The hierarchies of hydrogen bonds in salts/cocrystals of isoniazid and its Schiff base - A case study

Article abstract of DOI:10.1039/c5ra14951g

A series of two salts of isoniazid and two cocrystals of its Schiff base have been synthesised and characterized using FT-IR, ¹H-NMR, DSC, XRPD and SCXRD. The crystal structures with 2,5-dihydroxybenzoic acid, 2,6-dihydroxy benzoic acid, 3-amin

Full text of DOI:10.1039/c5ra14951g

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The hierarchies of hydrogen bonds in salts/
cocrystals of isoniazid and its Schiff base – a case
study†
Cite this: RSC Adv., 2016, 6, 15868
a
b
c
a
*
Madhavi Oruganti, Pavan Khade, Uttam Kumar Das and Darshak R. Trivedi
A series of two salts of isoniazid and two cocrystals of its Schiff base have been synthesised and
characterized using FT-IR, 1H-NMR, DSC, XRPD and SCXRD. The crystal structures with 2,5-
dihydroxybenzoic acid, 2,6-dihydroxy benzoic acid, 3-aminobenzoic acid and o-phthalic acid have been
deduced. In all complexes the involvement of pyridine N (proton transfer/robust synthon) is noticed. The
unit cell similarity index was calculated between two cocrystals (N-(propan-2-ylidene)
isonicotinohydrazide)$(2,5-dihydroxybenzoic acid) and (3-aminobenozic acid)$(N-(propan-2-ylidene)
isonicotinohydrazide). Furthermore, the index was compared with the reported complexes and it was
found to be close to zero indicating isostructurality. The correlation between the NPyr–H/O (acid)
hydrogen bond distance for the reported cocrystals and their corresponding pKa values has been
deduced and validated.
Received 28th July 2015
Accepted 18th January 2016
DOI: 10.1039/c5ra14951g
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p–p stacking, and ionic and electrostatic interactions), molec-
ular shapes and crystal structures can be determined. In addi-
Introduction
tion, the successful design/development of pharmaceutical
cocrystals paves the way for the opportunity for patenting and
innovative intellectual property.9
Active pharmaceutical ingredients (APIs) undergo various tests
and clinical trials before being deemed as drugs. The challenge
to the whole process is oen the physicochemical properties
like poor solubility, low stability and inefficient bioavailability1
that may result in withdrawal from the market2 if not addressed.
In addition, polymorphism is a bottleneck in the drug devel-
opment process as it has an impact on the physicochemical
properties.3
Acid–base complexes and complexes of multiple compo-
nents have thus drawn attention in the last decade4,5 due to the
presence of fascinating structural motifs5,6 and their ability to
act as functional materials.6,7 Furthermore, they are a means to
improve the physicochemical properties without making or
breaking the covalent bond meaning that the biological activity
of the API remains unaltered.8 The design of cocrystals/salts is
advantageous because the relationships between the intermo-
lecular forces (hydrogen bonding, van der Waals interactions,
The formation of neutral hydrogen bonds (cocrystal) or
charge assisted hydrogen bonds (salt/acid–base complex) is
governed by the pKa rule.10 The rule states that there should be
a difference of at least 2 pKa units between the conjugate acid
and corresponding base for salt formation and vice versa for
cocrystal formation. As there are exceptions to the rule, the
a priori prediction of salt/cocrystal formation has been under
debate for decades.
