Structural, spectroscopic and thermal analysis of cocrystals of carbamazepine and piracetam with hydroquinone

Article abstract of DOI:10.1007/s10870-011-0147-y

Cocrystals of two important active pharmaceutical ingredients, carbamazepine and piracetam, with hydroquinone are reported. Cocrystal formation between the selected APIs and hydroquinone is investigated with the aid of solid-state grinding methods. Both the crystal structures belong to the triclinic, P 1 space group, with the cocrystal involving carbamazepine and hydroquinone having the unit cell parameters a = 6.9725 (14) A, b = 8.8175 (18) A, c = 15.083 (3) A, α = 106.96 (3)°, β = 92.16 (3)°, γ = 103.23 (3)°, V = 858.0 (4) A³ and Z = 2; and the cocrystal involving piracetam and hydroquinone has the unit cell parameters a = 6.4909 (13) A, b = 6.5410 (13) A, c = 11.612 (2) A, α = 103.92 (3)°, β = 104.53 (3)°, γ = 91.06 (3)°, V = 461.59 (18) A³ and Z = 2. Analysis of the cocrystals revealed that they are sustained by an alcohol-carboxamide heterosynthon. In addition, the cocrystal of carbamazepine and hydroquinone features an amide-alcohol heterosynthon and an alcohol-alcohol homosynthon. The cocrystal of piracetam and hydroquinone features an amide-amide dimer synthon. Cocrystal formation was evidenced from the shifts in the vibrational frequencies corresponding to the functional groups present on the cocrystal components.

Full text of DOI:10.1007/s10870-011-0147-y

J Chem Crystallogr (2011) 41:1604–1611
DOI 10.1007/s10870-011-0147-y
ORIGINAL PAPER
Structural, Spectroscopic and Thermal Analysis of Cocrystals
of Carbamazepine and Piracetam with Hydroquinone
•
Srinivasulu Aitipamula Pui Shan Chow
•
Reginald B. H. Tan
Received: 6 April 2011 / Accepted: 31 May 2011 / Published online: 11 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Cocrystals of two important active pharma-
ceutical ingredients, carbamazepine and piracetam, with
hydroquinone are reported. Cocrystal formation between
the selected APIs and hydroquinone is investigated with
the aid of solid-state grinding methods. Both the crystal
ꢀ
structures belong to the triclinic, P1 space group, with the
cocrystal involving carbamazepine and hydroquinone
vibrational frequencies corresponding to the functional
groups present on the cocrystal components.
Keywords Cocrystal Á Carbamazepine Á Piracetam Á
Hydroquinone Á Crystal structure Á Synthon Á Infrared
˚
having the unit cell parameters a = 6.9725 (14) A,
Introduction
˚
˚
b = 8.8175 (18) A, c = 15.083 (3) A, a = 106.96 (3)°,
3
˚
Crystal engineering has matured into a multi-disciplinary
area of research which encompasses material science,
supramolecular chemistry, molecular recognition, biology,
pharmaceutical sciences, etc. [1]. It aims to understand
intermolecular interactions between two or more kinds of
functional groups by analyzing crystal structures of related
compounds and the information thus obtained is used to
design novel structures with the desired properties [2]. One
of the fascinating fields of current interest is the design of
multi-component crystals or cocrystals, which are being
developed to fine tune various properties of active phar-
maceutical ingredients (APIs), such as hydration, stability,
solubility, dissolution rate, bioavailability, etc. [3]. A major
advantage of cocrystal engineering is that the nonionizable
APIs are also amenable to cocrystal design and successful
application of crystal engineering strategies witnessed co-
crystals of several APIs exhibiting promising physico-
chemical properties [4].
b = 92.16 (3)°, c = 103.23 (3)°, V = 858.0 (4) A and
Z = 2; and the cocrystal involving piracetam and hydro-
˚
quinone has the unit cell parameters a = 6.4909 (13) A,
˚
˚
b = 6.5410 (13) A, c = 11.612 (2) A, a = 103.92 (3)°,
3
˚
b = 104.53 (3)°, c = 91.06 (3)°, V = 461.59 (18) A and
Z = 2. Analysis of the cocrystals revealed that they are
sustained by an alcohol–carboxamide heterosynthon. In
addition, the cocrystal of carbamazepine and hydroquinone
features an amide–alcohol heterosynthon and an alcohol–
alcohol homosynthon. The cocrystal of piracetam and
hydroquinone features an amide–amide dimer synthon.
