Multiple crystal forms of p-aminosalicylic acid: Salts, salt co-crystal hydrate, co-crystals, and co-crystal polymorphs

Article abstract of DOI:10.1021/cg3015332

Crystallization of p-aminosalicylic acid, an anti-tuberculosis drug, in the presence of pyridine derivatives as coformers led to formation of nine multicomponent solids that include salts, a salt co-crystal hydrate, co-crystals, and co-crystal polymorphs.

Full text of DOI:10.1021/cg3015332

Article
pubs.acs.org/crystal
Multiple Crystal Forms of p‑Aminosalicylic Acid: Salts, Salt Co-Crystal
Hydrate, Co-Crystals, and Co-Crystal Polymorphs
Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju
Pramod Kumar Goswami,† Ram Thaimattam,*,‡ and Arunachalam Ramanan*,†
†Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi-110016, India
‡Ranbaxy Laboratories Ltd., Chemical Research, Plot-20, Sector-18, Udyog Vihar Industrial Area, Gurgaon-122015 (Haryana), India
S
* Supporting Information
ABSTRACT: Crystallization of p-aminosalicylic acid, an anti-
tuberculosis drug, in the presence of pyridine derivatives as
coformers led to formation of nine multicomponent solids that
include salts, a salt co-crystal hydrate, co-crystals, and co-crystal
polymorphs. Seven of them are new solid forms. The influence
of the COOH···Nheterocycle synthon is examined in dictating the
various crystal forms, the manifestation of which depends on
solvent of crystallization and API-coformer composition in
solution.
us to further explore the structural landscape of the PAS-
pyridine/bpy derivative system. Therefore, co-crystal formation
of PAS with bpy, 4-amino pyridine (pap), 3-hydroxy pyridine
(mhp), 1,2-bis(4-pyridyl)ethane (bpe), and 1,2-bis(4-pyridyl)-
ethylene (bpee) were explored. In this paper, we describe 2:1
co-crystal of PAS and bpy (1), 2:3 co-crystal of PAS and bpy
(2), 1:2 salt co-crystal monohydrate of PAS and bpy (2a), 1:1
salts of PAS and pap (3), and PAS and mhp (4), 2:1 salt of PAS
and bpe (5), two polymorphs of 1:1 co-crystal of PAS and bpe
(6 and 6a), and 1:1 co-crystal of PAS and bpee (7).
INTRODUCTION
■
Active pharmaceutical ingredient (API) co-crystals have
demonstrated the ability to modify physicochemical properties
of the APIs.1 p-Aminosalicylic acid (PAS) is a well-known
antibiotic in tuberculosis (TB) treatment and also a promising
anticancer drug.2 Recently, there is a renewed interest in
obtaining the multicomponent crystals based on this molecule
to explore its solid state chemistry.3 PAS is also a potential
ligand in the context of coordination polymers with multi-
dentating functionality to stabilize metal ions in solution, and
along with bridging ligands such as like 4,4′-bipyridine (bpy) or
its analogues, it can lead to multidimensional extended
structures.4 PAS is one of the components of the anti-TB
combination drug used in second-line therapy. Recently PAS is
reported to form an unexpected salt co-crystal with bpy and
interesting drug-drug co-crystals with other anti-TB drugs,
isoniazid and pyrazinamide, used in first-line treatment to
prevent multiple drug-resistant TB.2,5,6a The reported crystal
structure of PAS with bpy is quite unusual in that both charged
and neutral bpy species are present in the same crystal.5a There
is a single hydrogen bond, COOH···Nheterocycle synthon,6b
between PAS and bpy that is distinct from the commonly found
two-point hydrogen bonded COOH···Nheterocycle interaction
wherein the interacting moieties are in the same plane. The
COOH···Nheterocycle synthon is also found to be the driving
force for the formation of PAS-isoniazid and PAS-pyrazinamide
drug-drug co-crystals.6a A 2:1 PAS/bpy salt/co-crystal involving
PAS···bpy···PAS trimer connected by COOH···Nheterocycle is
generally expected if they are co-crystallized. For instance, this
is demonstrated in ibuprofen-bpy co-crystals.7 This prompted
EXPERIMENTAL SECTION
■
All reagents and solvents were used as received from commercial
suppliers without further purification. All nine of the solid forms were
obtained by slow evaporation of acetone or acetone-MeOH mixtures.
