Isoniazid cocrystals with anti-oxidant hydroxy benzoic acids

Article abstract of DOI:10.1016/j.molstruc.2014.07.070

Isoniazid is the primary constituent of "triple therapy" used to effectively treat tuberculosis. In tuberculosis and other diseases, tissue inflammation and free radical burst from macrophages results in oxidative stress. These free radicals cause pulmona

Full text of DOI:10.1016/j.molstruc.2014.07.070

Journal of Molecular Structure 1076 (2014) 446–452
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Isoniazid cocrystals with anti-oxidant hydroxy benzoic acids
a
a,
⇑
a
b
Syed Muddassir Ali Mashhadi , Uzma Yunus , Moazzam Hussain Bhatti , Muhammad Nawaz Tahir
a
Allama Iqbal Open University, Department of Chemistry, Islamabad, Pakistan
University of Sargodha, Department of Physics, Sargodha, Pakistan
b
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ
ꢀ
Cocrystals of isoniazid with four anti-
oxidant hydroxy benzoic acids.
Single crystal XRD studies of the
isoniazid–hydroxy benzoic acid
cocrystals.
ꢀ
ꢀ
Infra-red (IR) studies of the isoniazid–
hydroxy benzoic acid cocrystals.
Differential Scanning Calorimetric
(DSC) studies of the Isoniazid–
hydroxy benzoic acid cocrystals.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 May 2014
Received in revised form 26 July 2014
Accepted 28 July 2014
Available online 10 August 2014
Isoniazid is the primary constituent of ‘‘triple therapy’’ used to effectively treat tuberculosis. In tubercu-
losis and other diseases, tissue inflammation and free radical burst from macrophages results in oxidative
stress. These free radicals cause pulmonary inflammation if not countered by anti-oxidants. Therefore, in
the present study cocrystals of isoniazid with four anti-oxidant hydroxy benzoic acids have been
reported. Gallic acid, 2,3-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, and 3-hydroxybenzoic acid
resulted in the formation of cocrystals when reacted with isoniazid. Cocrystal structure analysis con-
firmed the existence of pyridine–carboxylic acid synthon in the cocrystals of isoniazid with Gallic acid,
Keywords:
Isoniazid
Cocrystal
Anti-oxidants
Hydroxybenzoic acids
2,3-dihydroxybenzoic acid and 3-hydroxybenzoic acid. While cocrystal of 3,5-dihydroxybenzoic acid
formed the pyridine–hydroxy group synthon. Other synthons of different graph sets are formed between
hydrazide group of isoniazid and coformers involving NAHꢁ ꢁ ꢁO and OAHꢁ ꢁ ꢁN bonds. All the cocrystals
were in 1:1 stoichiometric ratio.
Ó 2014 Elsevier B.V. All rights reserved.
Introduction
interactions in the context of crystal packing and the utilization
of such understanding in the design of new solids with desired
Supramolecular Chemistry [1,2] gained attention when Nobel
Prize of the year 1987 in chemistry was awarded to the founders
of this field. This domain can be portrayed as ‘‘chemistry beyond
the molecule’’ [3] and can be applied in the field of crystal engi-
neering. It is described as ‘‘the understanding of intermolecular
physical and chemical properties’’ [4]. Cocrystallization of two or
more pure compounds by crystal engineering to create a new func-
tional material such as pharmaceutical cocrystal is of great aca-
demic and industrial interest [5]. Cocrystal can be defined as ‘‘a
stoichiometric multi component crystal in which all its compo-
nents are neutral and solid under ambient conditions when in pure
form’’ [6], and can be constructed through several types of interac-
tions, including hydrogen bonding, pi-stacking, and van der Waals
forces.
⇑
Corresponding author. Address: Allama Iqbal Open University, Department of
Chemistry, Sector H-8 Islamabad, Pakistan. Tel.: +92 519057755.