Isoniazid is an anti-TB drug and it is generally used in
combination with pyrazinamide, rifampicin and ethambutol in
xed dose combinations (3FDC, 4FDC).11 Tuberculosis (TB) is
the main global concern next to HIV. According to the WHO,
8.6 million people are estimated to be suffering from TB and
1.3 million people (including 320 000 deaths due to HIV) are
known to have died from the disease in 2012.12 The FDCs were
recommended by the WHO for six to nine months as a treat-
ment. However, the activity of the FDCs was limited by poor
stability and low bioavailability.13 Furthermore, isoniazid is
prone to hydrolysis and oxidation, and interacts with reducing
sugars to form hydrazones; thus the incompatibility of isoni-
azid and lactose (milk) is well known.14 Generally, combina-
tions of anti-TB drugs are administered owing to drug
resistance, and hence there arises the need to design and
develop stable FDC formulations. Hence cocrystallisation and
salt formation are resorted to.
aSupramolecular Chemistry Laboratory, Department of Chemistry, National Institute
of Technology Karnataka (NITK)-Surathkal, Mangalore-575 025, India. E-mail:
darshak_rtrivedi@yahoo.co.in; Tel: +91-824-2474000 ext. 3205
bDepartment of Chemical Engineering, National Institute of Technology Karnataka
(NITK) Surathkal, Mangalore-575 025, India
cDepartment of Organic Chemistry, Indian Association for the Cultivation of Science,
Jadavpur, Kolkata, West Bengal, India
† Electronic supplementary information (ESI) available: IR spectral data of the
salts; 1H NMR spectra of the salts; DSC of the salts; XRPD of the bulk salt
samples; crystallographic information les (CIFs). CCDC 1045622–1045625. For
ESI and crystallographic data in CIF or other electronic formats see DOI:
10.1039/c5ra14951g
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Cocrystals of isoniazid with different coformers were studied The structure solution and renement was carried out by using
by Lemmerer et al.15 and multidrug cocrystals of isoniazid and SHELXL 97. In all of the cases, the non-hydrogen atoms were
another anti-TB drug, 4-aminosalicylic acid, were reported by rened anisotropically and all of the hydrogen atoms were
Grobelny et al.16 Aitipamula et al.17 studied polymorphic cocrys- located on a difference Fourier map and rened.
tals of isoniazid with p-hydroxybenzoic acid, fumaric acid, and
1a. A mixture of 200 mg of isoniazid (1.45 mmol) and 224 mg
ternary cocrystals of isoniazid, nicotinamide and fumaric acid or of 2,5-dihydroxybenzoic acid (1.45 mmol) was dissolved in 5 ml
succinic acid. The cocrystals of isoniazid with a series of of a mixture of (5 : 3) ethanol and methanol and heated under
carboxylic acids were reported by Sarcevica et al.18 Cherukuvada mild conditions, and then le for slow evaporation at room
et al.19 has reported binary and ternary eutectic compositions of temperature. No crystals were observed.
isoniazid and pyrazinamide with pharmaceutically acceptable
1b. A mixture of 200 mg of isoniazid (1.45 mmol) and 224 mg
dicarboxylic acids. The cocrystals of isoniazid with four anti- of 2,5-dihydroxybenzoic acid (1.45 mmol) was dissolved in 7 ml
oxidant hydroxy benzoic acids (gallic acid, 2,3-dihydroxybenzoic of a mixture of (5 : 2) ethanol and methanol and 1 ml of DMSO
acid, 3,5-dihydroxybenzoic acid, and 3-hydroxybenzoic acid) were and heated under mild conditions, and then le for slow
reported by Mashhadi et al.,20 and Swapna et al.21 studied the evaporation at room temperature. Rod shaped colourless crys-
cocrystals of isoniazid with vanillic acid, ferulic acid, caffeic acid tals were obtained aer 2 days.
and resorcinol.