Cocrystal formation was evidenced from the shifts in the
Electronic supplementary material The online version of this
article (doi:10.1007/s10870-011-0147-y) contains supplementary
material, which is available to authorized users.
S. Aitipamula (&) Á P. S. Chow Á R. B. H. Tan
Institute of Chemical and Engineering Sciences,
Agency for Science, Technology and Research (A*STAR),
1 Pesek Road, Jurong Island 627833, Singapore
e-mail: srinivasulu_aitipamula@ices.a-star.edu.sg
In this study, we report the synthesis, structural, spec-
troscopic, and thermal analysis of cocrystals of two
important APIs, namely carbamazepine (CBZ) and pi-
racetam (PA), with hydroquinone (HQ) (Scheme 1). HQ
exists in four polymorphic forms (a, b, c, and d) [5–8],
among which b-HQ clathrate is the most well studied form
because of the resemblance of rhombohedral host lattice to
b-polonium and its ability to encage a variety of small and
R. B. H. Tan (&)
Department of Chemical and Biomolecular Engineering,
National University of Singapore, 4 Engineering Drive 4,
Singapore 117576, Singapore
e-mail: reginald_tan@ices.a-star.edu.sg
123

J Chem Crystallogr (2011) 41:1604–1611
1605
belongs to its monoclinic polymorph (CSD Refcode: BIS-
MEV01), and HQ belongs to its rhombohedral polymorph
(b, CSD Refcode: HYQUIN02). All the solvents used were
of analytical grade. Crystallization experiments were con-
ducted by dissolving a 1:1 stoichiometric mixture of CBZ
(100 mg, 0.42 mmol) and HQ (46.6 mg, 0.42 mmol), and a
2:1 stoichiometric mixture of PA (100 mg, 0.70 mmol) and
HQ (38.73 mg, 0.35 mmol) in a minimum amount of sol-
vent (approximately 3–5 mL) followed by slow evaporation
of the solvent at ambient conditions. Crystals that belong to
the cocrystals were obtained within 2–5 days. When CBZ
and HQ were cocrystallized in a 2:1 stoichiometric ratio,
crystals of 1:1 CBZ-HQ cocrystal and a powder of CBZ
were obtained.
Scheme 1 Molecular structures of the APIs and HQ
large molecules (Ne, HF, H2S, MeOH, C60) in the doubly
interpenetrating cubic cage [9–11]. Quinhydrone was
believed to be the first cocrystal that was prepared by
¨
Wohler in 1844 by grinding a 1:1 stoichiometric ratio of
quinone and HQ [12]. Several cocrystals/solvates of HQ
have been reported and an analysis of the Cambridge
Structural Database (CSD) revealed that more than a
hundred crystal structures contain HQ. CBZ is an anti-
convulsant and also an analgesic drug [13]. It has been
found to crystallize as four anhydrous polymorphs [14–20].
CBZ has been subjected to a thorough cocrystal screening
that resulted in the identification of as many as 50 co-
crystals [21–24], which also include a cocrystal with sac-
charin that showed improved bioavailability in dogs when
compared to the CBZ marketed drug (Tegretol tablets)
[24]. Interestingly, most of these cocrystals contain car-
boxylic acids as coformers. Crystal structure analysis of
these cocrystals revealed that a majority of them were
sustained by an amide–acid heterosynthon, because of the
hydrogen bonding complementarity between the carbox-
amide and carboxylic acid groups. PA is a noortropic drug
for the treatment of memory and balance problems [25]
and it crystallizes in five polymorphic forms [26]. Several
cocrystals of PA with OH-group functionalized aliphatic
and aromatic carboxylic acids have been reported recently
[27, 28]. Our objectives in this study are to prepare, char-
acterize and analyze the cocrystals between the selected
APIs and HQ using various analytical techniques, such as
nuclear magnetic resonance (NMR) and Fourier-transform
infrared (FT-IR) spectroscopy, differential scanning
calorimetry (DSC), thermogravimetric analysis (TGA),
powder X-ray diffraction (PXRD), and single-crystal X-ray
diffraction.
