Structural, spectroscopic (FT-IR, FT-Raman) and theoretical studies of the 1:1 cocrystal of isoniazid with p-coumaric acid

Article abstract of DOI:10.1016/j.molstruc.2012.10.029

The 1:1 cocrystal of isoniazid (INH) with p-coumaric acid (pCA) has been prepared by slow evaporation method in methanol, which was crystallized in monoclinic P2₁/n space group having four molecules in the asymmetric unit. The cocrystal has bee

Full text of DOI:10.1016/j.molstruc.2012.10.029

Journal of Molecular Structure 1033 (2013) 272–279
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Structural, spectroscopic (FT-IR, FT-Raman) and theoretical studies of the 1:1
cocrystal of isoniazid with p-coumaric acid
⇑
N. Ravikumar, Gopikrishna Gaddamanugu, K. Anand Solomon
Department of Chemistry, Sankar Foundation Research Institute, Visakhapatnam 530 047, Andhra Pradesh, India
h i g h l i g h t s
"
"
"
This research paper describes the experimental and theoretical studies on a co-crystal-which are usually prepared to enhance the physiochemical
property of a molecule (usually an active pharmaceutical ingredient).
Here the API is an anti-tuberculosis drug (Isoniazid) and the cocrystal former is a nutraceutical (p-coumaric acid). This combination can be termed as a
‘‘synergistic pharmaceutical co-crystal’’ as p-coumaric is sure to add its inherent anti-oxidant property, etc.
Instead of using a GRAS listed compound (as a co-crystal former)- a molecule with well documented pharmacological property has been used. This can
also be programmed in such a way that the side-effects of the API can be reduced by the co-crystal former.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2012
Received in revised form 6 October 2012
Accepted 9 October 2012
Available online 23 October 2012
The 1:1 cocrystal of isoniazid (INH) with p-coumaric acid (pCA) has been prepared by slow evaporation
method in methanol, which was crystallized in monoclinic P21/n space group having four molecules in
the asymmetric unit. The cocrystal has been characterized by single crystal X-ray analysis, FTIR, FT
Raman and DFT calculations. The crystal structure was stabilized by OAHphenolÁ Á ÁNpyridine, NAHÁ Á ÁO@C,
COOHÁ Á ÁNAH and CAHÁ Á ÁO hydrogen bonding interactions. The geometry optimized structure of the
cocrystal at the B3LYP/6-31G(d,p) level of theory has been used to calculate the vibrational frequencies.
Ó 2012 Elsevier B.V. All rights reserved.
Keywords:
API-nutraceutical
Cocrystal
X-ray crystallography
Ab initio
1. Introduction
becomes resistant when INH is administered as a single drug. This
is the main reason why INH will always be used in combination
The physicochemical properties like stability and bioavailability
play a major role in the development of an active pharmaceutical
ingredient (API) into a drug candidate [1]. Often it is necessary to
formulate an API into its corresponding salt or solvate for improved
stability and bioavailability [2]. A cocrystal is a multicomponent
molecular complex with definite stoichiometric ratio of two com-
pounds that can interact through predominantly non-covalent
with other anti-tuberculosis drugs [6]. In the recent years INH
has drawn numerous attentions from the crystal engineering com-
munity due to its robust interactions with molecules having car-
boxylic acid groups to obtain pharmaceutical cocrystals [7]. INH
has three pKa values: pKa1 = 1.8 based on the hydrazine nitrogen,
pKa2 = 3.5 based on the pyridine nitrogen and pKa3 = 10.8 based
on the acidic group [8]. pCA is a hydroxy derivative of the cinnamic
acid and naturally occurs in three isomers (ortho-, meta-, and para-
); pCA is the most commonly occurring isomer in nature. pCA is
found in various edible plants, such as peanuts, carrots, and toma-
toes [9,10] and it is classified as a phytochemical nutraceutical. A
number of promising pharmacokinetic studies have been con-
ducted on pCA showing a positive response in protection against
colon cancer on cultured mammalian cells [11] as well as antioxi-
dant and anti-inflammatory properties in rats and rabbits [12–14].
pCA has two pKa values: pKa1 = 4.6 based on the carboxylic acid
oxygen and pKa2 = 9.3 based on the phenolic oxygen [15]. Herein
we report the preparation, structural, vibrational and theoretical
studies of the INH and pCA cocrystal.
interactions such as hydrogen bonding,
p–p interactions and van
der Waals forces [3]. A pharmaceutical cocrystal is a combination
of an active pharmaceutical ingredient (API) with the GRAS (gener-
ally regarded as safe by US FDA) listed cocrystal former [4]. INH is a
widely used drug alone in the prophylaxis and in combination with
other anti-tuberculosis drugs in the treatment of all forms of tuber-
culosis [5]. Isoniazid proved to be a very potent and cost effective
anti-tuberculosis drug, but Mycobacterium tuberculosis quickly
⇑
Corresponding author. Tel.: +91 9000888382.
