Homo- or heterosynthon? A crystallographic study on a series of new cocrystals derived from pyrazinecarboxamide and various carboxylic acids equipped with additional hydrogen bonding sites

Article abstract of DOI:10.1021/cg300140w

Four new cocrystals of a well studied active pharmaceutical ingredient (API), namely, pyrazinecarboxamide (PZA), with various monocarboxylic acids equipped with additional hydrogen bonding sites such as vanillic acid (VA), gallic acid (GA), 1-hydroxy-2-naphthoic acid (1HNA), and indole-2-carboxylic acid (I2CA) have been successfully prepared and characterized by FT-IR, ¹H NMR, differential scanning calorimetry (DSC), and single crystal and powder X-ray diffraction (SXRD and PXRD, respectively) techniques. In the majority of the cases, preferential occurrence amide-amide and acid-acid homosynthons has been observed. Since the heterosynthon is energetically preferred to homosynthon, such unusual occurrence of homosynthon in these cocrystals is intriguing.

Full text of DOI:10.1021/cg300140w

Article
pubs.acs.org/crystal
Homo- or Heterosynthon? A Crystallographic Study on a Series of
New Cocrystals Derived from Pyrazinecarboxamide and Various
Carboxylic Acids Equipped with Additional Hydrogen Bonding Sites
Tapas Kumar Adalder,† Ravish Sankolli,‡ and Parthasarathi Dastidar*,†
†Department of Organic Chemistry, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur,
Kolkata 700032, West Bengal, India
‡Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, Karnataka, India
S
* Supporting Information
ABSTRACT: Four new cocrystals of a well studied active
pharmaceutical ingredient (API), namely, pyrazinecarboxamide
(PZA), with various monocarboxylic acids equipped with additional
hydrogen bonding sites such as vanillic acid (VA), gallic acid (GA),
1-hydroxy-2-naphthoic acid (1HNA), and indole-2-carboxylic acid
(I2CA) have been successfully prepared and characterized by FT-
1
IR, H NMR, differential scanning calorimetry (DSC), and single
crystal and powder X-ray diffraction (SXRD and PXRD,
respectively) techniques. In the majority of the cases, preferential
occurrence amide−amide and acid−acid homosynthons has been
observed. Since the heterosynthon is energetically preferred to
homosynthon, such unusual occurrence of homosynthon in these
cocrystals is intriguing.
frequently occur in supramolecular structures (for example,
crystals) are supramolecular synthons that can be relied upon
to generate supramolecular functional materials. The concept
has already been demonstrated in molecular templating,18 NLO
materials,19 photoreactions,20 organo gels,21 etc. While design-
ing cocrystals of APIs, it is important to pay attention to the
various noncovalent functionalities (for example, hydrogen
bonding) present in both the target API and the cocrystal
formar; the noncovalent functionality of the cocrystal formar
should be able to form complementary noncovalent inter-
actions with the target API without getting involved in chemical
reaction. In other words, the supramolecular synthon
considered should be robust enough to ensure cocrystal
formation.
INTRODUCTION
■
Active pharmaceutical ingredients (APIs) have to go through a
series of biological tests and clinical trials before they can be
accepted as drug candidates. In many cases, particularly in their
solid form, they do not perform well due to their poor solubility
and consequently inefficient bioavailability1 resulting in their
withdrawal from the market.2 Some of the commonly used
techniques exploited to address the solubility and bioavailability
issues of APIs are salt formation,3 suitable solvate4 (particularly
hydrates5) formation, and polymorph6 selections. Cocrystals of
APIs popularly known as pharmaceutical cocrystals1,7 have also
become popular in improving the physical properties of APIs.
Cocrytallization of APIs with other bioacceptable molecules,
such as aminoacids and nutrients,8 even with other drug
molecules,9 have been reported wherein the stability of the
parent APIs with respect to relative humidity,10 solubility,11
dissolution rate, and bioavailability12 have been shown to have
improved. Since no covalent bond formation is required in
making the cocrystals, the bioactivity of the APIs of interests is
not expected to alter. Supramolecular synthon, a concept
originally developed by Desiraju,13 can be used to generate
desired cocrystals of APIs.14 With the advancement of
supramolecular chemistry15 and crystal engineering,16 the
concept of supramolecular synthon has become a matured
and accepted tool in crystal engineering. Supramolecular
synthon plays the same fundamental role in supramolecular
synthesis that a synthon17 does in covalent synthesis; spatial
arrangements of intermolecular noncovalent interactions that
Pyrazinecarboxamide (PZA) is a bacteriostatic drug and
administered along with Isoniazid and Rifampicin in the
treatment of tuberculosis to reduce the duration of treatment.22
A CSD (version 5.33, November 2011) search on PZA reveals
that four different polymorphic forms (α, β, γ, and δ)23 and
three cocrystals of it have so far been reported in the structural
database. The first binary cocrystal (ref code ASAYIC) with 4-
nitrobenzamide was reported by Aakeroy et al.,24 and the
̈
amide−amide homodimer is preserved in the structure. The
second one with 2,5-dihydroxybenzoic acid (ref code
Received: January 31, 2012
Revised: March 21, 2012
Published: March 21, 2012
© 2012 American Chemical Society
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XAQQOW) was reported by Zaworotko et al.,25 and the
formation of an acid−amide heterosynthon is noteworthy in
that structure. The third one was a hydrated cocrystal with 4-
aminosalicylic acid (ref code URUGIY) reported by Desiraju et
al.,26 and the amide−amide homosynthon was maintained in
the crystal srtucture. Recently, another cocrystal with 2-amino
benzoic acid was reported by Abourahma et al.27, and the
amide−amide homeric homosynthon was manifested in the
crystal structure. In a most recent example, two other cocrystals
of PZA with succinic and fumaric acid were reported by Nangia
et al.28 wherein amide−amide homosynthon was observed
along with the acid-py heterosynthon.