Grinding Experiments
Grinding was performed using a Retsch Mixer Mill model
MM301 with 10 mL stainless steel grinding jars with one
7 mm stainless steel grinding ball at a rate of 30 Hz for
15 min. Experiments were carried out with varied stoi-
chiometric ratios of CBZ and HQ, and PA and HQ. A small
amount of methanol (ca. 0.05 mL or 2 drops from a pip-
ette) was added to the reactants prior to the grinding. The
resulting powder samples were analyzed by PXRD for the
cocrystal formation. The external temperature of the
grinding jar at the completion of the experiments did not
exceed ca. 30 °C.
Single-Crystal X-ray Diffraction
X-ray reflections were collected on a Rigaku Saturn CCD
area detector with graphite monochromated Mo–Ka radi-
˚
ation (k = 0.71073 A). Data were collected and processed
using CrystalClear (Rigaku) software. Structures were
solved by direct methods and SHELX-TL [29] was used for
structure solution and least-squares refinement. The non-
hydrogen atoms were refined anisotropically. All hydrogen
atoms were fixed at idealized positions except for the N–H
and O–H hydrogen atoms which were located from the
difference Fourier map and allowed to ride on their parent
atoms in the refinement cycles. The O–H bond distance of
one of the hydroxyl groups of HQ in CBZ–HQ cocrystal
was found to be longer than usual in the normal refinement
cycles, and hence this distance was fixed using DFIX
command in the SHELX. For the calculation of hydrogen
bond metrices, all O–H, N–H, and C–H distances are
Experimental
Preparation of Cocrystals by Solution Crystallization
˚
neutron normalized to 0.983, 1.009, and 1.083 A, respec-
CBZ, PA and HQ were purchased from Sigma-Aldrich, and
used as received without any further purification. PXRD
analysis of these samples revealed that CBZ belongs to its
trigonal polymorph (CSD Refcode: CBMZPN03), PA
tively. Data collection and refinement details are listed in
Table 1, and pertinent hydrogen bond distances are pro-
vided in Table 2.
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J Chem Crystallogr (2011) 41:1604–1611
Powder X-ray Diffraction (PXRD)
and 1.5 cm diameter. The data were collected over an angle
range of 2° to 50° with a scanning speed of 2° per minute.
Powder diffractograms were recorded on a Bruker D8
Advance (Bruker AXS GmbH, Karlsruhe, Germany) in
Bragg–Brentano geometry equipped with a Cu–Ka source
Thermal Analysis
˚
(k = 1.54056 A), 2.5° primary and secondary soller slits,
DSC was performed with a Perkin Elmer, Diamond DSC
with an Autosampler. Crystals taken from the mother liquor
were blotted dry on a filter paper and placed in crimped but
vented aluminium sample pans. The sample size was
2–5 mg and the temperature range was typically 25–200 °C
at a heating rate of 5 °C min-1. The samples were purged
with a stream of flowing nitrogen (20 mL min-1). The
instrument was calibrated using indium as the reference
material.
0.3° divergence slit, an 0.3° antiscatter slit and a position
sensitive microgap detector, Vantec-1, (Bruker AXS
GmbH, Karlsruhe, Germany). The voltage and current
applied were 35 kV and 40 mA, respectively. Samples
were placed on a sample holder which has 1 mm thickness
Table 1 Crystal data of the cocrystals
TGA was performed on a TA instruments, TGA Q500
thermogravimetric analyzer. Approximately 15 mg of the
sample was added to an alumina crucible. The samples
were heated over the temperature range of 25 to 300 °C at
a constant heating rate of 5 °C min-1. The samples were
purged with a stream of flowing nitrogen throughout the
Compound reference
CBZ–HQ
PA–HQ
Molar ratio
1:1
1:0.5
Empirical formula
Mr
C
21H18N2O3
C9H13N2O3
197.21
346.37
Crystal size (mm)
Crystal system
20 9 16 9 10
Triclinic
18 9 15 9 10
Triclinic
experiment at 40 mL min-1
.
˚
a/A
6.9725(14)
8.8175(18)
15.083(3)
106.96(3)
92.16(3)
6.4909(13)
6.5410(13)
11.612(2)
103.92(3)
104.53(3)
91.06(3)
˚
b/A
Spectroscopic analysis
˚
c/A
1
All the H NMR spectra were recorded at 400 MHz on a
Bruker instrument in DMSO-d6 at 25 °C. The samples
obtained from the crystallization experiments were air
dried before the analysis.
a/°
b/°
c/°
103.23(3)
858.0(3)
3
˚
Unit cell volume/A
461.59(18)
110(2)
Transmission infrared spectra of the solids were
obtained using a Fourier-transform infrared spectrometer
(Bio-Rad, FTS 3000MX IR spectrometer). Typically,
*25 mg of the sample was ground with KBr in an agate
mortar and pressed with a steel die into a pellet. The FT-IR
spectra were collected for 64 scans at 4 cm-1 resolution.