1c. A mixture of 200 mg of isoniazid (1.45 mmol) and 200 mg
Thus, there are numerous reports on acid–pyN synthons. of 3-aminobenzoic acid (1.45 mmol) was dissolved in 8 ml of
However the studies pertaining to the product formation in the a mixture of (1 : 1) tetrahydrofuran and methanol and soni-
presence of other competing functional groups [hydrazide (API), cated, and then le for slow evaporation at room temperature.
hydroxyl (coformer)] are relatively fewer. Thus the presence of No crystals were observed.
multifunctionalities in the isoniazid provokes the opportunity
1d. A mixture of 200 mg of isoniazid (1.45 mmol) and 242 mg
for the design of pharmaceutical cocrystals/salts. Furthermore, of phthalic acid (1.45 mmol) was dissolved in 5 ml of methanol
when the analysis of the top 100 drugs22 that are prescribed was and sonicated, and then le for slow evaporation at room
carried out, it was found that 30% of the APIs contain at least temperature. Plate shaped yellow coloured crystals were ob-
one carboxylic acid, 39% contain at least one alcohol group and tained aer 4 days.
12% contain aromatic N which is in accordance with the
2a. A mixture of 200 mg of isoniazid (1.45 mmol) and 224 mg
percentage alcohol, carboxylic acid and pyridine in the Merck of 2,5-dihydroxybenzoic acid (1.45 mmol) was dissolved in 8 ml
Index.23 Hence, it is interesting to address the ability of these of a mixture of (5 : 3) acetone and methanol and heated under
functional groups to form supramolecular synthons. Carboxylic mild conditions, and then le for slow evaporation at room
acids have been chosen as coformers as they are ideal candi- temperature. Plate shaped colourless crystals were obtained
dates with both hydrogen bond donating and accepting sites.
aer 3 days.
In this milieu, the current study was done. The Schiff base of
2b. A mixture of 200 mg of isoniazid (1.45 mmol) and 224 mg
the API (with acetone) was synthesised (to be used as one of the of 2,6-dihydroxybenzoic acid (1.45 mmol) was dissolved in 8 ml
coformers) because the drug efficacy against Mycobacterium of a mixture of (5 : 3) acetone and methanol, and then le for
tuberculosis was reported to increase.24 A series of the cocrystals/ slow evaporation at room temperature. No crystals were
salts of isoniazid (Schiff base) with 2,5-, 2,6-, dihydroxy benzoic observed.
acids, 3-aminobenzoic acid and o-phthalic acid were attempted
2c. A mixture of 200 mg of isoniazid (1.45 mmol) and 200 mg
with an intent to compare and study the hydrogen bonding of 3-aminobenzoic acid (1.45 mmol) was dissolved in 8 ml of
patterns.
a mixture of (1 : 1) tetrahydrofuran and acetone and sonicated,
and then le for slow evaporation at room temperature. Needle
shaped yellow coloured crystals were obtained aer 2 days.
2d. A mixture of 200 mg of isoniazid (1.45 mmol) and 242 mg
of phthalic acid (1.45 mmol) was dissolved in a 2 : 3 mixture (5
ml) of acetone and methanol and sonicated, and then le for
slow evaporation at room temperature. An amorphous powder
was noticed.
Experimental section
Materials and general methods
The coformers were purchased from Sigma-Aldrich and the
isoniazid was purchased from LOBA CHEMIE chemicals. The
FT-IR spectra were recorded using a Nicolet Avatar 330 instru-
ment in the range 4000–400 cmꢀ1. Differential scanning calo-
rimetry (DSC) was recorded on a Shimadzu DSC-60 with
a heating rate of 10 ꢁC minꢀ1. NMR was recorded on a FT-NMR
Bruker, Avance II (500 MHz) with TMS as an internal reference.
XRPD was recorded on a JEOL JDX-8P-XRD in the range 5–50ꢁ at
the rate of 0.02 per s.