The solutions were prepared by dissolving the components in the
solvent or solvent mixture, or by slowly adding a clear solution of the
coformer to the API solution. Stoichiometry of the components in the
solution had an effect on the outcome (Table 3).
Synthesis of PAS·(bpy)0.5, 1. PAS (0.65 mmol, Merck 99%) was
dissolved in 7 mL of acetone (Merck 99%) followed by the addition of
4 mL of solution of bpy (0.32 mmol, Merck 99%). The resulting
yellow color solution was stirred and kept at room temperature for
crystallization. Yellow plate shaped crystals of 1 after 4−5 days in
about 85% yield (based on PAS) were filtered and dried in desiccators.
Elem. Anal. (%) Calcd for 1: C, 62.06; H, 5.21; N, 12.06. Found: C,
62.41; H, 4.73; N, 12.18. IR (cm−1): 3460 (s), 3366 (s), 3233 (s),
Received: October 18, 2012
Revised: November 14, 2012
© XXXX American Chemical Society
A
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1633 (s), 1576 (s), 1506 (m), 1413 (m), 1370 (m), 1330 (w), 1253
(s), 1146 (s), 1060 (s), 1003 (m), 966 (s), 830 (w), 780 (s).
Synthesis of PAS·(bpy)1.5, 2. Solution of PAS (0.32 mmol) was
prepared in 10 mL of acetone. To the above solution bpy (0.65 mmol)
was added slowly. The resulting solution was stirred and kept at room
temperature for crystallization. Plate shaped yellow crystals of 2 in
about 80% yield (based on PAS) were obtained after 3 days. Elem.
Anal. (%) Calcd for 2: C, 68.03; H, 5.19; N, 14.12. Found: C, 67.89;
H, 4.84; N, 14.35. IR (cm−1): 3333 (s), 3213 (s), 1643 (s), 1583 (s),
1396 (s), 1333 (m), 1213 (s), 1156 (m), 1056 (s), 963 (m), 836 (s),
796 (s).
Synthesis of PAS·pap, 3. To a 5 mL solution of PAS (0.65 mmol)
in acetone was added a solution of pap (0.65 mmol, Merck 99%) in 5
mL. Yellow plate shaped crystals of 3 in about 75% yield (based on
PAS) collected after 5 days of slow evaporation under ambient
conditions. Elem. Anal. (%) Calcd for 3: C, 58.29; H, 5.30; N, 16.99.
Found: C, 57.26; H, 5.37; N, 17.18. IR (cm−1): 3433 (s), 3321 (s),
3219 (s), 1644 (s), 1525 (m), 1506 (m), 1435 (s), 1358 (m), 1196
(s), 1155 (m), 990 (m), 819 (s), 778 (m), 702 (m).
Synthesis of PAS·mhp, 4. Five milliliters of acetone solution of
mhp (0.65 mmol, Merck 99%) was mixed to 7 mL acetone solution of
PAS (0.65 mmol), and the light yellow clear colored solution was kept
for slow evaporation at room temperature. Yellow colored plate
shaped crystals in about 85% yield (based on PAS) were obtained after
5 days. Elem. Anal. (%) Calcd for 4: C, 58.06; H, 4.87; N, 11.29.
Found: C, 58.08; H, 4.84; N, 11.62. IR (cm−1): 3413 (m), 3340(m),
3220 (m), 1630 (w), 1575 (s), 1503 (s), 1433 (m), 1361 (s), 1277 (s),
1157 (s), 1096 (w), 963 (w), 830 (m), 699 (m).