E-mail address: uzma_yunus@yahoo.com (U. Yunus).
http://dx.doi.org/10.1016/j.molstruc.2014.07.070
0
022-2860/Ó 2014 Elsevier B.V. All rights reserved.

S.M.A. Mashhadi et al. / Journal of Molecular Structure 1076 (2014) 446–452
447
O
OH
O
NHNH2
O
OH
HO
OH
N
OH
OH
Gallic acid
Isoniazid (INH)
3-Hydroxybenzoic acid
O
OH
O
OH
OH
OH
HO
OH
3,5-Dihydroxybenzoic acid
2,3-Dihydroxybenzoic acid
Fig. 1. Structural formulas of cocrystal components.
Pharmaceutical cocrystal is relatively new solid form of Active
Pharmaceutical Ingredient (API) that has appealed the scientists
as a mean of altering the physicochemical properties of API [7].
Pharmaceutical cocrystallization is an opportunity for the optimi-
zation of important physiochemical properties of an API while
retaining its molecular structure and having improved bioavail-
ability, increased resistance to hydrate formation, improved com-
paction properties for tablet formulation of two APIs into one
dose. In spite of the fact that relationship between crystal structure
and physicochemical properties of cocrystals has been studied [8–
acids and bears possible attaching point for other heterosynthons.
The carbohydrazide group of isoniazid has both functionalities of
good hydrogen bonding acceptor in form of O and N atoms and
donor in the form of three H atoms. Therefore, it is a potentially
very important supramolecular reagent to synthesize cocrystals.
Cocrystals of isoniazid having carboxylic-pyridine synthons with
4-aminosalicylic acid [31], 2-hydroxybenzoic acid, 4-hydroxyben-
zoic acid, 2,4-dihydroxybenzoic acid [32], malonic acid, succinic
acid, glutaric acid, adipic acid, and pimelic acid [32–34] sebacic
acid, suberic acid, cinnamic acid [35], tartaric acid [36], and 2,2-
dithiodibenzoic acid have been reported.
1
1], but still not completely understood. For example, no logical
explanation of the variation in melting points of cocrystals can
be given because of complicated nature of hydrogen bonding pres-
ent in a cocrystals [12]. The melting point is also influenced by
other intermolecular interactions, molecular conformations, pack-
ing, and entropy factors [13,14].
Study of hydrogen bond is heart of all intermolecular interac-
tions [15]; it is energetic and directional [16,17] in nature and has
been successfully identified in different environments among spe-
cific sets of functional groups having hydrogen bond formation
capacity. It is therefore utilized in synthetic schemes to create
specific assemblies [18–22]. Carboxylic acid–pyridine hydrogen
bond in cocrystals is an established fact. It is due to strong
donor and strong acceptor functionality of the carboxylic and
pyridine functional groups respectively as described by Etter’s
rules for the formation of hydrogen bonds [23,24]. A numbers of
cocrystals of isoniazid have been made with this hydrogen bond
Crystalline isoniazid is reported to be stable for long time peri-
ods however, its tablet formulations undergo degradation, particu-
larly under high temperature and humid climatic conditions (40 °C,
75% RH) [37,38]. Exposure to light and presence of other drugs
(pyrazinamide, ethambutol) being used in combination therapy
also enhance isoniazid tablet’s degradation [39,40]. It is therefore
important to develop stable formulations of isoniazid.
In tuberculosis and other diseases, tissue inflammation and free
radical burst from macrophages results in oxidative stress. These
free radicals cause pulmonary inflammation if not countered by
anti-oxidants [41–43]. On the other hand oxidation reaction is
the main reason of degradation of molecules (APIs). The shelf life
of pharmaceutical formulations depends on their ability to resist
to oxidation of APIs. Anti-oxidants are used to stop the oxidation
processes. Therefore, in the present study cocrystals of isoniazid
with gallic acid, 2,3-dihydroxy benzoic acid, 3,5-dihydroxy benzoic
acid and 3-hydroxy benzoic acid, which are known anti-oxidants,
have been developed by slow evaporation method, and character-
ized by Fourier transform infrared spectroscopy (FTIR), single crys-
tal X-ray diffraction (XRD) and Differential Scanning Calorimetry
(DSC). Fig. 1 shows the structural formulas of the cocrystal
components.