E-mail address: anand.dcb@gmail.com (K. Anand Solomon).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.10.029

N. Ravikumar et al. / Journal of Molecular Structure 1033 (2013) 272–279
273
Table 2
2. Experimental
Atomic coordinates (Â104) and equivalent isotropic displacement parameters
(Å2 Â 103) for the 1:1 cocrystal of isoniazid with p-coumaric acid. U (eq) is defined
as one third of the trace of the orthogonalized Uij tensor.
2.1. Synthesis
Atom
x
y
z
U (eq)
Both the starting materials INH and pCA were obtained from
Sigma–Aldrich chemical suppliers. Analytical grade solvent was
used for preparation of the cocrystal. The 1:1 mixture of INH
(137 mg, 1 mmol) and pCA (164 mg, 1 mmol) was dissolved in
5 mL of methanol by heating at 60 °C. The obtained clear solution
was filtered and slowly cooled to ambient temperature. The sol-
vent was then allowed to evaporate at ambient temperature to ob-
tain transparent yellow colored rectangular block crystals for 72 h.
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
À452(10)
5333(14)
3260(14)
1797(14)
2363(13)
4462(14)
5922(14)
777(14)
8583(2)
8475(2)
8774(2)
9189(2)
9289(2)
8993(2)
9496(2)
9898(2)
40(2)
44(2)
43(2)
37(2)
41(2)
43(2)
41(2)
43(2)
39(2)
40(2)
39(2)
48(2)
57(2)
62(3)
55(2)
58(2)
41(2)
45(2)
58(2)
52(2)
50(2)
60(2)
53
51
50
51
49
51
58
68
75
65
87
77
60(30)
60(30)
70(30)
323(11)
1069(11)
1061(9)
257(10)
À495(10)
1868(10)
2078(11)
2883(10)
4709(10)
4930(10)
5827(12)
6000(13)
4445(14)
4209(12)
5343(11)
5281(9)
5160(11)
À1210(8)
3217(8)
3224(8)
4055(9)
342
1113(14)
C(9)
À551(13)
5151(14)
3846(14)
1769(15)
815(17)
3753(18)
4836(17)
1778(14)
4079(13)
5207(13)
6843(11)
À2622(9)
À54(10)
7096(11)
2850
10,193(2)
8653(2)
8262(2)
8231(3)
7849(3)
7536(3)
7902(3)
7501(2)
9002(2)
9382(2)
8302(2)
10,044(2)
10,555(2)
8651(2)
8199
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
N(1)
N(2)
N(3)
O(1)
O(2)
O(3)
O(4)
H(2)
H(3)
H(5)
H(6)
H(7)
H(8)
H(12)
H(13)
H(14)
H(15)
H(1)
H(2B)
H(2A)
H(3A)
H(3B)
2.2. Measurements
Single crystal X-ray diffraction measurements of the 1:1 cocrys-
tal of INH with pCA (I) were carried out on Bruker axs kappa apex2
CCD Diffractometer with Mo Ka radiation at 293 K [16]. Data
reduction was performed with the SAINT program [16] and the
structure was solved using the SIR92 program [17]. SHELXL97 pro-
gram was used for the refinement of the structure [18]. Structure-
invariant direct methods were used for primary atom site locations
and secondary atom site locations were found from the difference
Fourier map. Hydrogen atom site locations were inferred from
neighbouring sites. The final R factor is 0.036 by 2472 reflections
and 211 refined parameters. The crystal data and the details of data
processing are given in Table 1. The final fractional atomic coordi-
nates listed in Table 2, bond lengths, bond angles and torsion an-
gles are given in Table 3. The complete set of structural
parameters in the CIF format is available from the Cambridge Crys-
tallographic Database Center under No. CCDC 889545.
