Co-crystals of caffeine with substituted nitroanilines and nitrobenzoic acids: Structure-mechanical property and thermal studies

Article abstract of DOI:10.1039/c2ce06754d

Nine new 1:1 co-crystals of caffeine with some halogenated nitroanilines and two nitrobenzoic acids have been synthesized. These new caffeine (CAF) co-crystals, with 4-nitroaniline (4NA), 4-fluoro-3-nitroaniline (4F3NA), 4-chloro-3-nitroaniline (4Cl3NA), 4-iodo-3-nitroaniline (4I3NA), 2-fluro-5-nitroaniline (2F5NA), 2-chloro-5-nitroaniline (2Cl5NA), 2-iodo-4-nitroaniline (2I4NA), 2,4-dinitrobenzoic acid (24DNB), 2-fluoro-5-nitrobenzoic acid (2F5NB), are characterized by single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and infrared spectroscopy. The co-crystals adopt a range of structures, namely two-dimensional (2D) flat layer, corrugated layer and 3D interlocked structures. The series of crystals allowed us to establish a structure-mechanical property relationship by using a simple mechanical deformation (qualitative) method. The 2D flat layer crystals (CAF/24DNB, CAF/2Cl5NA and CAF/2I4NA), which have strong intralayer and weak interlayer interactions show shear deformation behaviour, while those with weak intralayer interactions (CAF/4Cl3NA and CAF/4I3NA) show brittle fracture on application of a mechanical stress. The structures with corrugated layers (CAF/2F5NA) or 3D interlocked packing (CAF/NA, CAF/2F5NB and CAF/4F3NA) also show brittle behaviour. We also show the need for a wide initial search, targeting even the least expected synthons, to improve the efficiency of co-crystal screening. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ce06754d

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PAPER
Co-crystals of caffeine with substituted nitroanilines and nitrobenzoic acids:
Structure–mechanical property and thermal studies†
*
Soumyajit Ghosh and C. Malla Reddy
Received 30th December 2011, Accepted 10th February 2012
DOI: 10.1039/c2ce06754d
Nine new 1 : 1 co-crystals of caffeine with some halogenated nitroanilines and two nitrobenzoic acids
have been synthesized. These new caffeine (CAF) co-crystals, with 4-nitroaniline (4NA), 4-fluoro-3-
nitroaniline (4F3NA), 4-chloro-3-nitroaniline (4Cl3NA), 4-iodo-3-nitroaniline (4I3NA), 2-fluro-5-
nitroaniline (2F5NA), 2-chloro-5-nitroaniline (2Cl5NA), 2-iodo-4-nitroaniline (2I4NA), 2,4-
dinitrobenzoic acid (24DNB), 2-fluoro-5-nitrobenzoic acid (2F5NB), are characterized by single crystal
X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and infrared
spectroscopy. The co-crystals adopt a range of structures, namely two-dimensional (2D) flat layer,
corrugated layer and 3D interlocked structures. The series of crystals allowed us to establish a structure–
mechanical property relationship by using a simple mechanical deformation (qualitative) method. The
2D flat layer crystals (CAF/24DNB, CAF/2Cl5NA and CAF/2I4NA), which have strong intralayer and
weak interlayer interactions show shear deformation behaviour, while those with weak intralayer
interactions (CAF/4Cl3NA and CAF/4I3NA) show brittle fracture on application of a mechanical stress.
The structures with corrugated layers (CAF/2F5NA) or 3D interlocked packing (CAF/NA, CAF/
2F5NB and CAF/4F3NA) also show brittle behaviour. We also show the need for a wide initial search,
targeting even the least expected synthons, to improve the efficiency of co-crystal screening.
candidates, thus improving the success rate. However, in this
Introduction
process, one may miss some co-formers that can form the least
expected synthons which may have the potential to occur
repeatedly in co-crystals with a set of similar co-formers.
Co-crystallization of active pharmaceutical ingredients (APIs)
represents a viable means of enhancing the physical properties of
a drug substance, particularly when the API is nonionizable for
salt formation and the amorphous material is undesired due to its
inherent instability.1 In recent times, co-crystal formation using
the crystal engineering2 approach has been shown to be effective
for altering physicochemical properties of APIs such as melting
point,3 solubility,4 thermal5 and photostability,6 as well as
mechanical properties.7 The first and simple step in this process is
generally a careful selection of co-formers, targeting some
specific supramolecular synthons,8 and/or with suitable size and
shape that match to the target API. In recent studies, the synthon
based co-crystal search has been shown to be very efficient.9
Because this approach helps to quickly narrow down the list of
potential co-formers by eliminating the most improbable
Caffeine (CAF), a central nervous system stimulant and
a smooth muscle relaxant, is known to exist in two anhydrous
polymorphic forms (a, b), a hydrated form and a number of co-
crystal and salt forms.10 The polymorphs display poor stability
under higher relative humidities (RHs) due to their conversion
into the hydrate form. The hydrate in low RHs loses water to
transform into anhydrate form, hence it is also not desired for
pharmaceutical applications. The associated poor stabilities of
these crystalline forms have sparked research interest in
improving the physicochemical properties of caffeine. Among all
the caffeine co-crystals (47) reported in the Cambridge Structural
Database (version 5.33, update Nov 2011), the majority of
co-formers contain carboxylic acid (15), phenolic OH (11) or
both the functional groups (15), leaving some exceptions (6)
where none of these two groups are present. The carboxylic acids
mostly form synthon-1 (Scheme 1) involving caffeine’s free
aromatic N-atom. While, there are only two cases (Refcodes:
SACCAF, VIGVOW) where the co-formers possess sulfanil-
amide groups that form N–H/N hydrogen bonds (synthon-2,
R ¼ C(]O)Me or C(]O)Ar) with caffeine.
Department of Chemical Sciences, Indian Institute of Science Education
and Research, Kolkata, West Bengal, 741252, India. E-mail: cmreddy@
iiserkol.ac.in; cmallareddy@gmail.com; Fax: +91-33-25873020; Tel:
+91-33-25873118, Ext.No.: 238
† Electronic supplementary information (ESI) available: List of some
unsuccessful co-formers used in the co-crystal screening, geometrical
parameters of molecules from crystal structures, melting points table,
powder X-ray diffraction patterns, infrared spectra, ORTEP diagrams
and some optical images of crystals. CCDC reference numbers
860122–860130. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2ce06754d
With this in mind, to expand the caffeine co-crystal landscape,
we made a search using a variety of co-formers by targeting
synthons, mostly unexplored previously. In our search, we
2444 | CrystEngComm, 2012, 14, 2444–2453
This journal is ª The Royal Society of Chemistry 2012