[
25–30].
Isoniazid is highly active against Mycobacterium tuberculosis and
is the primary constituent of ‘‘triple therapy’’ used to effectively
treat tuberculosis since 1952. It is very versatile supramolecular
reagent to synthesize novel supramolecular structures. Pyridine
ring of INH is excellent hydrogen bond acceptor for carboxylic

4
48
S.M.A. Mashhadi et al. / Journal of Molecular Structure 1076 (2014) 446–452
Table 1
IR spectral data of isoniazid and cocrystals.
ꢂ1
ꢂ1
ꢂ1
ꢂ1
ꢂ1
Functional groups
Isoniazid (
t
cm
)
C-1 (t
cm
)
C-2 (t
cm
)
C-3 (t
cm
)
C-4 (
t cm )
Asymmetric-NH
Aromatic CAH stretching
C@O stretching
2
stretching
3430
3172
1670
1600
3441
3140
1674
1614
3420
3285
3145
1700
1608
3303
3198
1672
1585
3195
1677
1608
C@N stretching
Aromatic ring vibration
Pyridine ring
1500, 1465
1410
1523, 1469
1408
1511, 1464
1412
1534, 1493
1412
1522, 1454
1410
Table 2
Single crystal XRD data of cocrystals (C-1–C-4).
Cocrystal
C-1
C-2
C-3
C-4
Empirical formula
Formula weight
C
26
H
26
N
6
O
12
C
13
H
13
N
3
O
5
C
13
H
13
N
3
O
5
13 13 3 4
C H N O
614.53
296(2)
291.26
296(2)
0.71073
291.26
296(2)
0.71073
275.26
296(2)
0.71073
Temperature (K)
0
0.71073
Wavelength ( ÅA )
Crystal system
Space group
Triclinic
P-1
2
Monoclinic
P 21/c
4
Monoclinic
P 21/n
4
Orthorhombic
P c a 21
8
Cell formula unit-Z
Unit cell dimensions
0
8
1
1
.7178(7)
13.638(10)
7.0669(5)
3.7659 (5)
24.345(3)
14.018(16)
25.165(2)
4.8636(3)
21.2572(15)
a ( AÅ )
0
1.9273(8)
3.396(10)
b ( AÅ )
0
13.6823(11)
c ( AÅ )
a
(°)
b (°)
(°)
93.696(3)
98.707(4)
108.217(4)
1298.54(17)
90
95.126(4)
90
90
91.390(7)
90
90
90
90
2601.7
c
0
3
1313.4(17)
1284.8(3)
Volume ( AÅ )
Absorption coefficient (mm
R factor (%)
ꢂ1
)
0.127
5.81
0.107
3.95
0.118
4.97
0.107
4.87
close agreement with the results of Differential Scanning Calorim-
etry (DSC). DSC experiments were performed with Mettler Toledo
instrument. The samples (15–20 mg) were heated in open alumi-
num pans at a rate of 10 °C/min in nitrogen (flow of 20.0 mL/
min). DSC experiments were carried out to study the thermal
behavior of the cocrystals. Melting point can also be determined
from the melting curve. If the low temperature side of melting
peak is almost a straight line, the melting point corresponds to
the onset and if melting curve are concave in shape the melting
point are characterized by the peak maxima. The Infrared spectra
were recorded on Varian 640-IR spectrophotometer in ATR mode.
Single crystal X-ray data was collected by using Bruker Kappa APEX
II CCD diffractometer equipped with a graphite monochromator at
Table 3
Hydrogen bond distances in isoniazid-cocrystals (C-1–C-4).