In the present study, we focus our attention to PZA as a
target API to form cocrystals with various cocrystal formars in
order to study the synthon perference in the corresponding
crystal structures of the cocrystals and their impact on the
solubility. Out of 40 odd various cocrystal formars scanned in
the present study (Supporting Information), only four
carboxylic acid based cocrystal formars gave PZA cocrystals
(Scheme 1). PZA has a primary amide group and an N-
warming wherever necessary. The homogeneous solution was
kept undisturbed for slow evaporation. The crystalline material
was then subjected to various physicochemical analyses. The
formation of cocrystals were confirmed by FT-IR, powder X-ray
diffraction (PXRD), thermogravimetric analysis (TGA), differ-
ential scanning calorimetry (DSC), and, finally, by single crystal
X-ray diffraction (SXRD).
FT-IR. Table 1 enlists the FT-IR bands of amide-I and >C
O stretching of COOH of the resultant cocrystals as well as the
parent API and cocrystal formars. The FT-IR spectra of the
cocrystals and the individual components are depicted in Figure
1; the absence of any new band within the range of 1550−1650
cm−1 (νC−O of COO−) indicates that no proton transfer has
taken place; the amide-I band of PZA (1712 cm−1) underwent
significant red-shift in the corresponding cocrystals.
The same is true for the ν >CO of COOH moiety as
compared to the corresponding cocrystal formars except in the
case of PZA-1HNA; the single crystal structure of the parent
cocrystal formar 1HNA reveals that the COOH moiety is
involved in both intramolecular (with o-hydroxyl group) and
intermolecular (self-complementary) hydrogen bonding.29 As a
result, the COOH band appears significantly red-shifted (1633
cm−1) as compared to the other carboxylic acid cocrystal
formars studied herein. Even if an acid−amide heterosynthon is
formed in PZA-1HNA, it is not expected to influence the
COOH band further because of its hydrogen bond saturation
(both intra- and intermolecular hydrogen bonding), and
therefore, the COOH band in PZA-1HNA appears at 1631
cm−1. In PZA-1HNA, both amide−amide homosynthon and
amide−COOH heterosynthon are possible. Therefore, the
amide-I band is not expected to appear significantly red-shifted.
However, it is interesting to note that the amide-I band of PZA
(1712 cm−1) is significantly red-shifted to 1685 cm−1 in PZA-
1HNA indicating further participation of hydrogen bonding in
the cocrystals.
Scheme 1. Chemical Structure of Pyrazinecarboxamide
(PZA) and Various Cocrystal Formars; Vanilic Acid (VA),
Gallic Acid (GA), 1-Hydroxy-2-naphthoic Acid, (1HNA),
and Indole-2-carboxylic Acid (I2CA); PZA-VA, PZA-GA,
PZA-IHNA, and PZA-I2CA Are the Corresponding
Cocrystals
Differential Scanning Calorimetry (DSC) and Ther-
mogravimetric Analyses (TGA). The cocrystals were further
characterized by DSC and TGA. In DSC experiments, the
sample was heated at a rate of 10 °C per minute. The data were
recorded from 30 °C and continued until the decomposition
was commenced as indicated by the corresponding TGA
thermogram (Supporting Information).
The endotherm peaks at 150.09 °C (heat of fusion, 119. 98 J
g−1) for PZA-VA, 116.86 °C, 153.05, and 206.26 °C (heat of
fusion, 28.23, 27.71, and 169.25 J g−1, respectively) for PZA-
GA, 144.06 °C (heat of fusion, 153.02 J g−1) for PZA-1HNA,
and 214.70 °C (247.89 J g−1) for PZA-I2CA were noted in
DSC analysis (Figure 2). Except PZA-GA, all the other
cocrystals displayed a sharp endotherm indicating the binary
nature of these cocrystals. However, in the case of PZA-GA, the
appearance of three endothermic peaks at 116.86 °C, 153.05
°C, and 206.26 °C indicates the presence of another
component (solvates) in the cocrystals. It is interesting to
note tha, except in PZA-I2CA, the melting points of the other
cocrystals lies in between the melting points of the individual
components (Table 2).
containing electron rich aromatic heterocyclic nucleus. As a
result, the most plausible supramolecular synthons expected in
the crystal structures of the binary cocrystals of PZA with
various functionalized aromatic acids as enlisted in Scheme 1
are shown in Scheme 2.
Single Crystal X-ray Diffraction. To study the synthon
preferences in the resultant cocrystals reported herein, serious
attempts were made to grow the corresponding X-ray quality
single crystals. Fortunately, it was possible to grow the suitable
single crystals of all the cocrystals studied herein (Table 3).