Results and discussion
Scheme 1
ꢀ
1b. 1b crystallizes in the space group P1 with one molecule of
isoniazid and two molecules of 2,6-dihydroxybenzoic acid in the
asymmetric unit. The proton transfer is observed from the API
+
ꢀ
˚
to the coformer and are held by N –H/O , 2.577(3)A hydrogen
bond with one molecule and N+–H (hydrazide)/Oꢀ (carbox-
Crystallography
˚
Diffraction data were collected using Mo-Ka radiation (l ¼ ylate), 2.655(2) A (Fig. 1a) with other molecule. The hydrazide
0.71073 A) with a Bruker AXS APEX II system (Bruker, Germany). units of the isoniazid form N–H/Oꢀ (carboxylate), 2.682(2)A
˚
˚
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+
˚
and N –H/O (carboxylate), 2.887 (3)A, the coformer. These
units duplicate to form a 2D network that is stabilised by p–p
˚
interactions with centroid–centroid distances of 3.782 A. The
2D network is held due to N+–H (hydrazide)/O (hydroxyl of
˚
another coformer), 2.770(3)A forming a 3D arrangement stabi-
lised by p–p interactions with centroid–centroid distances of
˚
4.383 A (Fig. 1b).
ꢀ
1d. 1d crystallizes in P1 with one molecule of isoniazid and
one molecule of phthalic acid in the asymmetric unit. Proton
transfer is observed from one of the carboxylic acids to the
ꢀ
+
˚
isoniazid via the O /H–N , 2.659(2)A hydrogen bond (Fig. 2a).
The proton of the other acid is shared with the carboxylate via
O–H/O intramolecular hydrogen bonding. Two molecules of
isoniazid and two molecules of o-phthalate are connected by
Fig. 1 (a) The asymmetric unit comprising API and the coformers in
salt 1b. (b) The 2D network stabilised by p–p interactions in salt 1b.
Fig.
2
(a) The asymmetric unit encompassing the API and the
coformer in 1d. (b) The tetramer held by N–H/O and N+–H/Oꢀ
interactions in salt 1d (c) The one dimensional chain in salt 1d. (d) 3D
network stabilised by the C–H/Oꢀ interactions in 1d.
˚
(amide) N–H/–O]C (carboxyl), 2.960(2)A to form a tetramer
(Fig. 2b). These tetramers in turn are linked by (hydrazide) N–
H/O]C (amide) to form a 1D chain (Fig. 2c). These 1D chains
are linked with each other to form a 3D assembly (Fig. 2d) that is
˚
stabilised by C–H (isoniazid)/O (carboxylate) 3.443(2) A,
Scheme 1 API and coformers used in the present study: isoniazid (1),
2,5-dihydroxybenzoic acid (a), 2,6-dihydroxybenzoic acid (b), 3-ami-
nobenzoic acid (c), phthalic acid (d).
˚
3.316(2) A interactions.
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bond with the other coformer to form a 1D chain (Fig. 3b). These
1D chains recur to form a 3D network (Fig. 3c) which is stabilised
by the C–H (C adjacent to carboxyl of coformer)/O (N0-(propan-
2-ylidene) isoniazid) 3.035(2) interactions.
2c. The cocrystal 2c comprises one molecule each of (N0-
(propan-2-ylidene) isoniazid) and 3-aminobenzoic acid O–H
(carboxylic acid)/N (pyridine N of isoniazid) in the asymmetric
unit (Fig. 4a) and crystallizes in the P21/c space group. Two such
Scheme 2
2a. 2a crystallizes in P21/c with one molecule of (N0-(propan-2-
ylidene) isoniazid) and 2,5-dihydroxybenzoic acid in an asym-
metric unit. The coformer and the modied API are held by the
O–H (acid)/N (pyridine N), 2.616(2) hydrogen bond (Fig. 3a).
The (N0-(propan-2-ylidene) isoniazid) is connected via the H–O
(hydroxyl of 5th position)/O (C]O of Schiff base) hydrogen
Fig. 3 (a) The asymmetric unit in complex 2a. (b) 1D chain held by N–H/O interaction in cocrystal 2a. (c) 3D network held by C–H/O
interaction in 2a.
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units are connected via N–H (of one Schiff base)/–C]O (of the
˚
other Schiff base), 2.954(2)A which forms a 1D chain (Fig. 4b)
arrangement. These units self assemble to form a 3D network
(Fig. 4c) that is stabilised by (coformer) C–H/p (coformer),
˚
˚
4.571 A and (coformer) C–H/O (Schiff base), 3.285(2)A
interactions.