Synthesis of PAS·(bpe)0.5, 5. A solution of PAS (0.65 mmol) was
prepared in 10 mL of acetone. Five milliliters of acetone solution of
bpe (0.32 mmol, Merck 99%) was added to the above solution. The
resulting solution was stirred and kept at room temperature for
crystallization. Needle shaped yellow crystals of 5 in about 80% yield
(based on PAS) were obtained after 7 days. Elem. Anal. (%) Calcd for
5: C, 63.66; H, 5.34; N, 11.42. Found: C, 64.16; H, 5.27; N, 11.99. IR
(cm−1): 3400 (s), 3340 (s), 3240 (s), 1630 (s), 1581 (s), 1305 (m),
1276 (s), 1150 (s), 1090 (w), 782 (m).
geometrically calculated positions and refined as riding atoms. O−H
and N−H hydrogen atoms were located from difference Fourier maps
and refined isotropically. Images were created with the Diamond
program.11 Hydrogen bonding interactions in the crystal lattice were
calculated with SHELXTL. Crystal and refinement data are
summarized in Tables 1 and 2.
Table 1. Crystal Data and Structural Refinements for 1, 2,
and 3
parameter
formula
1
2
3
PAS·(bpy)0.5
462.46
PAS·(bpy)1.5
774.82
PAS·pap
247.25
150(2)
0.71073
orthorhombic
Pbca
formula wt, g mol−1
T (K)
150(2)
0.71073
monoclinic
P21/c
150(2)
wavelength (Å)
crystal system
space group
a (Å)
0.71073
triclinic
P1
̅
5.418(3)
8.764(5)
23.315(13)
90.00
8.191(3)
10.755(3)
11.897(4)
74.000(6)
84.991(6)
76.519(6)
979.5(5)
1
13.397(4)
12.547(4)
13.879(4)
90.00
b (Å)
c (Å)
α (°)
β (°)
γ (°)
V (Å3)
91.321(11)
90.00
90.00
90.00
1106.7(1)
2
2333.2(6)
8
Z
dcalc (g cm−3
)
1.388
1.314
1.408
μMoKα (cm−1
)
0.102
0.090
0.104
Rint
0.0494
0.0352
0.0522
0.0638
0.1281
1.256
R1 (I > 2σI)
wR2 (all)
GOF
0.0967
0.1021
0.1971
0.2043
1.248
1.232
CCDC no.
905631
905632
905634
Synthesis of PAS·bpe, 6. PAS (0.65 mmol) was dissolved in 7 mL
of acetone and to this solution 5 mL acetone solution of bpe (0.97
mmol) was mixed slowly. The solution was kept at room temperature
for crystallization. Plate shaped crystals of 6 in about 70% yield (based
on PAS) were obtained after 5 days. Elem. Anal. (%) Calcd for 6: C,
67.64; H, 5.68; N, 12.46. Found: C, 68.20; H, 5.79; N, 13.09. IR
(cm−1): 3460 (s), 3313 (s), 3166 (s), 2980 (m), 1633 (m), 1597 (s),
1503 (s), 1414 (s), 1335 (m), 1193 (s), 1151 (m), 1033 (s), 993 (w),
820 (s).
Synthesis of PAS·bpe, 6a. Seven milliliter acetone solution of
PAS (0.65 mmol) was mixed slowly with 4 mL acetone solution of bpe
(0.65 mmol). Plate shaped crystals of 6a in about 90% yield (based on
PAS) were obtained at room temperature after 3 days. Elem. Anal. (%)
Calcd for 6a: C, 67.64; H, 5.68; N, 12.46. Found: C, 68.32; H, 5.81; N,
13.16. IR (cm−1): 3465 (s), 3387 (s), 3304 (s), 3194 (s), 2928 (m),
1640 (s), 1511 (s), 1420 (m), 1387 (m), 1294 (s), 1228 (m), 1195
(m), 1157 (m), 1040 (s), 829 (s).
Synthesis of PAS·bpee, 7. PAS (0.65 mmol) was dissolved in 10
mL of acetone and to this solution 4 mL acetone solution of bpee (0.65
mmol) was mixed slowly .The solution was stirred and kept at room
temperature for crystallization. Plate shaped crystals of 7 were
obtained after 2 days. IR (cm−1): 3426 (m), 3306 (m), 3146 (m),
3033 (m), 2973 (m), 1633 (m), 1595 (s), 1415 (s), 1250 (s), 1195
(w), 1140 (m), 997 (m), 824 (s).