Atoms
DAH (A°)
Hꢁ ꢁ ꢁA (A°)
DꢁꢁꢁA (A°)
<DAHꢁꢁꢁA (°)
Cocrystal C-1
O1AH1ꢁ ꢁ ꢁN6
N4AH4Aꢁ ꢁ ꢁO3
N5AH5Aꢁ ꢁ ꢁO10
O4AH4ꢁ ꢁ ꢁN4
0.280
1.937
0.860
0.820
1.826
2.525
2.525
1.937
2.645
2.853
2.937
2.736
176.37
103.6
132.4
164.3
Cocrystal C-2
O3AH3Aꢁ ꢁ ꢁN3
N1AH1ꢁ ꢁ ꢁO4
O5AH5Aꢁ ꢁ ꢁN2
1.040
0.860
0.890
1.600
2.299
1.880
2.636
2.940
2.715
176.0
131.52
156.0
2
96 K. Fine focus of molybdenum Ka tube was used. Data was col-
Cocrystal C-3
O3AH3Aꢁ ꢁ ꢁN1
O4AH4ꢁ ꢁ ꢁN3
O1AH1ꢁ ꢁ ꢁO3
lected using APEX2 software, SAINT for indexing the reflections
and determining the unit cell parameters. The structure was solved
by direct methods and refined by full-matrix least square calcula-
tions using SHELXL-97 software. Structures of the cocrystals were
drawn and other calculations were carried out by using Mercury
0.820
0.819
0.821
1.907
1.941
1.855
2.714
2.750
2.651
168.2
169.1
172.5
Cocrystal C-4
O1AH1ꢁ ꢁ ꢁN3
N2AH2ꢁ ꢁ ꢁO4
0.820
0.860
1.846
2.130
2.649
2.931
166.4
154.7
3
.1 software.
Slow evaporation cocrystallization
Experimental section
Isoniazid–gallic acid cocrystal (C-1)
Substrates and reagents
Isoniazid (0.137 g, 1 mmol) and gallic acid (0.170 g, 1 mmol)
were dissolved separately in 20 ml of methanol each then mixed
together at room temperature (22 °C). The solution was kept for
slow evaporation for 15 days. Brown Prism crystals were isolated
by filtration and dried in the air. Melting point was determined
to be 221 °C.
All the chemicals were used as received from the supplier with-
out any further purification. Solvents were dry distilled according
to standard procedures before use. Isoniazid was purchased from
Alfa Aeser, gallic acid, 2,3-dihydroxy benzoic acid, 3,5-dihydroxy
benzoic acid and 3-hydroxy benzoic acid were purchased from
Acros.
Isoniazid–2,3-dihydroxybenzoic acid cocrystal (C-2)
Melting point range was studied by using a Gallenkamp (UK)
0 Hz 220/240 volt melting point apparatus. The results were in
Isoniazid (0.137 g, 1 mmol) and 2,6-dihydroxybenzoic acid
(0.154 g,1 mmol) were dissolved separately in 20 ml solvent (etha-
5

S.M.A. Mashhadi et al. / Journal of Molecular Structure 1076 (2014) 446–452
449
Fig. 2. The cocrystal structure of Isoniazid–gallic acid (C-1). (a) Hydrogen bonding between nitrogen of pyridine ring and hydrogen of carboxylic acid group, (b) the packing
and layer structure of motif (C-1) and (c) graph sets in the cocrystal structure of (C-1).
nol:acetonitrile, 2:1) and then mixed together and heated up to
0 °C for 10 min. The solution was left for slow evaporation. Brown
needle crystals were isolated after 11 days. Melting point of this
spectroscopy, single-crystal X-ray diffraction and thermal analysis.