1589
230
402
4881
7307
8698
9565
9068
9399
10,000
8466
7833
7296
7909
À1034
2284
À636
1681
6311
6614
3946
2524
1019
À589
4444
3570
6225
6322
À3454
À1124
8070
FTIR spectrum of I was recorded on a Bruker Alpha-T Fourier
transform infrared spectrophotometer, using the KBr pellet meth-
od in the spectral range 4000–400 cmÀ1 with resolution of
2 cmÀ1 and the data were analyzed using the OPUS 6.5 software.
3666
10,229
9020(30)
9360(30)
9420(30)
5720(120)
5660(110)
4010(100)
2660(170)
6630(140)
5400(170)
Table 1
Crystal data and structure refinement details for the 1:1 co-crystal of isoniazid with p-
coumaric acid.
FT-Raman spectrum of I was recorded on a Bruker RFS 27, stand
alone Fourier transform Raman spectrometer, using the KBr pellet
method in the spectral range 4000–50 cmÀ1 with resolution of
Empirical formula
Formula weight
T (K)
C15H15N3O4
301.30
293(2)
2 cmÀ1
.
Tripos SYBYL expert molecular modeling environment was used
to calculate the partition coefficient octanol/water (logP) of INH,
pCA and I.
k (Å)
0.71073
Crystal system
Space group
a (Å)
Monoclinic
P21/n
7.5750(3)
b (Å)
c (Å)
5.7100(2)
32.5700(5)
2.3. DFT calculations
a
b (°)
(°)
90.00
94.0450(10)
90.00
1405.25(8)
The DFT calculations for the cocrystal I, were performed with
the GAUSSIAN 03 program package [19]. The calculations em-
ployed the B3LYP exchange–correlation functional using 6-
31G(d,p) basis set [20–23]. The single crystal X-ray geometry
was used as a starting point for the optimization of the geometry
of the cocrystal I. Both FTIR and FT Raman frequencies were calcu-
lated by the B3LYP/6-31G(d,p) level of theory. The calculated IR
and Raman frequencies were positive and confirmed that the opti-
mized structure is a local minimum on the potential energy
hypersurface.
c
(°)
V (Å3)
Z
4
Dx (g cmÀ3
)
1.424
0.106
632
l
(mmÀ1
)
F(000)
Crystal size (mm)
h range for data collection (°)
Limiting indices
Reflections collected/unique
Refinement method
0.20 Â 0.20 Â 0.15
2.5–30.4
À6 6 h 6 9, À6 6 k 6 6, À38 6 l 6 37
12100/2472 [R(int) = 0.025]
Full-matrix least-squares on F2
2472/4/211
Data/restraints/parameters
Goodness-of-fit on F2
1.04
3. Results and discussion
Final R indices [I > 2
R indices (all data)
Largest diff. peak and hole
Data collection
Data reduction
Structure solution
Structure refinement
r(I)]
R1 = 0.0364, wR2 = 0.0879
R1 = 0.0443, wR2 = 0.0942
0.15 and À0.22 e ÅÀ3
Bruker APEX-II CCD
Bruker SAINT/XPREP
SIR92
3.1. Crystal structure
The 1:1 M ratio cocrystal I, was crystallized in monoclinic sys-
tem with space group P21/n with four molecules in the asymmetric
unit. The structure of the cocrystal I with the atom numbering
SHELXL97

274
N. Ravikumar et al. / Journal of Molecular Structure 1033 (2013) 272–279
Table 3
Table 3 (continued)
Bond lengths (Å), bond angles (°) and torsion angles for the 1:1 cocrystal of isoniazid
with p-coumaric acid.