Table 2. Crystal Data and Structural Refinements for 4, 5, 6,
and 7
parameter
formula
4
5
6
7
PAS·mhp
PAS·(bpe)0.5
PAS·bpe
PAS·bpee
formula
weight, g
mol−1
248.24
490.51
337.37
335.36
T (K)
150(2)
150(2)
150(2)
150(2)
wavelength
(Å)
0.71073
0.71073
0.71073
0.71073
crystal system orthorhombic
monoclinic
P21/n
monoclinic
P21/n
triclinic
space group
a (Å)
Pca21
P1
̅
12.951(4)
5.1138(15)
17.068(5)
90.00
7.949(3)
11.747(4)
12.875(3)
90.00
11.196(3)
8.041(2)
19.179(6)
90.00
6.2977
9.1148
15.243
72.801
84.100
77.889
816.5
2
b (Å)
c (Å)
α (°)
β (°)
90.00
103.417(6)
90.00
96.644(6)
90.00
γ (°)
90.00
V (Å3)
1130.5(6)
4
1169.3(7)
2
1715.0(9)
4
Z
dcalc (g cm−3
μMoKα
)
1.459
1.395
1.307
1.364
0.094
X-ray Structure Determination. X-ray diffraction studies of
crystal mounted on a capillary were carried out on a BRUKER AXS
SMART-APEX diffractometer with a CCD area detector (Kα =
0.71073 Å, monochromator: graphite).8 Frames were collected at T =
150 K by ω, ϕ and 2θ-rotation at 10 s per frame with SAINT.9 The
measured intensities were reduced to F2 and corrected for absorption
with SADABS.9 Structure solution, refinement, and data output were
carried out with the SHELXTL program.10 Non-hydrogen atoms were
refined anisotropically. C−H hydrogen atoms were placed in
0.111
0.101
0.090
(cm−1
)
Rint
0.0418
0.0720
0.1507
1.291
0.0502
0.0572
0.1567
1.043
0.0867
0.0848
0.1865
1.098
0.0202
0.0363
0.0976
1.047
R1 (I > 2σI)
wR2 (all)
GOF
CCDC no.
905635
905636
905637
905639
B
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Other Physical Measurements. ATR-FTIR was recorded on a
Perkin-Elmer spectrum one spectrometer (Figure S1, Supporting
Information). Elemental analyses (C, H, N) were determined on
Perkin-Elmer 2400 series II C, H, N analyzer. DSC analysis was carried
out using Perkin−Elmer DSC system on well ground samples in
flowing nitrogen atmosphere with a heating rate of 5 °C/min. All the
solid forms of PAS show a single endothermic peak in DSC (Table 3
supramolecular aggregation (Figure 1). Location of the acidic
proton via Fourier map and further refinements is consistent
with the two C−O bond lengths of the neutral group in 1 and
2. In addition, in both cases, PAS···bpy···PAS trimer formed
between bpy and a pair of PAS molecules is responsible for the
formation of co-crystals (Figures 1 and 2). On closer
inspection, it became evident that the relative orientations of
the three interacting molecules in the trimer are different in 1
and 2, which are connected by COOH···Nheterocycle synthons I
and II respectively (Scheme 2). In other words, the aromatic
ring planes of interacting species are out of plane13 in 1 while
they are in plane14 in 2. Retrosynthesis of 1 and 2 showed how
the system judiciously engineers the compositional variation
through N−H···O interactions by adopting different kinds of
growth for the trimer observed in the two solids (Table 4). In
1, the trimers are interconnected by N−H···O, C−H···π
hydrogen bonds generating ribbons, which in turn are
interconnected via N−H···N hydrogen bonds generating layers
Table 3. Composition and Physical Properties of Salts/Co-
Crystals Based on PAS
composition in solution composition in
color and