Cocrystal of Pyrazinecarboxamide and Vanilic Acid
(PZA-VA). A single crystal of PZA-VA was grown from a 1:1
RESULTS AND DISCUSSION
■
Cocrystal Screening. All the cocrystals were grown by
slow evaporation technique. The equivalent amount of PZA
and cocrystal formar were taken in a 20 mL beaker and
dissolved in methanol by sonication or by applying mild
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Scheme 2. Plausible Supramolecular Synthons in the Cocrystals Studied Herein
Table 1. Selected FT-IR Bands
distances of 1.253(2) Å and 1.281(2) Å clearly indicate the
cocrystal (no salt formation) nature of PZA-VA. In the crystal
structure, the classical acid−acid [O···O = 2.621(2) Å; ∠O−
H···O = 170.6°] as well as amide−amide [N···O = 2.956(3) Å;
∠N−H···O = 176.3°] supramolecular homosynthons are
preserved even in the presence of a pyridine moiety, which
frequently gets involved in acid−pyridine heterosynthon.14f
The crystal structure can be best described as a 2-D sheet
wherein the hydrogen bonded dimer of VA participates in
hydrogen bonding via O−H···N interactions [O···N = 2.799(3)
Å; ∠O−H···N = 149.9°] with the PZA dimer that in turn
displayed intermolecular hydrogen bonding involving the
amide N−H and pyridyl N atoms [N···N = 3.061(3) Å;
∠N−H···N = 140.4°] (Figure 3). The 2-D sheets are further
packed in parallel fashion along the b axis sustained by weak
π−π stacking interactions (3.880 Å) involving the PZA and VA
name of the compound
ν-amide-I (cm−1
)
ν-COOH (cm−1
)
PZA
1712
VA
1681
1701
1633
1685
1668
1674
1631
1656
GA
1HNA
I2CA
PZA-VA
PZA-GA
PZA-1HNA
PZA-I2CA
1701
1693
1685
1693
mixture of acetonitrile and methanol. It was crystallized in the
centrosymmetric triclinic space group P1. The asymmetric unit
̅
contains two molecules of PZA and VA each. The C−O bond
Figure 1. FT-IR comparison plot of cocrystals, PZA, and cocrystal formers.
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aromatic nucleus of the adjacent 2-D sheet (Supporting
Information).
Cocrystal of Pyrazinecarboxamide and Gallic Acid
(PZA-GA). The single crystals of PZA-GA crystallized in the
centrosymmetric monoclinic space group P21/c were harvested
from acetonitrile solution. The asymmetric unit contains one
molecule of PZA, GA, and H2O each. It is clear from the C−O
distances (1.2326−1.3131 Å) of the COOH moiety that no
proton transfer (salt formation) has taken place in PZA-GA.
Crystal structure of this hydrated cocrystal showed that the
well-known acid−acid [O···O = 2.6612(15) Å; ∠O−H···O =
179.9°] and amide−amide [N···O = 2.877(2) Å; ∠N−H···O =
171.9°] homosynthons were maintained. The hydrogen
bonded dimer of GA makes further contact with the PZA
dimer via O−H···N interactions [N···O = 2.768(2) Å; ∠N−
H···O = 152.3°] involving one of the m-OH groups of GA and
pyridyl N of PZA. The solvate water molecule participates in
hydrogen bonding interactions with one of the m-OH and two
p-OH groups of GA [O···O = 2.7732 and 2.5878 Å] (Figure 4).
The overall crystal structure may be best described as a 3-D
hydrogen bonded network wherein there is a weak π−π
stacking interaction (4.004 Å) involving PZA and GA aromatic
rings (Supporting Information).
Figure 2. DSC traces of all the cocrystals studied herein.
Table 2. Melting Points of the Cocrystals and Their
Individual Components
name of
the
compounds
reported melting points
of the individual
components (°C)
name of
the
melting point of the
cocrystals (°C) as
cocrystal obtained in DSC trace
PZA
VA
189
Cocrystal of Pyrazinecarboxamide and 1-Hydroxy-2-
naphthoic Acid (PZA-1HNA). The single crystals of PZA-
1HNA were grown from ethanol; it belonged to the
centrosymmetric monoclinic space group P21/c. The asym-
metric unit contains one molecule of PZA and 1HNA each.
The C−O distances of 1.228(2)−1.3139(18) Å clearly supports
the formation of a binary cocrystal (no salt formation). Strong
intramolecular hydrogen bonding [O···O = 2.5889(15) Å;
208−210
250
PZA-VA
PZA-GA
150.09
206.26
144.06
GA
1HNA
195
PZA-
1HNA
I2CA
202 - 206
PZA-
I2CA
214.70
Table 3. Crystallographic Parameters for the Cocrystals
crystal parameters
PZA-VA
864871
PZA-GA
864872
PZA-1HNA
864873
PZA-I2CA
864874
CCDC no
empirical formula
formula weight
crystal size (mm)
crystal system
space group
a (Å)
C13H13N3O5
291.26
C12H13N3O7
311.25
C16H13N3O4
311.29
C14H12N4O3
284.28
0.32 × 0.26 × 0.12
triclinic
0.28 × 0.22 × 0.16
monoclinic
P21/c
0.40 × 0.36 × 0.35
monoclinic
P21/c
0.24 × 0.18 × 0.08
monoclinic
P21/n
P1
̅
7.424(7)
7.628(7)
25.70(2)
88.959(7)
87.126(8)
66.359(8)
1332(2)
7.2384(3)
27.1544(7)
7.5412(3)
90.00
14.389(2)
6.5565(9)
15.523(2)
90.00
5.5331(3)
29.5175(10)
8.3142(4)
90.00
b (Å)
c (Å)
α (deg)
β (deg)
115.909(5)
90.00
94.289(4)
90.00
108.789(5)
90.00
γ (deg)
volume/Å3
1333.27(8)
4
1460.4(4)
4
1285.54(10)
4
Z
4
F(000)
μ MoKα (mm−1
608
648
648
592
)
0.114
0.130
0.104
0.107
temp (K)
100(2)
100(2)
100(2)
100(2)
Rint
0.0256
0.0415
0.0365
0.0350
range of h, k, l
−8/8, −9/9, −30/30
7.67/25.00
11 494/4519/3332
−8/8, −32/32, −8/8
3.00/25.00
12 63/2350/1544
−18/18, −8/8, −19/19
1.42/27.10
15 296/3204/2153
−6/6, −34/35, −9/9
2.68/25.00
6659/2224/1418
θ min/max (deg)
reflections collected/unique/observed [I >
2σ(I)]
data/restraints/parameters
goodness of fit on F2
4519/0/385
0.971
2350/1/191
0.935
3204/0/198
1.044
2224/0/174
0.982
final R indices [I > 2σ(I)]
R1 = 0.0395
wR2 = 0.1121
R1 = 0.0580
wR2 = 0.1283
R1 = 0.0432
wR2 = 0.1066
R1 = 0.0727
wR2 = 0.1167
R1 = 0.0460
wR2 = 0.1212
R1 = 0.0690
wR2 = 0.1353
R1 = 0.0474
wR2 = 0.1171
R1 = 0.0782
wR2 = 0.1265
R indices (all data)
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Figure 3. Supramolecular synthons (marked in accordance with Scheme 2) present in the crystal structure of PZA-VA.