Parameters
X-ray
B3LYP/6-31G(d,p)
N(2)AN(3)AH(3A)
N(2)AN(3)AH(3B)
H(3A)AN(3)AH(3B)
C(1)AO(1)AH(1)
C(9)AO(2)AH(2B)
108(6)
108(6)
108(8)
109.5
112.51
111.85
111.94
113.55
108.93
Parameters
X-ray
B3LYP/6-31G(d,p)
Bond lengths
C(1)AO(1)
C(1)AC(2)
C(1)AC(6)
C(2)AC(3)
C(3)AC(4)
C(4)AC(5)
C(4)AC(7)
C(5)AC(6)
C(7)AC(8)
C(8)AC(9)
C(9)AO(3)
C(9)AO(2)
C(10)AO(4)
C(10)AN(2)
C(10)AC(11)
C(11)AC(12)
C(11)AC(15)
C(12)AC(13)
C(13)AN(1)
C(14)AN(1)
C(14)AC(15)
N(2)AN(3)
1.354(9)
1.379
1.403
1.405
1.393
1.412
1.415
1.458
1.395
1.354
1.456
1.242
1.393
1.266
1.359
1.493
1.405
1.403
1.398
1.351
1.353
1.396
1.408
1.378(11)
1.380(11)
1.375(11)
1.388(11)
1.394(11)
1.452(11)
1.368(11)
1.323(11)
1.454(11)
1.222(9)
109.5
Torsion angles
O(1)AC(1)AC(2)AC(3)
C(6)AC(1)AC(2)AC(3)
C(1)AC(2)AC(3)AC(4)
C(2)AC(3)AC(4)AC(5)
C(2)AC(3)AC(4)AC(7)
C(3)AC(4)AC(5)AC(6)
C(7)AC(4)AC(5)AC(6)
C(4)AC(5)AC(6)AC(1)
O(1)AC(1)AC(6)AC(5)
C(2)AC(1)AC(6)AC(5)
C(3)AC(4)AC(7)AC(8)
C(5)AC(4)AC(7)AC(8)
C(4)AC(7)AC(8)AC(9)
C(7)AC(8)AC(9)AO(3)
C(7)AC(8)AC(9)AO(2)
O(4)AC(10)AC(11)AC(12)
N(2)AC(10)AC(11)AC(12)
O(4)AC(10)AC(11)AC(15)
N(2)AC(10)AC(11)AC(15)
C(15)AC(11)AC(12)AC(13)
C(10)AC(11)AC(12)AC(13)
C(11)AC(12)AC(13)AN(1)
N(1)AC(14)AC(15)AC(11)
C(12)AC(11)AC(15)AC(14)
C(10)AC(11)AC(15)AC(14)
C(12)AC(13)AN(1)AC(14)
C(15)AC(14)AN(1)AC(13)
O(4)AC(10)AN(2)AN(3)
C(11)AC(10)AN(2)AN(3)
À179.9(8)
À0.8(12)
0.03(12)
0.5(12)
À179.8(7)
À0.2(11)
À179.9(7)
À0.6(12)
À179.8(7)
1.1(12)
175.2(8)
À5.0(13)
179.3(7)
171.6(8)
À8.3(12)
172.3(8)
À7.0(12)
À6.1(12)
174.5(7)
1.5(12)
À176.9(8)
À0.2(15)
À0.2(15)
À1.3(13)
177.2(8)
À1.3(15)
1.5(15)
À177.82
À0.030
0.101
À0.091
179.86
0.011
179.94
0.058
179.88
À0.049
À179.59
0.358
1.309(9)
1.216(10)
1.335(10)
1.496(11)
1.374(11)
1.378(11)
1.374(12)
1.326(11)
1.326(13)
1.368(13)
1.404(9)
179.94
À179.93
0.041
156.45
À24.12
À22.45
156.91
À0.862
À179.76
À0.046
À0.616
1.173
Bond angles
O(1)AC(1)AC(2)
O(1)AC(1)AC(6)
C(2)AC(1)AC(6)
C(3)AC(2)AC(1)
C(3)AC(2)AH(2)
C(1)AC(2)AH(2)
C(2)AC(3)AC(4)
C(2)AC(3)AH(3)
C(4)AC(3)AH(3)
C(3)AC(4)AC(5)
C(3)AC(4)AC(7)
C(5)AC(4)AC(7)
C(6)AC(5)AC(4)
C(6)AC(5)AH(5)
C(4)AC(5)AH(5)
C(5)AC(6)AC(1)
C(5)AC(6)AH(6)
C(1)AC(6)AH(6)
C(8)AC(7)AC(4)
C(8)AC(7)AH(7)
C(4)AC(7)AH(7)
C(7)AC(8)AC(9)
C(7)AC(8)AH(8)
C(9)AC(8)AH(8)
O(3)AC(9)AO(2)
O(3)AC(9)AC(8)
O(2)AC(9)AC(8)
O(4)AC(10)AN(2)
O(4)AC(10)AC(11)
N(2)AC(10)AC(11)
C(12)AC(11)AC(15)
C(12)AC(11)AC(10)
C(15)AC(11)AC(10)
C(11)AC(12)AC(13)
C(11)AC(12)AH(12)
C(13)AC(12)AH(12)
N(1)AC(13)AC(12)
N(1)AC(13)AH(13)
C(12)AC(13)AH(13)
N(1)AC(14)AC(15)
N(1)AC(14)AH(14)
C(15)AC(14)AH(14)
C(14)AC(15)AC(11)
C(14)AC(15)AH(15)
C(11)AC(15)AH(15)
C(13)AN(1)AC(14)
C(10)AN(2)AN(3)
C(10)AN(2)AH(2A)
N(3)AN(2)AH(2A)
122.9(7)
117.4(7)
119.7(7)
120.2(7)
119.9
119.9
121.2(7)
119.4
122.18
117.75
120.06
119.41
120.83
119.75
121.66
119.32
119.01
117.10
118.85
123.44
121.20
118.94
119.84