Temperature/K
110(2)
ꢀ
P1
ꢀ
P1
Space group
Z
2
2
No. of reflections measured
No. of independent reflections
Rint
12317
4220
6491
2274
0.0400
0.0801
0.2002
0.0920
0.2141
0.0188
0.0457
0.1131
0.0478
0.1151
Final R1 values (I [ 2r(I))
Final wR(F2) values (I [ 2r(I))
Final R1 values (all data)
Final wR(F2) values (all data)
Cambridge Structural Database (CSD)
The CSD (November 2010 update) was searched for the
crystal structures of CBZ, PA and HQ. Only organic crystal
Table 2 Hydrogen bond parameters (D–H distances were neutron normalized)
˚
˚
˚
Cocrystal
CBZ–HQ
D–HÁÁÁAa
HÁÁÁA/A
DÁÁÁA/A
D–HÁÁÁA/A
Symmetry code
O1–H1ÁÁÁO3
O2–H4ÁÁÁO1
N2–H7ÁÁÁO2
N2–H8ÁÁÁO2
O3–H1ÁÁÁO1
N2–H4ÁÁÁO2
N2–H6ÁÁÁO1
C3–H3ÁÁÁO3
1.67
1.68
2.09
2.09
1.73
1.91
1.94
2.38
2.648(2)
2.655(2)
3.024(3)
2.963(3)
2.702(1)
2.914(2)
2.933(2)
3.445(2)
171
170
153
143
170
171
167
166
-1 ? x, y, z
1 ? x, y, z
1 - x, 1 - y, -z
x, -1 ? y, z
PA–HQ
1 - x, -y, 1 - z
1 - x, 1 - y, 1 - z
x, 1 ? y, z
x, 1 ? y, z
a
D Donor, A Acceptor
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J Chem Crystallogr (2011) 41:1604–1611
1607
structures for which 3D coordinates were determined, with
no errors, and that were not ionic and not polymeric were
retrieved. The crystal structures solved from PXRD data
were excluded.
corresponding to the excess component. These observa-
tions suggest that a cocrystal can be obtained by cocrys-
tallization of CBZ and HQ in 1:1 stoichiometric ratio.
Cocrystallization of CBZ and HQ from methanol in the 1:1
molar ratio afforded a cocrystal and single-crystal X-ray
diffraction confirmed that CBZ and HQ are present in 1:1
stoichiometry. Cocrystal stoichiometry involving PA and
HQ was identified as 2:1 (PA:HQ) by grinding methods
(Fig. 1b). Single crystals suitable for X-ray analysis were
obtained from ethyl acetate and confirmed that the PA and
HQ are present in the crystal structure in 1:0.5 stoichi-
ometry ratio. Interestingly, the PXRD patterns of the
powder resulted in grinding experiments on PA and HQ in
1:2 and 1:1 stoichiometric ratios contain some new peaks
which did not match with any of the polymorphs of PA and
HQ. No study was undertaken to fully analyze these peaks
in detail. However, we surmise that these peaks may be the
result of phase transformation to unknown forms of any of
the cocrystal components.
Results and Discussion
The possible hydrogen bond recognition patterns between
alcohols and primary amides have been analyzed recently
based on the structures deposited in the CSD [22]. It was
found that supramolecular heterosynthons involving the
amide NH and alcohol or alcohol and amide carbonyl, are
the most probable synthons which contribute to 44 and
43%, respectively, of the total structures in which both a
primary amide and an alcohol moiety are present. Fur-
thermore, it was also found that amide–amide and alcohol–
alcohol homosynthons are found in 31 and 24%, respec-
tively, of the total crystal structures. In the present study,
the presence of multiple functional groups, such as two
hydroxyl groups in HQ and an extra carbonyl on the PA,
lead to an imbalance between hydrogen bond acceptors and
donors, and prediction of cocrystal stoichiometry is diffi-
cult in these cases. Solid-state grinding has been evolved as
an effective method for cocrystal screening and also to
achieve the stoichiometric diversity in cocrystal formation
[30]. Hence, we employed this method to investigate the
cocrystal formation between the selected compounds.