∠O−H···O = 145.0°] involving the COOH and OH moieties
of the 1HNA could be observed in the crystal structure. The
API PZA is found to display amide−amide homosynthon
[N···O = 2.9126(17) Å and ∠N−H···O = 171.8°], which in
turn participates in intermolecular hydrogen bonding via O−
H···N interactions [O···N = 2.6894(18) Å; ∠O−H···N =
170.0°] involving the pyridyl moiety of PZA and COOH of
1HNA. Thus, the crystal structure may be best described as a
discrete hydrogen bonded complex of PZA and 1HNA (Figure
5). The crystal structure was further stabilized by reasonably
strong π−π stacking interactions (3.666 Å) involving the
aromatic moieties of the API and cocrystal formar (Supporting
Information).
Cocrystal of Pyrazinecarboxamide and Indole-2-
carboxylic Acid (PZA-I2CA). The single crystals of PZA-
I2CA were grown from ethanol; SXRD experiments revealed
that they crystallized in the centrosymmetric monoclinic space
group P21/n. The asymmetric unit contains one molecule of
PZA and I2CA each. The C−O bond distances [1.208(2)−
1.324(2) Å] of the COOH moiety supports the formation of
cocrystal (no salt formation). In the crystal structure, the acid−
amide heterosynthon [O···O = 2.5779(15) Å; ∠O−H···O =
169.3° and N···O = 2.945(3) Å; ∠N−H···O = 160.9°] was
found to be responsible for the cocrystal formation. The
hydrogen bonded PZA and I2CA were further involved in
hydrogen bonding interactions with the neighboring molecules
via N−H···O [N···O = 2.972(3)Å; ∠N−H···O = 128.4°] and
N−H···N [N···N = 3.079(3) Å; ∠N−H···O = 165.7° ]
interactions involving amide NH and O atom of COOH, and
indole NH and pryridyl N, respectively, resulting a 1-D
hydrogen bonded tape, which is further packed in parallel
fashion sustained by weak π−π stacking interactions (3.739 Å)
involving the PZA and I2CA aromatic ring (Figure 6 and
Supporting Information)
Powder X-ray Diffraction. The fact that the crystallized
bulk samples actually represent the cocrystals as revealed by
SXRD is further supported by PXRD experiments. It is clear
from Figure 7 that the PXRD pattern of the bulk sample in each
case is superimposable with that of the simulated pattern
obtained from SXRD data and that it does not have any
resemblance to the PXRD patterns of the parent components.
Thus, the majority of the structures displayed the presence of
homosynthons (acid−acid and amide−amide). Since the acid−
amide heterosynthon is energetically more favored than the
corresponding homosynthons,14f this observation is quite
intriguing. To gain more insight into the synthon preference,
we decided to look at the related cocrystal structures reported
in the literature. A CSD (version 5.33, November 2011) search
with PZA as the search molecule resulted in 18 hits of which
only two examples were relevant to our present study. Further
literature search gave another three such examples. The details
are enlisted in Table 4. It is interesting to note that amide−
amide homosynthon is present in the majority of the reported
cases as well. However, acid−acid homosynthon as observed in
PZA-VA and PZA-GA was observed only once in the reported
cases. Thus, it appears that homosynthon is preferred to
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Figure 4. Supramolecular synthons (marked in accordance with Scheme 2) present in the crystal structure of PZA-GA displaying the lattice
occluded water molecules (orange ball).
Figure 5. Supramolecular synthons (marked in accordance with Scheme 2) present in the crystal structure of PZA-1HNA.
Figure 6. Supramolecular synthons (marked in accordance with Scheme 2) present in the crystal structure of PZA-I2CA.
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Figure 7. PXRD patterns of the cocrystals and the individual components under various conditions.
heterosynthon in the cocrystals of PZA with carboxylic acid
cocrystal formars. Understandbly, further investigation would
be required to address this unusual behavior of PZA cocrystals.