119.95
121.36
118.68
127.35
117.09
115.54
123.72
122.63
113.63
120.75
125.20
114.04
122.15
120.53
117.35
118.29
123.59
118.09
118.80
121.91
119.23
123.12
116.14
120.72
123.07
116.04
120.87
118.94
121.41
119.64
117.74
123.98
120.98
115.02
À179.86
0.627
0.150
À0.84(12)
À1.799
119.4
178.6(7)
178.80
117.5(7)
119.6(7)
123.0(7)
121.7(7)
119.2
119.2
119.8(7)
120.1
120.1
127.4(8)
116.3
116.3
125.1(8)
117.4
scheme is shown in Fig. 1. The aim of the present study is to com-
pare the structural features in the crystal structure with the DFT
optimized structure. The crystal was stabilized by intermolecular
OAHÁ Á ÁN, NAHÁ Á ÁO hydrogen bonding interactions forming R22 (7)
ring motifs (Fig. 2). The phenolic OH group of pCA forms moderate
hydrogen
bonding
[O(1)AH(1)Á Á ÁN(1) = 2.742(10) Å
and
<O(1)AH(1)AN(1) = 148.8°] with the nitrogen atom of the pyridine
moiety of INH [24]. The amine nitrogen of INH also forms moderate
hydrogen
bonding,
[N(3)AH(3A)Á Á ÁO(3) = 3.028(10) Å
and
117.4
<N(3)AH(3A)AO(3) = 169 (9)°] with the carboxylic acid’s carbonyl
group of pCA. But the carboxylic acid OH group of pCA forms weak
122.3(7)
122.4(7)
115.3(7)
122.1(8)
121.4(7)
116.6(7)
117.5(8)
125.2(7)
117.3(7)
119.1(8)
120.4
120.4
123.8(9)
118.1
118.1
124.0(9)
118.0
hydrogen
bonding
[O(2)AH(2B)Á Á ÁN(2) = 3.338(9) Å
and
<O(2)AH(2B)AN(2) = 150.2°] with the amide nitrogen of INH
[23]. The crystal structure is also stabilized by both inter and
intra molecular CAHÁ Á ÁO hydrogen bonding interactions forming
R44 (22) ring motifs (Fig. 3). The range of HÁ Á ÁO distances (Table 4)
found in I agrees with those found for CAHÁ Á ÁO hydrogen bonds
[25]. The crystal is also stabilized by van-der-Waals interactions.
The crystal packing of I down the crystallographic b-axis is shown
in Fig. 4.
3.2. B3LYP/6-31G(d,p) calculations
118.0
119.2(9)
120.4
The DFT optimizations were performed on the X-ray structure I
at B3LYP/6-31G(d,p) level which afforded the optimized structure
(II) shown in Fig. 5. As evident from the results in Table 3, the bond
lengths and bond angles of I and II correlate well. The angle be-
tween the planes defined by the aromatic ring atoms
(N1C14C15C11C12C13) and (C3C4C5C6C1C2) in I is 4°, whereas
in II the angle is 83° which is reflected in the variation of torsion
angles of II listed in Table 3.
120.4
116.3(8)
120.1(7)
125(6)
114(6)

N. Ravikumar et al. / Journal of Molecular Structure 1033 (2013) 272–279
275
Fig. 1. Atom numbering scheme showing 50% probability displacement ellipsoids of the 1:1 cocrystal of isoniazid with p-coumaric acid.
Fig. 2. Ring motif – R22 [7] in the cocrystal.
Fig. 3. Ring motif R44 [22] in the cocrystal.

276
N. Ravikumar et al. / Journal of Molecular Structure 1033 (2013) 272–279
Table 4
Hydrogen bonds for the 1:1 co-crystal of isoniazid with p-coumaric acid (Å and °).