IR spectral data is given in Table 1. Crystallographic information is
shown in Table 2 and information regarding hydrogen bonds of
cocrystals is presented in Table 3. Crystal structures were depos-
ited at the Cambridge Crystallographic Data Centre. The data have
been assigned the following deposition numbers, CCDC 1005087-
100509.
7
cocrystal was 180 °C.
Isoniazid–3,5-dihydroxybenzoic acid cocrystal (C-3)
Isoniazid (0.137 g, 1 mmol) and 3,5-dihydroxybenzoic acid
(
0.154 g, 1 mmol) were separately dissolved in 20 ml each of the
mixture of ethanol and acetonitrile (2:1) then mixed together.
Solution was heated up to 70 °C for 10 min and then kept for slow
evaporation for 09 days. White needle like crystals were isolated.
Calculated melting point was 225 °C.
Isoniazid–gallic acid cocrystal (C-1)
The IR spectrum of cocrystal (C-1) shows stretching of NAH
bond in the high wave number region with a sharp band of weak
ꢂ1
intensity at 3372 cm
3
. Another sharp band is present at
Isoniazid–3-hydroxybenzoic acid cocrystal (C-4)
ꢂ1
140 cm , which is attributed to the CAH (aromatic) stretching.
Isoniazid (0.137 g, 1 mmol) and 3-hydroxybenzoic acid
ꢂ1
C@O stretching vibration is present at 1674 cm and C@N stretch-
(
0.138 g, 1 mmol) were separately dissolved in 20 ml of the mix-
ꢂ1
ing is observed at 1614 cm . Aromatic ring vibrations are attrib-
ture of ethanol and acetonitrile (2:1). The two solutions were
mixed together and heated up to 70 °C for 10 min and then kept
for slow evaporation for 09 days. Brown needle crystals were sep-
arated by filtration. Melting point of cocrystal was 132 °C.
ꢂ1
ꢂ1
ꢂ1
uted at 1523 cm and 1469 cm . C@N of pyridine ring shows
stretching vibration at 1408 cm . Cocrystal shows a distinct pat-
tern than isoniazid and coformer.
The cocrystal (C-1) crystallizes in the triclinic space group P-1.
Stoichiometry shows a discrete 1:1 adduct as gallic acid is hydro-
gen bonded to N of pyridine ring of isoniazid through OAHꢁ ꢁ ꢁN
Results and discussion
(Fig. 2a) having bond length 1.860 A°. The extended packing of
Cocrystallization of isoniazid with gallic acid, 2,3-dihydroxy-
benzoic acid, 3,5-dihydroxybenzoic acid and 3-hydroxybenzoic
acid produced cocrystals. These were characterized by infra-red
these discreet adducts forms layers (Fig. 2b). The angle between
the carboxyl group plane and the pyridine ring plane is 1.64° and
2
2
2
2
results in a R (7) ring motif. Another graph set of R (10) results

4
50
S.M.A. Mashhadi et al. / Journal of Molecular Structure 1076 (2014) 446–452
Isoniazid–2,3-dihydroxybenzoic acid cocrystal (C-2)
The IR spectrum of cocrystal (C-2) shows a sharp band at
ꢂ1
ꢂ1
3
3
420 cm
for NAH bond stretching while sharp band at
198 cm is attributed to the CAH (aromatic) stretching vibra-
ꢂ1
tions. C@O stretching vibration is present at 1672 cm and C@N
stretching at 1585 cm . Aromatic ring vibrations are observable
at 1511 cm and 1464 cm . C@N bond of pyridine ring in cocrys-
tal is identified at 1412 cm
ꢂ1
ꢂ1
ꢂ1
ꢂ1
.