Mixtures of different stoichiometric ratios (1:1, 1:2, and
2:1) of the cocrystal components were ground in a ball-mill
and the resulting powders were analyzed by PXRD. In the
case of CBZ and HQ, while all the grinding experiments
resulted in powders which contain new peaks compared to
the cocrystal components, grinding experiment in 1:1
(CBZ:HQ) stoichiometric ratio exclusively resulted in a
powder for which the PXRD pattern did not contain any of
the peaks corresponding to the cocrystal components
(Fig. 1a). PXRD patterns of the powders resulted from the
grinding experiments on 1:2 and 2:1 contain the peaks
Crystal Structure Analysis
Crystal structure of CBZ–HQ belongs to triclinic space
ꢀ
group P1 with one molecule each of CBZ and HQ in the
asymmetric unit (Fig. 2). Pertinent crystallographic
parameters are listed in Table 1, and hydrogen bonds
present in the crystal structures are listed in Table 2. The
hydroxyl groups of the HQ molecule point in the same
direction adopting cis-conformation. Analysis of the crystal
packing revealed that two molecules of each CBZ and HQ
form a four-component supramolecular unit that involves
the amide NH and oxygen of one of the hydroxyl groups of
˚
˚
HQ via two N–HÁÁÁO (2.09 A, 153°; 2.09 A, 143°) hydro-
gen bonds (Fig. 3a). The crystallographic inversion centre
resides in the centre of this four-component motif. The
hydroxyl groups of the HQ are involved in O–HÁÁÁO
˚
hydrogen bonds between two hydroxyl groups (1.68 A,
˚
170°), and hydroxyl and amide carbonyl (1.67 A, 171°),
generating a six-component supramolecular unit (Fig. 3b).
Fig. 1 Comparison of the
PXRD patterns of the powder
samples obtained by grinding
varied stoichiometric ratios of
CBZ and HQ (a), and PA and
HQ (b)
123

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J Chem Crystallogr (2011) 41:1604–1611
Fig. 4 ORTEP drawing of the components of the PA–HQ cocrystal.
Thermal ellipsoids are shown in 50% probability
Fig. 2 ORTEP drawing of the components of the CBZ–HQ
cocrystal. Thermal ellipsoids are shown in 50% probability
of the secondary amide of the PA molecule, and generates
hydrogen bonded ladder network along the crystallographic
b-axis (Fig. 5a). It is interesting to note that the rungs of the
ladder are formed with amide–amide homosynthons while
the sides of the ladder are formed with 2-oxo-pyrrolidone
moieties. The ladders are connected to each other via the
The overall crystal structure is an extended hydrogen
bonded ladder network along the crystallographic a-axis
which is connected to another ladder network via the HQ
molecules (Fig. 3c).
˚
Cocrystal PA–HQ crystallized in the triclinic space
ꢀ
group P1 with one molecule of PA and half a molecule of
HQ molecules involving O3–H1ÁÁÁO1 (1.73 A, 170°)
hydrogen bond between the hydroxyl group of HQ mole-
cule and the carbonyl of the secondary amide of the PA
HQ in the asymmetric unit (Fig. 4). The crystallographic
inversion centre generates the other half molecule of the
HQ. Interestingly, the hydroxyl groups of the HQ molecule
are now pointing in the opposite direction and adopting
trans-conformation. In the crystal structure, the amide
group of the PA molecule forms an amide–amide homo-
˚
molecule (Fig. 5b). A short C3–H3ÁÁÁO3 (2.38 A, 166°)
interaction between the 3-C–H and the hydroxyl oxygen of
another HQ moiety further stabilizes the crystal structure.
Comparative analysis of the crystal structures in terms
of supramolecular synthons revealed that while both the
structures contain the alcohol–amide carbonyl heterosyn-
thon, the alcohol–alcohol homosynthon and amide–alcohol
heterosynthons were observed only in the crystal structure
˚
synthon via N2–H4ÁÁÁO2 (1.91 A, 171°) hydrogen bond.