morphology
m.p. (°C)
(from DSC)
(PAS:coformer)
solid
2:1
1:2
1:1
1:1
2:1
2:3
1:1
PAS·(bpy)0.5
PAS·(bpy)1.5
PAS·pap 3
PAS·mhp 4
PAS·(bpe)0.5
PAS·bpe 6
1
2
yellow, plate
yellow, plate
yellow, plate
yellow, plate
yellow, needle
yellow, plate
yellow, plate
157
162
167
122
142
145
140
5
PAS·bpe 6a
parallel to (104) planes that stack to generate the crystal
̅
structure stabilized by C−H···O and C−H···π interactions
(Figure 1). In 2, the additional two bpy molecules bridge the
trimers through synthon III to generate linear chains (Figure
2). The two bpy molecules in synthon III also interact with each
other via π···π interactions. The occurrence of bpy molecules in
this configuration is quite rare. A Cambridge Structural
Database (CSD) analysis revealed that synthon III does not
occur in any of the bpy based solids. The linear chains in 2 are
interconnected by C−H···O, C−H···N, and C−H···π inter-
and Figure S2, Supporting Information). Room-temperature powder
X-ray diffraction data were collected on a Bruker D8 Advance
diffractometer using Ni-filtered CuKα radiation. Data were collected
with a step size of 0.05° and at count time of 1 s per step over the
range 2° < 2θ < 60°. Rietveld powder diffraction analysis of all the
powders were carried out using TOPAS 4.2, Bruker for ensuring
homogeneity of the synthesized products.12
RESULTS AND DISCUSSION
■
actions generating layers parallel to (112) planes which stack to
̅
In this study, we explored the utility of the well-known
COOH···Nheterocycle synthon in crystallizing multiple forms of
the drug molecule, PAS with pyridine and bpy based coformers.
Crystallization was carried out at ambient conditions but with
different mole ratios of API to coformer in selected solvents.
We isolated several new solids (Scheme 1) based on PAS.
When PAS was reacted with bpy in acetone, we obtained two
new co-crystals 1 (2:1 PAS:bpy) and 2 (2:3 PAS:bpy), and a
known salt co-crystal hydrate, 2a (1:2:1 PAS:bpy:water)5b
depending on the mole ratio of PAS/bpy and solvent of
crystallization. Crystal structures of both 1 and 2 showed the
domination of COOH···Nheterocycle synthon in dictating the
complete the structure stabilized by C−H···O and C−H···π
interactions.
Reacting PAS with another coformer, pap yielded a 1:1 salt,
3. Here, as expected, PAS−−papH+ dimer is formed. In the
dimer the ions are connected by synthon IV (Figure 3). The
donor rich PAS−−papH+dimers close pack in the crystal
connected by N−H···π and several N−H···O and hydrogen
bonds. Reaction of PAS with mhp led to a 1:1 PAS−/mhpH+
salt, 4. Crystal structure of 4 also showed the occurrence of a
synthon IV based dimer. These dimers aggregate to form linear
chains connected by O−H···O hydrogen bonds involving the
pyridine OH group (Figure 4). The dimers are perpendicularly
oriented in the chain, and the chains closely pack to generate
bilayers parallel to the ab plane. The chains within the bilayer
are connected by N−H···O hydrogen bonds involving the
amino group. The bilayers are stacked along [001] connected
by N−H···O and C−H···O hydrogen bonds. We could not
identify any other forms for PAS−pap and PAS−mhp systems
by varying composition and solvent.