The cocrystal (C-2) has monoclinic space group P21/c with
molecular formula C13 and molar mass 291.26 amu. The
13 3 5
H N O
cocrystal stoichiometry is a discrete 1:1 adduct where distinct
hydrogen bonding is formed between nitrogen of pyridine ring of
isoniazid and hydrogen of carboxylic group of acid (Fig. 3a) having
bond length 1.602 A°. The extended packing of these discreet
adducts forms layers (Fig. 3b). These findings correlate well with
the predicted hydrogen bond interactions as found in the struc-
tures of previously reported cocrystals [31–36]. Intramolecular
hydrogen bonding is also present. 2,3-Dihydroxy benzoic acid is
hydrogen bonded to N of pyridine ring of isoniazid through
OAHꢁ ꢁ ꢁN. The angle between the carboxyl group plane and the pyr-
2
2
idine ring plane is 2.52° and results in a R (7) ring motif. A hetero
2
synthon is formed by the hydrogen bond of the terminal NH and
its adjacent NH with hydroxy groups of 2,3-dihydroxy benzoic acid
2
2
having a graph set R (8) (Fig. 3c).
DSC results of isoniazid and 2,3-dihydroxybenzoic acid cocrys-
tal (C-2) shows endothermic peak at 189 °C. Onset value 180 °C
is considered to be melting point which is in close agreement with
the measured melting range in the melting point determination.
The thermal profile of molecular cocrystal is distinct, with a differ-
ent melting transition from either of the individual components.
This indicates the formation of novel molecular complex. This sin-
gle endothermic transition also indicates the absence of any
unbound or absorbed solvent or water and also demonstrates the
stability of the phase until the melting point.
Cocrystal of isoniazid and 3,5-dihydroxybenzoic acid (C-3)
The NAH bond in the high frequency region of the IR spectrum
of cocrystal (C-3) shows a sharp band of medium intensity at
ꢂ1
ꢂ1
3
285 cm . Sharp band at 3145 cm is due to the CAH (aromatic)
stretching vibrations. C@O stretching vibration is present at
ꢂ1
ꢂ1
1
700 cm and C@N stretching at 1608 cm . Aromatic ring vibra-
ꢂ1
ꢂ1
tions are attributed at 1534 cm , 1493 cm . Pyridine C@N
stretching is identified at 1412 cm
ꢂ1
.
Cocrystal (C-3) crystallizes in the monoclinic crystal system
having space group P 21/n. Molecular formula of cocrystal is deter-
13 3 5
mined to be C13H N O and molar mass 291.26 amu. Distinct 1:1
Fig. 3. Cocrystal of isoniazid and 2,3-dihydroxybenzoic acid (C-2). (a) Hydrogen
bonding between nitrogen of pyridine ring and hydrogen of carboxylic acid group,
adduct is resulted by hydrogen bonding between nitrogen of pyri-
dine ring of isoniazid and hydroxy group of 3,5-dihydroxybenzoic-
acid (Fig. 4a) instead of carboxylic group with bond length
(
b) the packing and layer structure of motif (C-2) and (c) graph sets in the cocrystal
structure of (C-2).
1
.941 A°. Cocrystal shows distinct behavior as other cocrystals of
isoniazid are formed by the hydrogen bonding between N of pyri-
dine ring and carboxylic acid through OAHꢁ ꢁ ꢁN which is not the
case for this particular cocrystal. The extended packing of these
discreet adducts forms layers (Fig. 4b). The angle between the
hydroxy group plane and the pyridine ring plane is 7.67°. A hetero-
between two homosynthons of carboxylic acid. A heterosynthon is
formed by the hydrogen bond of the terminal NH and its adjacent
2
NH with hydroxy groups of two gallic acid molecules having a
3
3
graph set R (7) (Fig. 2c).
The DSC thermogram of cocrystal (C-1) shows endothermic
peak at 232 °C, thermal profile of molecular cocrystal is distinct
showing different melting transition from either of the individual
components. Onset value 221 °C is considered to be melting point
which is in close agreement to the value taken by melting point
apparatus. This indicates the formation of novel molecular com-
plex. This single endothermic transition indicates the absence of
any unbound or absorbed solvent or water and also demonstrates
the stability of the phase until the melting point.