The in situ Schiff base cocrystal formation
The Schiff base cocrystal formation was observed with the
coformers 2,5-dihydroxy benzoic acid (a) and 3-aminobenzoic
acid (c). However, such Schiff base cocrystal formation was
found to be absent with the coformers 2,6-dihydroxy benzoic
acid (b) and o-phthalic acid (d). This could be due to the fact
that the formation of a cocrystal with both of the coformers is
sterically hindered (owing to the presence of hydroxyl groups/
carboxyl groups closer to each other/closer to carboxylic acid).
Furthermore, Schiff base cocrystal formation was attempted
with the coformer 2,3-dihydroxybenzoic acid. Nevertheless, it
failed to occur owing to the presence of sterically hindered
hydroxyl groups at the 2nd and 3rd positions.
Scheme 2 Schiff base and coformers used in the present study: N-
(propan-2-ylidene)isonicotinohydrazide (2), 2,5-dihydroxybenzoic
acid (a), 2,6-dihydroxybenzoic acid (b), 3-aminobenzoic acid (c), and
phthalic acid (d).
Since there are four functional groups, acid (coformer),
alcohol (coformer), hydrazide (API) and PyN (API), there are four
possibilities of synthon formation.
(1) Acid–acid homosynthon.
(2) Acid–amide heterosynthon.
(3) Acid–pyridine heterosynthon.
(4) Alcohol–pyridine heterosynthon.
The acid–pyridine,25 acid–amide26 and alcohol–pyridine27
synthons are robust, as per CSD. However, the acid–pyridine
heterosynthon/involvement of pyridine N is noticed in the
present study.
Furthermore, in the complex 1b, the API : coformer ratio was
found to be 1 : 2, although the experimental molar ratio taken
was 1 : 1. The typical 1 : 2 complex formation could be due to
the following ndings:
(a) The availability of hydrogen bond forming sites (such
sites are absent in the other two cocrystals i.e. 1a and 1c due to
Schiff base formation because it reduces the hydrogen bonding
ability of isoniazid by two thirds i.e. the omittance of the
hydrazide functionality results in the removal of the two of the
three hydrogen atoms of the hydrazide) (Lemmerer, 2011).15b
(b) The stabilization of the carboxylate moiety by intra-
molecular hydrogen bonding.
The hydrogen bonding hierarchies in the cocrystals/salts of
the current study
The coformers in the current study are GRAS. Furthermore, the
Schiff base of isoniazid (with acetone) was proved to have
greater anti TB activity. In cocrystal 2c, the amine functionality
of the 3-aminobenzoic acid is not involved in the hydrogen
bond formation. The hydrazide group is deviated from the
pyridine ring with an angle of 32ꢁ with the result that both the
amide N–H and C]O functionalities are in plane with each
other, thus resulting in the formation of a one dimensional
chain. In contrast to 2c, in cocrystal 2a the hydroxyl group at the
5th position forms a hydrogen bond with C]O, thus preventing
Fig. 4 (a) The asymmetric unit depicting the robust synthon in coc-
rystal 2c. (b) The 1D chain in 2c. (c) 3D network stabilised by C–H/O
and C–H/p interactions in 2c.
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hydrogen bonding of C]O with the N–H of hydrazide. involvement of C]O in the hydrogen bonding. The reason could
Furthermore, the O–H/O hydrogen bond is stronger than that be attributed to the difference in the deviation of the acid
of N–H/O (according to Etter’s 1st rule, a strong donor forms hydrazide from the benzene ring. The torsion angle of isoniazid
a hydrogen bond with a strong acceptor).
in the cocrystal with 4-hydroxybenzoic acid was observed to be
143.18ꢁ whereas in the other cocrystals the torsion angles were
found to be 146.18 (cocrystal with salicylic acid) and 163.8ꢁ
(cocrystal with 3-hydroxy benzoic acid). Since the C]O of the
isoniazid in the cocrystal with 4-hydroxybenzoic acid is deviated
to a considerably larger extent, it doesn’t participate in the
hydrogen bond formation.
