thomas, L. H.; Wales, C.; Zhao, L.; Wilson, C. C.
Crystal Growth Des. 2011, 11, 1450. (j) Losev, E. A.; Mikhailenko, M. A.;
Boldyreva, E. V. Proc. RAS, Ser. Phys. Chem. 2011, 439 (6), 1.
(27) Ting, P. C.; Kaminski, J. J.; Sherlock, M. H.; Tom, W. C.; Lee,
J. F.; Bryant, R. W.; Watnick, A. S.; McPhail, A. T. J. Med. Chem. 1990,
33, 2697.
(28) SAINT-Plus, version 6.45; Bruker AXS Inc., Madison, WI, 2003.
(29) Sheldrick, G. M. SADABS, Program for Empirical Absorption
Correction of Area Detector Data; University of G€ottingen, Germany,
1997.
(30) (a) SMART (Version 5.625) and SHELX-TL (Version 6.12);
Bruker AXS Inc., Madison, WI, 2000. (b) Sheldrick, G. M. SHELXS-97
and SHELXL-97; University of G€ottingen, Germany, 1997.
(31) Dolomanov, O. V.; Blake, A. J.; Champness, N. R.; Schr€oder, M.
J. Appl. Crystallogr. 2003, 36, 1283.
(12) Sarma, B.; Nath, N. K.; Bhogala, B. R.; Nangia, A. Cryst. Growth
Des. 2009, 9, 1546.
(13) (a) Johnson, S. L.; Rumon, K. A. J. Phys. Chem. 1965, 69, 74.
(b) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4, 323.
(c) Sarma, B.; Thakuria, R.; Nath, N. K.; Nangia, A. CrystEngComm
2011, 13, 3232.
(32) Barbour, L. J. X-Seed, Graphical Interface to SHELX-97 and
POV-Ray; University of Missouri—Columbia, 1999.
(14) (a) Lide, D. R. CRC Handbook of Chemistry & Physics, 86th ed.;
CRC Press: Boca Raton, FL, 2004; pp 42ꢀ51, Chapter 8. (b) Linnell,
R. H. J. Org. Chem. 1960, 25, 290.
(15) Nangia, A. Acc. Chem. Res. 2008, 41, 595.
(16) Sanphui, P.; Sarma, B.; Nangia, A. J. Pharm. Sci. 2011, 100, 2287.
(17) Day, G. M.; Cooper, T. G.; Cruz-Cabeza, A. J.; Hejczyk, K. E.;
Ammon, H. L.; Boerrigter, S. X. M.; Tan, J. S.; Della Valle, R. G.; Venuti,
E.; Jose, J.; Gadre, S. R.; Desiraju, G. R.; Thakur, T. S.; van Eijck, B. P.;
Facelli, J. C.; Bazterra, V. E.; Ferraro, M. B.; Hofmann, D. W. M.;
Neumann, M. A.; Leusen, F. J. J.; Kendrick, J.; Price, S. L.; Misquitta,
A. J.; Karamertzanis, P. G.; Welch, G. W. A.; Scheraga, H. A.; Arnautova,
Y. A.; Schmidt, M. U.; van de Streek, J.; Wolf, A. K.; Schweizer, B. Acta
Crystallogr. 2009, B65, 107.
(18) (a) Neumann, M. A.; Leusen, F. J. J.; Kendrick, J. Angew. Chem.,
Int. Ed. 2008, 47, 2427. (b) Thakur, T. S.; Desiraju, G. R. Cryst. Growth
Des. 2008, 8, 4031.
(19) (a) Leusen, F. J. J. Cryst. Growth Des. 2003, 3, 189.
(b) Karamertzanis, P. G.; Price, S. L. J. Phys. Chem. B 2005, 109, 17134.
(20) Aaker€oy, C. B.; Rajbanshi, A.; Li, Z. J.; Desper, J. CrystEngComm
2010, 12, 423.
(21) SPARTAN 10, Full Range of Computational Chemistry Software;
Wavefunction Inc.; www.wavefun.com.
4605
dx.doi.org/10.1021/cg200853u |Cryst. Growth Des. 2011, 11, 4594–4605