Scheme 1. Crystallization of Multiple Forms of the API, p-
Aminosalicylic Acid (PAS) with Different Coformers under
Varying API-Coformer Composition and Solvent of
Crystallization
We examined another coformer, bpe, which is a modification
of bpy with a larger spacing. Like bpy, the reaction resulted in
the crystallization of two solids with varying composition: a 2:1
salt 5 and a 1:1 co-crystal 6. The trimer in 5 was similar to the
one observed in 2 but with the proton located on the pyridine
N-atom. Thus the molecules are connected by synthon IV in
the trimer. However, these trimers do not self-assemble to form
any discernible H-bonded network structure. The discrete
trimers are stacked in an inclined manner along [001] as shown
in (Figure 5). Alternating stacks of these trimers, related by
about 90° rotation about [001], generate a bilayer parallel to
(220). These bilayers stack in such a way that the linear stacks
̅
of timers are close packed in a herringbone fashion. The inter-
and intra-bilayer interactions are stabilized by N−H···O and
C−H···π hydrogen bonds. The crystal structure of 6, that is, 1:1
C
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Crystal Growth & Design
Article
Figure 1. 2:1 Co-crystal of PAS and bpy (1). PAS···bpy···PAS trimers made of COOH···Nheterocycle synthon I occur as ribbons. The aromatic ring
planes of the interacting molecules in the trimers are out of plane. The trimers from each ribbon are oriented at angles and interact with each other
through N−H···O involving the hydroxyl group PAS. In this and in the subsequent figures, the C-atoms of coformers are rendered green. H-bonds
are shown in dashed lines and the H-atoms that are not involved in hydrogen bonding are omitted for clarity.
Figure 2. 2:3 Co-crystal of PAS and bpy (2). The PAS···bpy···PAS trimers are formed through COOH···Nheterocycle synthon II. Unlike 1, the aromatic
ring planes of the interacting molecules are in plane. The two additional bpy molecules in 2 in comparison to 1 are bridging the trimers through
synthon III forming infinite chains. C−H···O and C−H···π interactions link the chains into layers providing further stability to the solid.
co-crystal with bpe, showed a different arrangement in
comparison to 2. The flexibility of Csp3−Csp3 in bpe does not
allow the packing as in 2 by accommodating additional bpy
molecules in the crystal. Instead, the acid and pyridine
derivatives alternatively interact forming 1-D chains. The
PAS−bpe dimers, connected by synthon II, aggregate linearly
linked by N−H···N hydrogen bonds (Figure 6). These chains
are interconnected by N−H···π and C−H···π interactions
generating planes parallel to (103) that are stacked to generate
the crystal structure stabilized by C−H···O hydrogen bonds.
Surprisingly, in contrast to bpy, the reaction with bpe with a
different acid/base ratio yielded a polymorph of the 1:1 co-
crystal, 6a (Table 3). A close examination of the crystal
structure suggested that it is the same solid reported earlier.5b
Like in 6, the acid and base molecules in 6a are arranged
alternatively in a chain (Figure S10). An essential difference is
in the orientation of one of the PAS molecules in each chain
and the interaction between the adjacent chains. In 6a, unlike 6,
the PAS···bpe···PAS trimers, connected by synthon II, dominate
Scheme 2. Synthons Observed in Various Crystal Forms
Isolated in This Study
D
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Table 4. Selected Hydrogen Bond Geometries for
Normalized H-Atom Positions
interaction
H···A (Å) D···A (Å) D−H···A (deg)
PAS·(bpy)0.5
O1−H1···N2
N1−H3···O2
N1−H4···O3
C4−H5···π
O1−H1···N4
N1−H3···N2
N1−H4···N3
O3−H11···C21
C4−H6···π
1.828
2.480
2.329
3.793
1.658
2.328
2.269
2.516
2.966
1.713
2.118
2.146
2.040
2.834
2.521
1.576
1.712
2.399
2.424
1.779
2.444
2.430
3.413
1.592
2.265
2.802
2.535
2.952
1.470
2.071
2.910
2.729
2.564
2.654
3.206
3.093
4.376
2.626
3.034
3.108
3.326
3.786
2.664
3.109
2.981
2.903
3.426
3.295
2.699
2.544
3.187
3.313
2.650
3.188
3.093
3.934
2.600
3.015
3.384
3.421
3.739
2.569
2.955
3.491
3.488
3.375
155.2
148.5
165.2
123.4
174.8
142.3
156.6
145.7
147.6
172.1
166.6
163.6
166.3
122.6
153.9
174.3
153.0
163.2
153.7
175.2
144.4
128.2
115.8
170.3
157.8
121.7
159.3
148.8
171.4
173.3
121.8
139.4
149.3
PAS·(bpy)1.5
Figure 4. 1:1 Salt of PAS and mhp (4). The PAS−−mhpH+ dimer in 4
is similar to the one observed in 3; the O−H···O interactions orient
the dimers almost perpendicularly forming linear chains.