Comparison of the crystal structures of the dihydroxybenzoic
acids
In the cocrystal of isoniazid with 2,3-dihydroxybenzoic acid,
both isoniazid and the coformer are in the same plane and
hence form O–H (carboxyl)/N and C–H (isoniazid)/O
(carboxyl) bonds thus resulting in a R22(7) graph set. The two
hydroxyl groups in the coformer are adjacent to each other and
hence form a R22(8) graph set. In the cocrystal of isoniazid with
2,4-dihydroxybenzoic acid, both the API and the coformer are
not planar [torsion angle 174.4(1)ꢁ], hence the absence of
a R22(7) ring. In 1a, 1c and 1d a C–H/O interaction was found to
be present. In 1b, the two hydroxyl groups lock the distortion of
the carboxylate and thus make it planar, forming a R22(8) kind of
graph set. Hence, non-conventional hydrogen bonding (C–H/
O) was anticipated. However the C–H/O interaction was found
to be absent because carboxylate was deviated from the plane
and the torsion angle was found to be 174.8(2)ꢁ. Furthermore,
the proton transfer resulted in the increase in the C–N–C angle
(ꢂ117ꢁ to 121.6ꢁ) that contributed to failure in the bond
formation. Similar proton transfer is observed in 1d with
phthalic acid as the coformer. In the salt 1d, the ideal scenario
of the occurrence of a non-conventional hydrogen bond is
noticed. This is supported by the following observations:
(1) The carboxyl of the coformer deviates from the plane to
a relatively lesser extent (torsion angle: 178.4(1)ꢁ).
Comparison of the Npy–H/O (acid) bond distance with the
pKa of the coformer in the reported cocrystals of isoniazid
with aromatic acids
As per classic theory, as the pKa decreases, the acidity increases
which should be evident from shortened bond distances.
Hence, preferably the order for the NPyr–H/O bond distance
should have been of the order 1 > 2 > 3 > 4 > 5 > 6 > 7 > 8.
However there are exceptions. Cinnamic acid has a conjugated
double bond that has an additive effect on its acidity due to
which the distance is remarkably low although the pKa is on
a par with 4-hydroxybenzoic acid. In cocrystal 5, though the pKa
is considerably high, the NPyr–H/O bond distance is 2.605(5).
In this cocrystal, the benzene ring of isoniazid deviates from the
plane by 13.15ꢁ. Thus in order to form a bond with the pyridine
N, the acid functionality of 3-hydroxy benzoic acid also deviates
from the plane and the resultant bond is shortened. It is
interesting to note that the pKas of salicylic acid and 2,3-dihy-
droxybenzoic acid are almost same and the deviation of
carboxylic acid from the plane for both coformers is also
(2) The resultant C–N–C bond angle due to proton transfer
was found to be 121.3ꢁ.
Table 2 Correlation between Npyr/H–O (acid) bond distance and
their corresponding pKas
Comparison between the cocrystals of isoniazid with isomeric
monohydroxybenzoic acids (2-hydroxy, 3-hydroxy, and 4-
hydroxybenzoic acids)