DAHÁ Á ÁA
d(DAH)
d(HÁ Á ÁA)
d(DÁ Á ÁA)
<(DHA)
X-ray
O(1)AH(1)Á Á ÁN(1)a
N(2)AH(2A)Á Á ÁO(3)b
O(2)AH(2B)Á Á ÁN(2)b
O(2)AH(2B)Á Á ÁN(3)b
N(3)AH(3A)Á Á ÁO(3)c
N(3)AH(3B)Á Á ÁO(2)d
C(7)AH(7)Á Á ÁO(2)
0.82
0.88(10)
0.82
2.01
2.15(10)
2.60
2.742(10)
2.901(9)
3.338(9)
2.619(9)
3.028(10)
2.968(9)
2.7831
148.8
144(8)
150.2
174.9
169(9)
119(7)
101
0.82
1.80
0.90(7)
0.90(7)
0.93
2.14(8)
2.43(9)
2.45
a
b
c
Symmetry codes: Àx + 1/2, y + 1/2, Àz + 3/2.
Symmetry codes: Àx + 1, Ày, Àz + 2.
Symmetry codes: Àx + 1, Ày + 1, Àz + 2.
Symmetry codes: x, y + 1, z.
d
Fig. 5. The optimized structure at the B3LYP/6-31G(d,p) level of theory of the 1:1
cocrystal of isoniazid with p-coumaric acid.
3.3. Vibrational spectra
Fig. 6a shows the solid-state FTIR spectrum of the cocrystal I.
The crystal structure analysis showed that both the phenolic–OHar
and carboxylic acid–OHCOOH groups of pCA are involved in only
intermolecular hydrogen bonds of 3.338(9), 2.742(10), 2.619(9) Å
the second-derivative (d2) spectrum, the minima have the same
wavenumbers as the maxima in the absorbance spectrum. The rel-
ative intensities of the bands in the d2 spectrum vary inversely
with the square of the half-width of the absorption bands [27,28].
The IR frequencies, calculated for II are shown in Fig. 6c as ver-
tical lines. There are 105 modes in the 4000–0 cmÀ1 range and
their intensities vary from 1609 to 0.005 km/mol. The proposed
assignments of the IR bands are listed in Table 5. The most intense
(Table 4). The
3325 cmÀ1 due to an intermolecular hydrogen bonding with the
pyridinium nitrogen atom of INH. The amide NH band of INH
m
OHar band of pCA shifts from 3381 cmÀ1 to
m
shifts from 3304 cmÀ1 to 3285 cmÀ1, due to hydrogen bonding
interactions with the carbonyl group of the carboxylic acid of
pCA. The broad absorption in the 1500–400 cmÀ1 region, with
the centre of gravity at 1207 cmÀ1, in the IR spectrum of I, arises
from the stretching and bending vibrations of the OH groups, and
it is characteristic of the short OAHÁ Á ÁO hydrogen bonds [26]. No
change was observed in the C@C stretching frequency at
1629 cmÀ1 of the styrene moiety of pCA in I.
lines are assigned to the
m
NAHÁ Á ÁO,
m(C@O), m(CC)C@C, m(CAOH),
b(CH) and b(CH)ar vibrations. The experimental Raman spectrum
of I, is shown in Fig. 7a. The Raman frequencies, calculated for II
are shown in Fig. 7b as vertical lines. There are 105 modes in the
4000–0 cmÀ1 range and their intensities vary from 1411 to
0.005 km/mol. The tentative assignments of the Raman bands are
listed in Table 6. In the Raman spectrum, the intensity of the
The continuous absorption of the OAHÁ Á ÁO vibrations in the
1500–400 cmÀ1 region overlaps bands assigned to in-plane and
out-of-plane CAH, stretching and bending CAC, CAN, CAO vibra-
tions, as well as the skeletal and ring ones. Some of these vibrations
can be distinguished in the second-derivative (d2) spectrum
(Fig. 6b). The second-derivative (d2) spectrum can be used to deter-
mine the frequencies of the narrow bands covered by the broad
absorption due to the stretching and bending OHO vibrations. In
m
OH frequency is very weak [29] and the absorption due to
is absent. The spectrum shows strong absorption due to
vibrations. The band assigned to the C = O has weak intensity
m
OH
m
CAH
m
[30]. The IR frequency values obtained from the DFT calculations
are very similar to those of the experimental values which did
not require any further scaling [31].
Fig. 4. The crystal packing diagram of the 1:1 cocrystal of isoniazid with p-coumaric acid down the crystallographic b-axis (a) two-dimensional view and (b) three-
dimensional view.