Solubility. To assess the effect of cocrystal formation on the
solubility of the API, a stock solution of PZA (1.96 mg in 100
mL double distilled water (dd-water)) has been used to
generate a calibration plot by serial dilution using the
absorbance of λmax 268 nm. For solubility measurement, a
slurry containing 300 mg of each sample (PZA, PZA-VA, PZA-
GA, PZA-1HNA, and PZA-I2CA) in 1 mL of double-distilled
water was kept undisturbed for 72 h and then filtered through a
Whatman 40 filter paper. The filtrate was then diluted to 100
mL from which an aliquot of 0.5 mL was further diluted to 10
mL. The solubility of PZA was then measured in each case
using the absorbance data of this final stock solution with the
help of the calibration plot. The solubility of PZA, PZA-VA,
PZA-GA, PZA-1HNA, and PZA-I2CA thus obtained were
17.33, 37.18, 21.87, 13.51, and 1.34 μg L−1, respectively. While
the solubility of PZA-VA was remarkably improved, those of
PZA-1HNA and PZA-I2CA were considerably decreased,
whereas that of PZA-GA marginally increased.
revealed that in the majority of the cases, homosynthon
(amide−amide) is preferred to heterosynthon (acid−amide)
although acid−acid homosynthon is not observed in the
reported structures. The reason for preferring homosynthon in
PZA−carboxylic acid cocrystals is difficult to explain as the
conformation of PZA in the cocrystals reported herein is found
to be almost identical (Supporting Information) with each
other meaning that there must be some other factors
responsible for such unusual behavior. The fact that PZA-
I2CA has the highest melting point (216 °C) and lowest
solubility among the samples studied herein could be due to the
presence of a much stronger acid−amide heterosynthon in the
crystal structure of PZA-I2CA.
EXPERIMENTAL SECTION
■
Materials and Physical Measurements. PZA, VA, GA, 1HNA,
and I2CA were acquired from Sigma Aldrich and used as such without
further purification. Solvents were of L.R. grade (Ranchem,
Spectrochem, India etc.) and were used without further distillation.
Melting point was determined by a Veego programmable melting
point apparatus, India. IR spectra were recorded on an FT-IR
1
instrument (FTIR-8300, Shimadzu). H NMR spectra were recorded
CONCLUSIONS
■
on a Brukar AVANCE DPX 300 (for 300 MHz) and III 500 (for 500
MHz). The elemental compositions of the purified compounds were
confirmed by elemental analysis (Perkin-Elmer Precisely, Series-II,
CHNO/S Analyzer-2400). TGA analyses were performed on a SDT Q
Series 600 Universal VA.2E TA Instruments. DSC was recorded in a
Perkin-Elmer, Pyris Diamond DSC. Powder X-ray patterns were
recorded on a Bruker AXS D8 Advance Powder (Cu Kα1 radiation, λ =
1.5406 Å) diffractometer.
Single Crystal X-ray Diffraction. Data were collected using
MoKα (λ = 0.7107 Å) radiation on a BRUKER APEX II
diffractometer equipped with CCD area detector. Data collection,
data reduction, and structure solution/refinement were carried out
using the software package of SMART APEX II. All structures were
solved by the direct method and refined in a routine manner. In all the
cases, nonhydrogen atoms were treated anisotropically. All the
hydrogen atoms were geometrically fixed. CCDC (CCDC No.
864871−864874) contains the supplementary crystallographic data
Thus, four cocrystals of PZA with various carboxylic acid
cocrystal formars having additional hydrogen bond function-
ality have been successfully prepared and characterized. The
single crystal structures of the cocrystals revealed the presence
of both acid−acid and amide−amide homonsynthon in PZA-
VA and PZA-GA, whereas in the case of PZA-1HNA, amide−
amide homosynthon along with acid−pyridine heterosynthon
were observed. In the case of PZA-I2CA, acid−amide
heterosynthon was observed. Since acid−amide heterosynthon
is energetically more favored as compared to the corresponding
homosynthon,14f the presence of both acid−acid and amide−
amide homonsynthons in PZA-VA and PZA-GA, and also
amide−amide homonsynthon in PZA-1HNA, is noteworthy.
Comparing the present observation with the reported PZA
cocrystal structures (with carboxylic acid cocrystal formars)
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Crystal Growth & Design
Article
Table 4. List of Cocrystal Formars Reported in the Present Study (Entries 1−4), in the Literature (Entries 5−9) of PZA and the
Synthon Observed in the Crystal Structure; Synthon Numbering with Third Bracket in Accordance with Scheme 2; # Names
Synthons Not Shown in Scheme 2
for this article. These data can be obtained free of charge via www.
REFERENCES
■
ccdc.cam.ac.uk/conts/retrieving.html.
(1) (a) Shan, N.; Zaworotko, M. J. Drug Discovery Today 2008, 13,
440−446. (b) Vishweshwar, P.; Mcmahon, J. A.; Bis, J. A.; Zaworotko,
ASSOCIATED CONTENT
̈
■
M. J. J. Pharm. Sci. 2006, 95, 499−516. (C) Almarsson, O.; Zaworotko,
S
M. J. Chem. Commun. 2004, 1889−1896.
* Supporting Information
(2) (a) Morissette, S. L.; Soukasene, S.; Levinson, D.; Cima, M. J.;
List of other cocrystal formars that did not react with PZA in
̈
1
Almarsson, O. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 2180−2184.
the present study; FT-IR, H NMR, elemental analyses data,
(b) Chemburkar, S. R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.;
Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; Quick, J.;
Bauer, P.; Donaubauer, J.; Narayanan, B. A.; Soldani, M.; Riley, D.;
McFarland, K. Org. Process Res. Dev. 2000, 4, 413−417. (c) Bauer, J.;
Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J.