˚
S. no.
Coformer
pKa1
N
Pyr/H–O d (A)
In the cocrystals of isoniazid-2-hydroxybenzoic acid and
isoniazid-4-hydroxybenzoic acid, the API and the coformer are in
a different plane whereas in the isoniazid-3-hydroxybenzoic acid
cocrystal the API and the coformer are in the same plane. The
C]O of the acid hydrazide group of isoniazid is involved in
hydrogen bond formation with 2-hydroxy- and 3-hydroxybenzoic
acids in the corresponding cocrystals. On the contrary, the
isoniazid-4-hydroxybenzoic acid cocrystal does not show the
1
2
3
4
5
6
7
8
9
Malonic acid
Succinic acid
Glutaric acid
Adipic acid
Pimelic acid
Suberic acid
Sebacic acid
Terephthalic acid
Phthalic acid (C4b)
2.83
4.2
2.538(3)
2.617(2)
2.656(2)
2.689(1)
2.659(1)
2.665(2)
2.643(1)
2.697(2)
2.580(3)
4.31
4.43
4.71
4.52
4.72
3.51
2.89
Table 1 Correlation between the Npyr/H–O (acid) bond distance and their corresponding pKas
˚
S. no.
Coformer
pKa
NPyr/H–O d (A)
1
2
3
4
5
6
7
8
4-Hydroxybenzoic acid (ref. 15a)
Cinnamic acid (ref. 18)
Benzoic acid (ref. 18)
4.57
3.88/4.4
4.17
4.41
4.08
3.11
2.98
2.96
2.682(2)
2.616(2)
2.684(4)
2.670(3)
2.605(5)
2.660(2)
2.589(2)
2.636(2)
Gallic acid (ref. 20)
3-Hydroxy Benzoic acid (ref. 20)
2,4-Dihydroxy benzoic acid (ref. 15a)
Salicylic acid (ref. 15d)
2,3-Dihydroxy benzoic acid (ref. 20)
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Table 3 Isostructurality parameters for molecules under current study and those reported
Parameter
Q
S. no.
Related cocrystals
3
1
2
3
4
5
2a and 2c (current study)
0.04
0.001
0.01
0.012
0.009
0.013
2a and (3-hydroxybenzoic acid)$((Z)-N0-(butan-2-ylidene)isonicotinohydrazide)
2a and (3-hydroxybenzoic acid)$(N0-(propan-2-ylidene)isonicotinohydrazide)
2c and (3-hydroxybenzoic acid)$((Z)-N0-(butan-2-ylidene)isonicotinohydrazide)
2c and (3-hydroxybenzoic acid)$(N0-(propan-2-ylidene)isonicotinohydrazide)
0.03
0.044
0.003
0.002
Table 4 Crystallographic data of the cocrystals/salts (1b, 1d and 2a, 2c) of isoniazid
Cocrystals/salts
1b
1d
2a
2c
CCDC number
Formula
M
1045623
1045625
C14H2N3O3
303.27
1045622
C16H19N3O5
331.33
1045624
C16H18N4O3
314.34
C20H19O9N3
445.38
Crystal system
Space group
Triclinic
P1
Triclinic
P1
Monoclinic
P21/c
15.2726(7)
11.5810(5)
9.1189(4)
90.00
95.0230(10)
90.00
1606.68(12)
4
Monoclinic
P21/c
8.7707(4)
20.4025(8)
9.1687(4)
90.00
100.5140(10)
90.00
1613.14(12)
4
ꢀ
ꢀ
˚
a/A
7.6313(7)
7.8438(7)
17.8835(17)
81.836(3)
88.720(3)
64.742(3)
957.45(15)
2
6.9555(3)
9.2797(4)
11.0293(5)
97.828(2)
99.815(3)
100.154(2)
680.26(5)
2
˚
b/A
˚
c/A
a/ꢁ
b/ꢁ
g/ꢁ
Volume/A3
Z
Dcalc/g cmꢀ3
m/mmꢀ1
T/K
1.545
0.124
296(2)
1.480
0.115
296(2)
1.370
0.104
298(2)
1.294
0.092
296(2)
Rens collected
Unique rens
R1(I > 2s)
wR2(I > 2s)(I > 2s)
3363
2454
0.0415
0.1153
2582
2120
0.045
0.1393
2832
2179
0.0415
0.1125
2844
2503
0.0496
0.1286