N. Ravikumar et al. / Journal of Molecular Structure 1033 (2013) 272–279
277
Fig. 6. Infrared spectra of the 1:1 cocrystal of isoniazid with p-coumaric acid, I (a) the experimental solid-state spectrum of I, (b) the second-derivative spectrum of I, and (c)
IR frequencies calculated by the B3LYP/6-31G(d,p) approach for II.
Table 5
Table 5 (continued)
FTIR experimental (m mcal) by the B3LYP/6-
exp), second derivative (d2) and calculated (
31G(d,p) frequencies (cmÀ1) for the 1:1 cocrystal of isoniazid with p-coumaric acid.
I
II
mexp
d2
mcal
Intensitya
Assignmentsb
I
II
1002
1002
1048
1046
1031
1013
1005
993
988
927
922
916
902
886
879
874
865
848
819
798
779
756
727
693
672
650
553
524
437
435
329
30.48
1.21
0.76
0.80
2.24
b(CH)
b(CH)
b(CH)
b(CH)
b(CH)
mexp
d2
mcal
3470
Intensitya
169.21
Assignmentsb
m
m
m
m
m
m
m
m
m
m
m
m
m
m
m
m
m
m
OAHarÁ Á ÁN
3325
3285
3326
3286
NAHÁ Á ÁO@C
NAHÁ Á ÁO@C
NAHÁ Á ÁO@C
NAHÁ Á ÁO@C
NAHÁ Á ÁO@C
NAHÁ Á ÁO@C
NAHÁ Á ÁO@C
3250
3236
3233
3229
3226
3219
3195
3190
1671
1656
1639
1631
1592
1571
1553
1527
1502
1453
1433
1405
1377
1360
1350
1332
1324
1295
1285
1267
1265
1230
1225
1164
1145
1135
1109
1101
2.70
217.36
1609.8
19.33
146.14
25.02
15.99
0.02
980
980
1.47
m
m
c
c
c
c
c
c
c
c
c
c
(CCO)
(CCO)
(CH)ar
(CO)
(CO)
(CO)
(CH)
(CH)
(CH)
(CH)
(CH)
(CH)ar
10.60
10.05
98.52
7.28
48.48
91.49
4.69
21.51
96.48
27.40
6.66
377.41
48.73
1.13
68.02
0.38
1.73
153.52
30.99
27.69
9.92
946
920
947
922
3059
3017
1672
CHar
CHar
+
+
m
m
CHC@C
CHC@C
848
849
1672
236.35
240
(C@O)
(C@O)
(C@O)
(CC)C@C
(CC)ar
(CC)ar
(CN)ar, b(HANAN)
(CC)ar
15.92
231.55
82.84
97.02
222.92
44.34
32.55
12.30
144.51
93.30
74.42
81.25
2.28
12.26
1.58
7.68
479.06
10.75
0.42
1629
1605
1582
1560
1514
1479
1450
1629
1606
1583
1562
1518
1481
1450
836
750
837
750
a
a
a
a
(CCC)
(CCC)
(CCC)
(CCC)
b(CANAH)
b(CH)C@C
b(CH)C@C
687
687
b(CO)
b(CO)
ø(CO)
1408
1380
1409
1382
m(CC)ar
b(CH)C@C + b(OH)ar
b(CH)C@C + b(OH)ar
b(CH)C@C + b(OH)ar
b(CH)C@C + b(OH)ar
cOH
a
(C@CC)
b(CH)
b(CH)
c(OH)ar
0.12
2.30
1317
1283
1317
1285
m
m
m
m
m
CAN
(CAOH)
(CAOH)
(CAOH)
(CAOH)
m
– Stretching; b – deformation in-plane; c – deformation out-of-plane; a(CCC) –
aromatic ring in-plane deformation: ø – aromatic ring out-of-plane deformation.
a
Intensity in km/mol.
Assignments for calculated frequencies for II.
b
1238
1207
1175
1239
1208
1176
9.95
b(OH)ar
b(CH)
b(CH)ar
b(CH)ar
b(CH)ar
b(CH)
129.01
229.34
297.16
7.05
20.26
40.51
3.4. LogP calculations
1106
1106
b(CH)
The logP calculated by Tripos SYBYL expert molecular modeling
environment for the cocrystal I, is found to be 0.82, where as for

278
N. Ravikumar et al. / Journal of Molecular Structure 1033 (2013) 272–279
Fig. 7. Raman spectra of the 1:1 cocrystal of isoniazid with p-coumaric acid, I (a) the experimental solid-state spectrum of I and (b) Raman frequencies calculated by the
B3LYP/6-31G(d,p) approach for II.