Pharm. Res. 2001, 18, 859−866. (d) Law, D.; Krill, S. L.; Schmitt, E.
A.; Fort, J. J.; Qiu, Y.; Wang, W.; Porter, W. R. J. Pharm. Sci. 2001, 90,
1015−1025.
molecular plot with hydrogen bonding parameters, molecular
packing diagram, molecular overlay of PZA observed in the
reported cocrystals, and DSC-TGA overlay; crystallographic
data (CIF files) of the cocrystals PZA-VA, PZA-GA, PZA-
1HNA, and PZA-I2CA. This material is available free of charge
via the Internet at http://pubs.acs.org.
(3) (a) Stahly, G. P.; Wermuth, C. G., Eds. Handbook of
Pharmaceutical Salts: Properties, Selection and Use; Wiley-VCH/
VHCA: Weinheim, Germany, 2002. (b) Gould, P. J. Int. J. Pharm.
1986, 33, 201−217. (c) Banerjee, R.; Bhatt, P. M.; Ravindra, N. V.;
Desiraju, G. R. Cryst. Growth Des. 2005, 5, 2299−2309. (d) Reddy, S.;
Bethune, S. J.; Kampf, J. W.; Rodríguez-Hornedo, N. Cryst. Growth
Des. 2009, 9, 378−385. (e) Galcera, J.; Molins, E. Cryst. Growth Des.
2009, 9, 327−334. (f) Hathwar, V. R.; Pal, R.; Guru Row, T. N. Cryst.
Growth Des. 2010, 10, 3306−3310. (g) Thakuria, R.; Nangia, A.
CrystEngComm 2011, 13, 1759−1764. (h) Paulekuhn, G. S.;
Dressman, J. B.; Saal, C. J. Med. Chem. 2007, 50, 6665−6672.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Parthod123@rediffmail.com or ocpd@iacs.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.K.A. thanks CSIR, New Delhi, for a SRF fellowship, and P.D.
thanks DBT, New Delhi, for financial support.
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Article
(4) (a) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid State Chemistry
of Drugs, 2nd ed.; SSCI: West Lafayette, IN, 1999.
A. Pharm. Res. 2006, 23, 1888−1897. (d) Bak, A.; Gore, A.; Yanez, E.;
Stanton, M.; Sunita, T.; Rashid, S.; Akrami, A.; Rose, M.; Surapaneni,
S.; Bostick, T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A. J.
Pharm. Sci. 2008, 97, 3942−3956. (e) Cherukuvada, S.; Babu, N. J.;
Nangia, A. J. Pharm. Sci. 2011, 100, 3233−3244.
(5) (a) Gillon, A. L.; Feeder, N.; Davey, R. J.; Storey, R. A. Cryst.
Growth Des. 2003, 3, 663−673. (b) Roy, S.; Goud, N. R.; Babu, N. J.;
Iqbal, J.; Kruthiventi, A. K.; Nangia, A. Cryst. Growth Des. 2008, 8,
4343−4346. (c) Ueto, T.; Takata, N.; Muroyama, N.; Nedu, A.; Sasaki,
A.; Tanida, S.; Terada, K. Cryst. Growth Des. 2012, 12, 485−494.
(6) (a) Bernstein, J. Polymorphism in Molecular Crystals; Oxford
University Press: Oxford, U.K., 2002. (b) Datta, S.; Grant, D. J .W.
Nat. Rev. Drug Discovery 2004, 3, 42−57. (c) Brittain, H. G., Ed.
Polymorphism in Pharmaceutical Solids; Marcel Dekker, Inc.: New York,
1999. (d) Byrn, S.; Pfeiffer, R.; Stephenson, G.; Grant, D. J. W.;
Gleason, W. B. Chem. Mater. 1994, 6, 1148−1158. (e) Foster, J. A.;
Piepenbrock, M.-O. M.; Lloyd, G. O.; Clarke, N.; Howard, J. A. K.;
Steed, J. W. Nature Chem. 2010, 2, 1037−1043. (f) Sarma, B.; Chen, J.;
Hsi, H. Y.; Myerson, A. S. Korean J. Chem. Eng. 2011, 28, 315−322.
(g) Chieng, N.; Rades, T.; Aaltonen, J. J. Pharm. Biomed. Anal. 2011,
55, 618−644. (h) Diao, Y.; Whaley, K. E.; Helgeson, M. E.; Woldeyes,
M. A.; Doyle, P. S.; Myerson, A. S.; Hatton, T. A.; Trout, B. L. J. Am.
Chem. Soc. 2012, 134, 673−684.
(13) Desiraju, G. R. Angew. Chem., Int. Ed. 1995, 34, 2311−2327.
(14) (a) Srivijaya, R.; Vishweshwar, P.; Sreekanth, B. R.; Vyas, K.
CrystEngComm 2008, 10, 283−287. (b) Ghosh, S.; Bag, P. P.; Reddy,
C. M. Cryst. Growth Des. 2011, 11, 3489−3503. (c) Cheney, M. L.;
Weyna, D. R.; Shan, N.; Hanna, M.; Wojtas, L.; Zaworotko, M. J. Cryst.
Growth Des. 2010, 10, 4401−4413. (d) Elbagerma, M. A.; Edwards, H.
G. M.; Munshi, T.; Scowen, I. J. CrystEngComm 2011, 13, 1877−1884.
(e) Chadha, R.; Saini, A.; Arora, P.; Jain, D. S.; Dasgupta, A.; Guru
Row, T. N. CrystEngComm 2011, 13, 6271−6284. (f) Goud, N. R.;
Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 1930−1939.