PAS·pap
N3+−H2···O1−
N1−H5···O1
N1−H6···O3
N2−H3···O2
C10−H11···O2
N2−H4···π
the structure. The trimer observed in this case is very similar to
the one observed in 2 and 5. The trimers in 6a are linked to
each other in a linear fashion via a bridging bpe molecule
through N−H···N hydrogen bonds, whereas in 6, the linear
chains are formed by the assembly of dimers that are directly
connected to each other by N−H···N interactions. Thus, in 6,
all the PAS molecules are oriented in one direction along the
chain, while they are oppositely oriented in the chains of 6a.
This is the key difference between the two co-crystal
polymorphs, 6 and 6a. Co-crystal 7 was isolated when we
opted for bpee, a rigid analogue of bpe. The structure of 1:1 co-
crystal of PAS and bpee, 7, is isostructural to 6a (Figure 7 and
Figure S10). A closer comparison of 6a and 7 reveals that there
are two types of bpe molecules in 6a  the planar bpe
connecting the PAS molecules in the trimer and the bent type
connecting the trimers with the CC−C−C torsion angles of
1.01 and −1.01° and 69.47 and −69.47° respectively, while in
7, conformationally restricted planar bpee molecules are present
in both the intra- and inter-trimer contacts. The flexibility
around the Csp3−Csp3 bond in bpe is probably responsible for
the existence of co-crystal polymorphs of 6 and 6a. In 6, there is
only one type of conformer and its geometry is even more bent
(CC−C−C) (torsion angles: 135.67 and 91.69°). However,
unlike other crystals reported in this study, 7 invariably
appeared with an impurity phase, which does not rule out the
possibility of existence of other phase(s) that are yet to be
identified.
PAS·mhp
PAS·(bpe)0.5
PAS·bpe
N2+−H1···O1−
O4−H2···O2
N1−H3···O3
N1−H4···O4
N2+−H1···O2−
N1−H2···O2
C13−H5···O1
C11−H8B···π
O1−H1···N2
N3−H3···N1
C12−H10···O2
C9−H9···O3
N3−H4···π
PAS·bpee
O1−H1···N2
N1−H3···N3
C8−H8···O2
C9−H9···O2
N1−H4···π
Effect of Solvent in the Crystallization of PAS-Based
Co-Crystals. When we changed the solvent from acetone to
acetone−water mixture, we obtained concomitant crystals of 2
and 2a in the case of bpy. Crystal structure analysis of 2a
revealed that it is similar to the compound reported earlier.5a
The previous work reported the crystallization of 2a from
aqueous medium. Fourier map suggested that one of the
pyridine molecules is protonated. In the crystal structure of 2a
(Figure S9), PAS−−bpyH+ dimers, connected by synthon V,
aggregate to form infinite chains connected by N−H···N/O
hydrogen bonds. These chains are interestingly interlinked via
water molecules, generating an open square framework that is
filled with the neutral bpy molecules. This clearly shows that for
linear growth/aggregation of PAS and bpy molecules, either
additional bridging pair of bpy molecules are required as in case
of 2 or switching the orientation of one of the PAS molecules in
the trimer is required with additional bpy and water molecules
for close packing as in 2a; otherwise, the discrete trimers end
up close packing as in 1. The results strongly suggest that the
inclusion of solvent molecules at a supramolecular level is a
Figure 3. The hydrogen bond environment around PAS in 1:1 salt of
PAS and pap (3). PAS− and papH+ are connected by synthon IV and
N−H···π interactions. Notice that all the potential hydrogen bond
functionalities of PAS are involved in hydrogen bonding interactions.
E
dx.doi.org/10.1021/cg3015332 | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
Figure 5. 2:1 salt of PAS and bpe (5). Discrete PAS−···bpeH+···PAS− trimers, formed through COOH···Nheterocycle synthon IV, are stacked in an
inclined manner. Notice the occurrence of alternating stacks of the trimers, related by about 90° rotation about a horizontal axis generating a bilayer.