Table 6
Table 6 (continued)
Raman experimental (Rexp) and calculated (Rcal) by the B3LYP/6-31G(d,p) frequencies
(cmÀ1) for the 1:1 cocrystal of isoniazid with p-coumaric acid.
I
II
Rexp
Rcal
Intensitya
Assignmentsb
I
II
693
6.95
12.01
8.02
4.34
2.41
0.25
0.48
8.49
1.06
0.24
4.16
b(CC@O)
b(CC@O)
ø(CC)
Rexp
Rcal
Intensitya
Assignmentsb
672
650
624
553
531
524
463
437
435
329
3233
3195
3190
1411.49
79.60
13.51
m
m
m
m
m
m
m
m
m
m
NAHÁ Á ÁO
652
3060
CHar
CHar
CHar
+
+
+
m
m
m
CHC@C
CHC@C
CHC@C
a
c
a
(CCC)
OH
(C@CAC)
3025
1673
1624
1671
1656
1639
1631
1592
1571
1553
1527
1502
1350
1332
1324
1285
1267
1265
1230
1225
1164
1145
1135
1031
1013
1005
988
1236.13
168.07
65.96
503.23
38.42
25.47
15.3
5.34
12.39
4.50
71.42
261.55
147.81
89.93
89.98
54.13
103.64
161.01
224.98
1.26
1.55
8.10
31.68
5.57
0.40
4.55
21.20
9.70
26.76
3.34
2.58
(C@O)
ø(CC)
ø(CC)
b(CH)
b(CH)
(CC)C@C
(CC)C@C
(CC)ar
(CC)ar
(CC)ar
1607
1585
c
(OH)ar
m
– Stretching; b – deformation in-plane;
matic ring in-plane deformations; ø – aromatic ring out-of-plane deformations.
c
– deformation out-of-plane; a – aro-
b(HANAN)
(CC)ar
m
a
Intensity in km/mol.
Assignments for calculated frequencies for II.
b(CANAH)
b
1319
1273
b(CH)C@C + b(CH)ar
b(CH)C@C + b(CH)ar
b(CH)C@C + b(CH)ar
m(CAOH)
m(CAOH)
m(CAOH)
INH and pCA the logP values are À0.6680 and 1.5720. As INH is too
hydrophilic (negative logP) it is unable to pass through mem-
branes, as they hardly enter the hydrophobic interior of the lipo-
philic bilayer. Whereas pCA is too lipophilic (high logP) it poorly
permeates through membranes. Since the cocrystal I, has moderate
logP value it is neither too hydrophobic nor too lipophilic it would
be able to pass through the lipophilic bilayer [32,33].
1239
1206
1174
b(OH)ar
b(CH)
b(CH)ar
b(CH)ar
b(CH)ar
b(CH)
1003
b(CH)
b(CH)
983
893
m
m
(CCO)
(CCO)
993
916
902
886
879
874
865
848
4. Conclusions
b(CNC)ring
b(CNC)ring
b(CNC)ring
The crystal structure of the 1:1 cocrystal of INH with pCA is sta-
bilized by OAHphenolÁ Á ÁNpyridine, NAHÁ Á ÁO@C and COOHÁ Á ÁNAH
hydrogen bonding interactions. The crystal structure is also stabi-
lized by both intra and intermolecular CAHÁ Á ÁO hydrogen bonds.
In the optimized structure of I, estimated by the B3LYP/6-
31G(d,p) level of theory, the angle between the approximate
planes of the two molecules in the cocrystal is deviated by 80°
862
804
c
c
c
c
c
(CH)
(CH)
(CH)
(CH)ar
(CH)ar
3.63
30.19
3.99
819
798
a(CCC)

N. Ravikumar et al. / Journal of Molecular Structure 1033 (2013) 272–279
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INH amine (NH2) group are observed at 3285 cmÀ1
asymNH2) and
3167 cmÀ1 symNH2) which are shifted from 3304 cmÀ1 to
(
(
3112 cmÀ1 respectively due to hydrogen bonding interactions with
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Acknowledgements
The authors thank the Managing Trustee and the Founder Trus-
tee of the Sankar Foundation for their financial support and
encouragement. We thank Dr. Chelli Janardhana, Head of the
Chemistry department, Sri Sathya Sai University, Puttaparthi,
Andhra Pradesh, for the usage of Gaussian software. We also thank
the DST and SAIF, IIT Madras for the single crystal X-ray data
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