́ ́
(g) Fabian, L.; Hamill, N.; Eccles, K. S.; Moynihan, H. A.; Maguire, A.
R.; McCausland, L.; Lawrence, S. E. Cryst. Growth Des. 2011, 11,
3522−3528.
(15) (a) Vogtle, F. Supramolecular Chemistry: An Introduction; Wiley:
̈
New York, 1993. (b) Lehn, J.-M. Supramolecular Chemistry: Concepts
and Perspectives; Wiley-VCH: Weinheim, Germany, 1995. (c) Beer, P.
D.; Gale, P. A.; Smith, D. K. Supramolecular Chemistry; Oxford
University Press: Oxford, U.K., 1999. (d) Lehn, J.-M.; Ball, P. In The
New Chemistry; Hall, N., Ed.; Cambridge University Press: Cambridge,
U.K., 2000; pp 300−351. (e) Steed, J. W.; Atwood, J. L.
Supramolecular Chemistry; Wiley: Chichester, U.K., 2000. (f) Ariga,
K.; Kunitake, T. Supramolecular Chemistry: Fundamentals and
Applications; Springer: Berlin, Germany, 2005. (g) Steed, J. W.;
Turner, D. R.; Wallace, K. J. Core Concepts in Supramolecular Chemisty
and Nanochemistry; Wiley:Chichester, U.K., 2007. (h) Lehn, J.-M.
Angew. Chem., Int. Ed. 1988, 27, 89−112. (i) Lehn, J.-M. Chem. Soc.
Rev. 2007, 36, 151−160. (j) Dunitz, J. D.; Gavezzotti, A. Chem. Soc.
Rev. 2009, 38, 2622−2633.
̈
(7) (a) Morissette, S. L.; Almarsson, O.; Peterson, M. L.; Remenar, J.
F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R.
Adv. Drug Delivery Rev. 2004, 56, 275−300. (b) Khan, M.; Enkelmann,
V.; Brunklaus, G. J. Am. Chem. Soc. 2010, 132, 5254−5263. (c) Trask,
A. V.; Jones, W. Top. Curr. Chem. 2005, 254, 41−70. (d) Basavoju, S.;
Bostrom, D.; Velaga, S. P. Pharm. Res. 2008, 25, 530−541. (e) Sekhon,
̈
B. S. Ars Pharm. 2009, 50, 99−117. (f) Springuel, G.; Norberg, B.;
Robeyns, K.; Wouters, J.; Leyssens, T. Cryst. Growth Des. 2012, 12,
475−484. (g) Brittain, H. G. Cryst. Growth Des. 2012, 12, 1046−1054.
(h) Stanton, M. K.; Tufekcic, S.; Morgan, C.; Bak, A. Cryst. Growth
Des. 2009, 9, 1344−1352. (i) Schultheiss, N.; Newman, A. Cryst.
Growth Des. 2009, 9, 2950−2967. (j) Bat
́
hori, N. B.; Lemmerer, A.;
Venter, G. A.; Bourne, S. A.; Caira, M. R. Cryst. Growth Des. 2011, 11,
̌
̌
75−87. (k) Kastelic, J.; Hodnik, Z.; Sket, P. J.; Lah, N.; Leban, I.; Pajk,
M.; Planinsek, O.; Kikelj, D. Cryst. Growth Des. 2010, 10, 4943−4953.
(16) (a) Desiraju, G. R. Crystal Engineering: The Design of Organic
Solids; Elsevier: Amsterdam, The Netherlands, 1989. (b) Desiraju, G.
R. J. Chem. Sci. 2010, 122, 667−675. (c) Desiraju, G. R. Angew. Chem.,
Int. Ed. 2007, 46, 8342−8356. (d) Desiraju, G. R.; Vittal, J. J.;
Ramanan, A. Crystal Engineering: A Textbook; IISc Press and World
Scientific Publishing: Singapore, 2011. (e) Tiekink, E. R. T.; Vittal, J.
J., Eds. Frontiers in Crystal Engineering; John Wiley & Sons Ltd: New
York, 2006. (f) Braga, D.; Grepioni, F., Eds. Making Crystals by Design
Methods, Techniques and Applications; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, Germany, 2007.
̌
(l) Pop, M.; Sieger, P.; Cains, P. W. J. Pharm. Sci. 2009, 98, 1820−
1834. (m) Paluch, K. J.; Tajber, L.; Elcoate, C. J.; Corrigan, O. I.;
Lawrence, S. E.; Healy, A. M. J. Pharm. Sci. 2011, 100, 3268−3283.
(n) Mohamed, S.; Tocher, D. A.; Vickers, M.; Karamertzanis, P. G.;
Price, S. L. Cryst. Growth Des. 2009, 9, 2881−2889. (o) Babu, N. J.;
Reddy, L. S.; Nangia, A. Mol. Pharm. 2007, 4, 417−34. (p) Caira, M.
R. Mol. Pharm. 2007, 4, 310−316.
(8) (a) Schultheiss, N.; Bethune, S.; Henck, J.-O. CrystEngComm
2010, 12, 2436−2442. (b) Schultheiss, N.; Roe, M.; Boerrigter, S. X.
M. CrystEngComm 2011, 13, 611−619. (c) Bethune, S. J.; Schultheiss,
N.; Henck, J.-O. Cryst. Growth Des. 2011, 11, 2817−2823.