2
synthon is formed by the hydrogen bond of the terminal NH and
its adjacent NH of isoniazid with carboxyl group of one molecule of
3,5-dihydroxybenzoic acid and hydroxy group of other molecule
3
3
having a graph set R (9) (Fig. 4c).
The DSC thermogram of isoniazid and 3,5-dihydroxybenzoic
acid cocrystal (C-3) shows endothermic peak at 231 °C. Onset value
225 °C is considered to be melting point which is in close agree-
ment to the value taken by melting point apparatus. The thermal
profile of cocrystal is distinct, with a different melting transition

S.M.A. Mashhadi et al. / Journal of Molecular Structure 1076 (2014) 446–452
451
Fig. 4. Cocrystal of isoniazid and 3,5-dihydroxy benzoic acid (C-3). (a) Hydrogen
bonding between nitrogen of pyridine ring and hydroxy group, (b) the packing and
layer structure of motif (C-3) and (c) graph sets in the cocrystal structure of (C-3).
from either of the individual components. This indicates the forma-
tion of novel molecular complex. This single endothermic transi-
tion indicates the absence of any unbound or absorbed solvent or
water and also demonstrates the stability of the phase until the
melting point.
Fig. 5. Cocrystal of isoniazid and 3-hydroxybenzoic acid (C-4). (a) Hydrogen
bonding between nitrogen of pyridine ring and hydrogen of carboxylic acid group,
(
b) the packing and layer structure of motif (C-4) and (c) graph sets in the cocrystal
structure of (C-4).
Cocrystal of isoniazid and 3-hydroxybenzoic acid (C-4)
IR spectrum of cocrystal (C-4) shows the stretching of NAH
ꢂ1
bond in the high frequency region at wave number 3303 cm
.
(Fig. 5a). The extended packing of these adducts forms layers
(Fig. 5b). 3-Hydroxybenzoic acid is hydrogen bonded to N of pyri-
dine ring of isoniazid through OAHꢁ ꢁ ꢁN. The angle between the
ꢂ1
Another sharp band is present at 3195 cm , which is attributed
to the CAH (aromatic) stretching vibrations. C@O stretching vibra-
ꢂ1
tion is present at 1677 cm and C@N stretching is observed at
carboxyl group plane and the pyridine ring plane is 1.64° and
ꢂ1
ꢂ1
2
2
1
1
1
608 cm . Aromatic ring vibrations are present at 1522 cm
,
results in a R (6) graph set (Fig. 5c).
ꢂ1
454 cm
410 cm
while C@N stretching of pyridine is identified at
The distinct thermal profile of cocrystal shows endothermic
peak at 140 °C. Onset value 132 °C is considered to be melting
point which is in close agreement to the value obtained during
melting point determination and show different pattern from
either of the individual components. This confirms the formation
of novel molecular complex and indicates the absence of any
unbound or absorbed solvent or water and also demonstrates the
stability of the phase until the melting point.
ꢂ1
.
Cocrystal (C-4) crystallizes in the orthorhombic crystal system
having space group P c a 21. Molecular formula of the cocrystal is
with molar mass 275.26 amu. The stoichiometry of
cocrystal is a discrete 1:1 adduct where distinct hydrogen bonding
is formed between nitrogen of pyridine ring of isoniazid and
hydrogen of carboxylic group of acid having bond length 1.846 A°
13 13 3 4
C H N O

4
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S.M.A. Mashhadi et al. / Journal of Molecular Structure 1076 (2014) 446–452
[
[
14] V.R. Thalladi, M. Nüsse, R. Boese, J. Am. Chem. Soc. 122 (2000) 9227–9236.
15] A. Lemmerer, J. Bernstein, V. Kahlenberg, J. Chem. Crystallogr. 41 (2011) 991–
97.
Conclusion
In the present study four cocrystals of isoniazid with
9
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