The anti-N–H of the primary amide involved in a N2–
˚
H6ÁÁÁO1 (1.94 A, 167°) hydrogen bond with the carbonyl
Fig. 3 Hydrogen bonding ring
motifs in the crystal structure of
CBZ–HQ. a a four-component
ring motif, b a six-component
ring motif (HQ molecules were
truncated to hydroxyl moiety for
clarity), and c self-assembly of
the ring motifs to generate
extended hydrogen bonded
ladder network. Hydrogen
bonds were shown as dotted
lines
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J Chem Crystallogr (2011) 41:1604–1611
1609
Spectroscopic Analysis
1H NMR analysis of the crystals obtained from solution
crystallization confirmed the stoichiometry of the cocrystal
components (Supporting information). The cocrystals can
be readily identified by the significant differences in their
N–H and C=O stretching vibrations in FT-IR spectra. For
example, the amide carbonyl stretching band of CBZ was
observed at 1652 cm-1 in the CBZ–HQ cocrystal instead
of 1674 cm-1 in pure CBZ (Fig. 6a). This could be
because of the fact that it is involved in an O–HÁÁÁO
hydrogen bond with the hydroxyl of the HQ in the co-
crystal. This is also evident from a significant difference in
the O–H stretching vibration of the HQ which was
observed at 3228 cm-1 in the pure HQ but at 3169 cm-1 in
the cocrystal. In the pure PA, the stretching bands of the
amide carbonyl and cyclic ketone group were observed at
1689 cm-1 and 1648 cm-1, respectively (Fig. 6b). Inter-
estingly, despite being involved in N–HÁÁÁO hydrogen bond
with the amide in the PA–HQ cocrystal, the stretching
vibration of the amide carbonyl was not affected and
observed at the same frequency (1690 cm-1). However,
the cyclic ketone stretching vibration is significantly dif-
ferent from the pure PA and was observed at 1635 cm-1.
This could be because of the additional hydrogen bond
(O–HÁÁÁO) between the cyclic ketone group and the
hydroxyl of the HQ. The differences in hydrogen bonding
interactions of the hydroxyl group of the HQ in both the
cocrystals can be easily differentiated by the FT-IR. In the
case of CBZ–HQ, the hydroxyl of HQ is involved in a
finite cooperative chain of three strong hydrogen bonds
(Fig. 3b) which results in a bathochromic shift of
59 cm-1 (3228 vs. 3169 cm-1) in the O–H stretching
frequency. In contrast, the hydroxyl of the HQ in the PA–
HQ is involved in only one strong O–HÁÁÁO hydrogen
bond and hence it results in a lower bathochromic shift of
6 cm-1 (3228 vs. 3222 cm-1).
Fig. 5 Packing diagrams of PA-HQ cocrystal, a hydrogen bonded
ladder network of PA molecules, and b overall crystal packing of the
cocrystal showing the hydrogen bonds between the HQ and PA
molecules
of CBZ–HQ, and the amide–amide homosynthon was
observed only in the crystal structure of PA–HQ. These
observations suggest that the stoichiometry of the cocrystal
components determines the presence or absence of one or
more of the observed synthons between amide and
hydroxyl functional groups. In the case of PA–HQ, the
presence of an extra strong hydrogen bonding acceptor
(cyclic ketone) in PA favor the formation of a N–HÁÁÁO
hydrogen bond with the N–H of the amide over the for-
mation of a O–HÁÁÁO hydrogen bond with the hydroxyl of
the HQ molecule.
Fig. 6 Comparison of FT-IR
spectra of the cocrystals of
CBZ-HQ (a) and PA-HQ
(b) with their respective
cocrystal components
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J Chem Crystallogr (2011) 41:1604–1611
Fig. 7 TGA/DSC plots of
cocrystals, a CBZ–HQ, and
b PA–HQ
Thermal analysis
format, have been deposited with the Cambridge Crystal-
lographic Data Centre, CCDC 819996 and CCDC 819997.
Copies of this information can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB2.
1EZ, UK [fax: 44(0)-1223-336033 or email: deposit@ccdc.
cam.uk.]
Both the cocrystals were analyzed by DSC and TGA. The
cocrystals melt at a lower temperature than the corre-
sponding cocrystal constituents and observed as a sharp
endotherm in the DSC analysis (Fig. 7). Whereas the CBZ–
HQ cocrystal melts at 168 °C (CBZ: 189–193 °C, HQ:
173–174 °C), the PA–HQ cocrystal melts at 129 °C (PA:
152 °C). In the TGA analysis, there was no weight loss
before they decomposed in the temperature range of
175–275 °C, which was observed as a complete weight
loss within this temperature range. The TGA analysis also
confirms that the cocrystals obtained are pure cocrystals
with no solvent inclusion.
Acknowledgement This work was supported by Science and
Engineering Research Council of A*STAR (Agency for Science,
Technology and Research), Singapore.
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