(17) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
Wiley: New York, 1995. (b) Corey, E. J. Chem. Soc. Rev. 1988, 17,
111−133. (c) Corey, E. J. Angew. Chem., Int. Ed. 1991, 30, 455−465.
(18) (a) Mei, X.; Liu, S.; Wolf, C. Org. Lett. 2007, 9, 2729−2732.
(9) (a) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm
́
2009, 11, 1823−1827. (b) Evora, A. O. L.; Castro, R. A. E.; Maria, T.
(b) MacGillivray, L. R.; Papaefstathiou, G. S.; Frisc
B.; Hamilton., T. D. Top. Curr. Chem. 2004, 248, 201−221. (c) Gao,
X.; Frisc c, T.; MacGillivray, L. R. Angew. Chem., Int. Ed. 2004, 43,
̂ ̂ ́
ic, T.; Varshney, D.
M. R.; Rosado, M. T. S.; Silva, M. R.; Beja, A. M.; Canotilho, J.;
Euseb
R. A. E.; Ribeiro, J. D. B.; Maria, T. M. R.; Silva, M. R.; Yuste-Vivas, C.;
Canotilho, J.; Eusebio, M. E. S. Cryst. Growth Des. 2011, 11, 5396−
5404.
́
io, M. E. S. Cryst. Growth Des. 2011, 11, 4780−4788. (c) Castro,
̂ ̂ ́
i
232−236. (d) MacGillivray, L. R.; Reid, J. L.; Ripmeester, J. A. J. Am.
́
Chem. Soc. 2000, 122, 7817−7818.
(19) Huang, K. S.; Britton, D.; Etter, M. C.; Byrn, S. R. J. Mater.
Chem. 1997, 7, 713−720.
(10) (a) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth
Des. 2005, 5, 1013−1021. (b) Trask, A. V.; Motherwell, W. D. S.;
Jones, W. Int. J. Pharm. 2006, 320, 114−123.
(20) (a) Santra, R.; Biradha, K. CrystEngComm 2011, 13, 3246−3257.
(b) Odani, T.; Matsumoto, A. CrystEngComm 2002, 4, 467−471.
(21) (a) Dastidar, P. Chem. Soc. Rev. 2008, 37, 2699−2715.
(b) Piepenbrock, M.-O. M.; Lloyd, G. O.; Clarke, N.; Steed, J. W.
Chem. Rev. 2010, 110, 1960−2004.
(11) (a) Aakeroy, C. B.; Forbes, S.; Desper, J. J. Am. Chem. Soc. 2009,
̈
131, 17048−17049. (b) Bhatt, P. M.; Ravindra, N. V.; Banerjee, R.;
Desiraju, G. R. Chem. Commun. 2005, 1073−1075. (c) Cheney, M. L.;
Weyna, D. R.; Shan, N.; Hanna, M.; Wojtas, L.; Zaworotko, M. J. J.
Pharm. Sci. 2011, 100, 2172−2181. (d) Goud, N. R.; Gangavaram, S.;
Suresh, K.; Pal, S.; Manjunatha, S. G.; Nambiar, S.; Nangia, A. J.
Pharm. Sci. 2012, 101, 664−680.
(22) Becker, C.; Dressman, J. B.; Amidon, G. L.; Junginger, H. E.;
Kopp, S.; Midha, K. K.; Shah, V. P.; Stavchansky, S.; Barends, D. M. J.
Pharm. Sci. 2008, 97, 3709−3720.
́
(23) (a) Castro, R. A. E.; Maria, T. M. R.; Evora, A. O. L.; Feiteira, J.
io, M. E. S. Cryst.
(12) (a) Remenar, J. F.; Morissette, S. L.; Peterson, M. L.; Moulton,
̈
C.; Silva, M. R.; Beja, A. M.; Canotilho, J.; Eusieb
́
B.; MacPhee, J.; Guzman
́
, H. R.; Almarsson, O. J. Am. Chem. Soc. 2003,
Growth Des. 2010, 10, 274−282. (b) Cherukuvada, S.; Thakuria, R.;
125, 8456−8457. (b) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.;
Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P. J. Am. Chem. Soc. 2004,
126, 13335−13342. (c) McNamara, D. P.; Childs, S. L.; Giordano, J.;
Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park,
Nangia, A. Cryst. Growth Des. 2010, 10, 3931−3941. (c) Borba, A.;
Albrecht, M.; Gom
Chem. A 2010, 114, 151−161.
́
ez-Zavaglia, A.; Suhm, M. A.; Fausto, R. J. Phys.
2541
dx.doi.org/10.1021/cg300140w | Cryst. Growth Des. 2012, 12, 2533−2542

Crystal Growth & Design
Article
(24) Aakeroy, C. B.; Desper, J.; Helfrich, B. A. CrystEngComm 2004,
̈
6, 19−24.
(25) MacMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.;
McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340−
350.
(26) Grobelny, P.; Mukherjee, A.; Desiraju, G. R. CrystEngComm
2011, 13, 4358−4364.
(27) Abourahma, H.; Cocuzza, D. S.; Melendez, J.; Urban, J. M.
CrystEngComm 2011, 13, 6442−6450.
(28) Cherukuvada, S.; Nangia, A. CrystEngComm 2012, 14, 2579−
2588.
(29) Gupta, M. P.; Mahata, A. P. Cryst. Struct. Commun. 1976, 5, 553.
2542
dx.doi.org/10.1021/cg300140w | Cryst. Growth Des. 2012, 12, 2533−2542