Table 5 Metrics of hydrogen bonds for cocrystals/salts (1b, 1d and 2a, 2c) of isoniazid
D–H/A
d(D–H)
d(H/A)
D(D/A)
:DHA
Symmetry transformations
2a
O2–H2/N22
O10–H10/O13
0.82
0.82
1.80
1.95
2.616(2)
2.7515(18)
173.9
164.7
x ꢀ 1, y, z
x, y + 1, z
1b
N2–H5/O7
N3–H6/O7
N3–H6/O6
N1–H30/O2
0.93(2)
1.07(3)
1.07(3)
0.99(3)
1.82(2
2.61(3)
1.64(3)
1.59(3)
2.6823(19)
3.180(2)
2.655(2)
2.577 (2)
153(2)
112.5(17)
157(2)
x, y + 1, z ꢀ 1
x, y + 1, z ꢀ 1
x, y + 1, z ꢀ 1
x, y + 1, z ꢀ 1
177 (2)
2c
N2–H5/O1
N4–H17/N3
N–H16/O2
O3–H18/N1
0.86 (2)
0.90(3)
0.85(3)
0.82
2.09(2)
2.38(3)
2.66(3)
1.86
2.9538(17)
3.264(3)
3.453(2)
175(2)
167(2)
156(2)
170.5
x, ꢀy + 3/2, z + 1/2
ꢀx + 1, y ꢀ 1/2, ꢀz + 3/2
x, ꢀy + 1/2, z + 1/2
x, ꢀy + 3/2, z ꢀ 1/2
2.6763(18)
1d
N3–H7/O4
N3–H8/O1
N3–H8/O1
N1–H3/O3
N1–H3/O2
N2–H6/O5
0.92(2)
0.84(2)
0.84(2)
1.00(2)
1.00(2)
0.86
2.33(2)
2.276(19)
2.24(2)
2.52(2)
1.66(2)
2.03
3.219(2)
164.1(17)
114.1(16)
143.6(17)
122.5(16)
178.0(19)
148.1
ꢀx + 2, ꢀy + 2, ꢀz + 2
—
2.7267(16)
2.9602(18)
3.1702(18)
2.6591(16)
2.8016(16)
ꢀx + 2, ꢀy + 1, ꢀz + 2
x ꢀ 1, y, z
x ꢀ 1, y, z
ꢀx + 1, ꢀy + 2, ꢀz + 2
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similar. However there is considerable difference in the NPyr
–
zero indicating the isostructurality. Furthermore the indices
H/O bond distance. The reason may be attributed to the calculated between the reported molecules 2a and 2c were
following ndings: both the coformers are involved in intra- found to be close to zero, conrming isostructurality.
molecular hydrogen bonding owing to the presence of
a hydroxyl group at the 2nd position. Nevertheless, the hydroxyl
‘O’ of salicylic acid is involved in the bifurcated hydrogen bond
Acknowledgements
with the NH of the hydrazide (NH–NH2) functionality whereas DRT and MO would like to acknowledge the Director and HOD
there is no such bond formation in 2,3-dihydroxybenzoic acid. (Chemistry Department) for the research infrastructure. The
The bifurcated hydrogen bond formation is supported by the authors thank the DST (Department of Science and Technology,
fact that the torsion angle of H–N–N–H (hydrazide of isoniazid) Government of India, New Delhi, India) for the SCXRD facility
is 130(2) in cocrystal 7 and 135(1) in cocrystal 8 which accounts (procured under the FIST programme). MO is grateful to NITK
for the planarity of the hydrazide involved in the bond forma- for the fellowship. DRT and MO are also thankful to MIT
tion with the hydroxyl ‘O’ of the salicylic acid (Table 1).
Manipal for the DSC facility. DRT and MO are indebted to the
CSMCRI for extending the NMR facility.
Comparison of the NPyr–H/–O (acid) bond distance with the
pKa of the coformer in the reported cocrystals of isoniazid
with aliphatic and aromatic dicarboxylic acids
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ꢀ
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