Figure 6. 1:1 Co-crystal of PAS and bpe (6). Interestingly, instead of PAS···bpe···PAS trimers as observed in 5, PAS-bpe dimers are seen in 6. Note
that bpe is more flexible than bpy. The PAS-bpe dimers are connected by synthon II. These dimers are directly linked via N−H···N hydrogen bonds
generating chains of alternating PAS and bpe molecules. In 6, all the PAS molecules are oriented in one direction in the chains, while they are
oppositely oriented in the chains of 6a, a polymorph of 6. Compare this with Figure S10. Notice the N−H···π interactions interlinking the chains.
Figure 7. 1:1 Co-crystal of PAS and bpee (7). Note that bpee is conformationally more rigid than bpe. 7 is isostructural to 6a. Compare this with
Figure S10. The PAS···bpy···PAS trimers, connected by synthon II, generate chains of alternating PAS and bpee molecules connected by bridging
bpee through N−H···N hydrogen bonds and the chains are interlinked via N−H···π hydrogen bonds.
careful engineering ploy that the system does to optimize
various interactions.15 Solvent had no effect in the case of bpe
based co-crystals and the other solid forms reported herein. All
nine of the solid forms were obtained by evaporating acetone
solutions slowly at ambient conditions. The same results were
obtained by slow evaporation of MeOH and acetone-MeOH
F
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Crystal Growth & Design
Article
Drug Delivery Rev. 2007, 59, 617−630. (c) Schultheiss, N.; Newman,
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solutions. As discussed earlier in the previous sections, only the
compositional variation led to the isolation of the three
multicomponent crystals, of which two are co-crystal
polymorphs and the third one is a salt with distinct
stoichiomerty of PAS and bpe (Scheme 1 and Table 3);
incidentally the reported polymorph 6a was isolated from
aqueous ethanolic medium.5b
The melting points of the PAS solid forms were found to
range between 120 and 170 °C and lie above the corresponding
starting materials (Table 3 and Figure S2). The Rietveld
analysis of powder XRD of solids, 1 through 6, confirm the
monophasic nature of the bulk samples (Figure S3 through S8).
The stretching mode of carbonyl group of free carboxylic acid is
intense in co-crystals 1, 2, 6 and 7, confirming the presence of
neutral species in these solid forms, and found to be weak in
salts 4 and 5, while possibly merged with the aromatic CN
stretch in solid 3. Thus, in salts, 3−5, there is a possibility of
occurrence of both neutral and ionic species.
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CONCLUSION
■
We have shown that PAS-pyridine/bpy system exhibits rich
structural diversity that includes salt, co-crystal, salt co-crystal/
salt co-crystal hydrate and co-crystal polymorphs. Salt-co-crystal
continuum cannot be ruled out in some of these cases. Solid
solution formation between bpe and bpee is also currently being
explored. The study demonstrates the robustness of
COOH···Nheterocycle synthon and the utility of understanding
structural landscape in terms of supramolecular synthon
concept. There is a clear link between molecular and
supramolecular aggregation, and this may correlate with the
composition of the system. A trimer or a dimer connected by
COOH···Nheterocycle synthon is primarily responsible for salt/co-
crystal formation, while the stoichiometry of the resulting solids
is governed by conformational flexibilty and/or supramolecular
aggregation.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic information files (CIF) for 1−7, ATR-FTIR
spectra (Figure S1) for PAS, and 1−7, DSC scans (Figure S2)
for solids 1−6, Rietveld refinement plots for 1−6 (Figures S3−
S8), and crystal structures for solid 2a (Figure S9) and 6a
(Figure S10). This information is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: aramanan@chemistry.iitd.ac.in (A.R.),
ramthaimattam@yahoo.com (R.T.). Tel: +91-11-26591507.
Fax: +91-11-26581102.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.K.G. thanks UGC for a research fellowship and A.R.
acknowledges DST, Government of India, for financial support
and the powder and single crystal X-ray diffraction facility at the
Department of Chemistry, IIT Delhi, India.
REFERENCES
■
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dx.doi.org/10.1021/cg3015332 | Cryst. Growth Des. XXXX, XXX, XXX−XXX