Single crystal preparation
Caffeine and co-crystal former in a definite stoichiometric ratio
(1 : 1) were subjected to grinding with an addition of a few drops
of methanol solvent using an agate mortar and pestle for about
15 min. After grinding, the mixture was transferred to a 10 mL
conical flask followed by addition of methanol. The suspension
was heated until a clear solution was obtained. The resulting
mixture was boiled for 10 min before being filtered into a fresh
conical flask. The filtrate was left to evaporate slowly at ambient
conditions. Co-crystal screening was also carried out from other
solvents such as ethyl acetate, ethanol, acetonitrile, etc. In some
cases, co-crystals were obtained, but generally the yields were not
as good as compared to that from methanol, as confirmed by
powder X-ray diffraction. The single crystals suitable for X-ray
diffraction studies were obtained from methanol solution in 4 to
6 days. For CAF/24DNB co-crystal, acetonitrile was used
instead of methanol, as this yielded better quality single crystals
for XRD studies.
Scheme 1 Synthons between different groups and caffeine.
NMR
1H nuclear magnetic resonance (NMR) analysis of single crystals
(2 to 3) was performed on a JEOL 400 MHz NMR in CDCl3 at
ꢀ
25 C to confirm the API to co-former ratio.
Powder X-ray diffraction (PXRD)
The PXRD patterns were collected on a Rigaku SmartLab with
ꢀ
a Cu-Ka radiation (1.540 A). The tube voltage and amperage
were set at 40 kV and 50 mA respectively. Each sample was
scanned between 10 and 90ꢀ 2q with a step size of 0.02ꢀ. The
instrument was previously calibrated using a silicon standard.
Scheme 2 Chemical structures of the compounds used in this study.
Single crystal X-ray diffraction (SCXRD)
employed co-formers with functional groups such as –NH2,
–CONH2, –CHO, –OR as well as aza-aromatics (see ESI,
Scheme S1†) which have the potential to bind to the caffeine free
N-atom or form p-stacking interactions.11–13 The other criterion
we followed in co-formers was similar size and shape (flat) to
match the caffeine molecule. Our initial screening studies led us
to identify anilines as potential candidates for forming co-crys-
tals with caffeine. We further searched by employing several
commercially available halogenated nitroanilines, and then
extended to halogenated nitrobenzoic acids to successfully
obtain a series of co-crystals (Scheme 2). The co-crystals adopt
a variety of crystal structures, including 2D flat layers, corru-
gated layers and 3D interlocked structures. We took advantage
of the structural variations to study the structure–mechanical
property relationship in the series.14
Co-crystals of caffeine were individually mounted on a glass pip.
Intensity data were collected on a Bruker KAPPA APEX II
CCD Duo system with graphite-monochromatic Mo-Ka radia-
ꢀ
tion (l ¼ 0.71073 A) at 293 K for all the co-crystals, except
CAF/4F3NA, CAF/4Cl3NA and CAF/2Cl5NA, which were
collected at 100 K. Data reduction was performed using Bruker
SAINT software.15 Crystal structures were solved by direct
methods using SHELXL-97 and refined by full-matrix least-
squares on F2 with anisotropic displacement parameters for non
H-atoms using SHELXL-97. Hydrogen atoms associated with
carbon atoms were refined in geometrically constrained riding
positions. Hydrogen atoms associated with oxygen and nitrogen
atoms were included in the located positions. Crystallographic
data and structure refinement parameters are included in Table 1.
Structure graphics shown in the figures were created using the
X-Seed software package version 2.0.16
Experimental section
Materials
Melting point
Caffeine and all co-crystal formers were purchased from Sigma-
Aldrich. Commercially available solvents were used as received
without further purification.
Melting points of co-crystals and the individual co-formers were
measured using a digital melting point apparatus, SECOR
INDIA.
This journal is ª The Royal Society of Chemistry 2012
CrystEngComm, 2012, 14, 2444–2453 | 2445

Table 1 Crystallographic data and structure refinement parameters of CAF co-crystals
CAF/
24DNB
CAF/NA
C8H10N4
O2,C6H6N2O2 O2,C6H5F
N2O2
CAF/4F3NA CAF/4Cl3NA CAF/4I3NA CAF/2F5NA CAF/2Cl5NA CAF/2I4NA
CAF/2F5NB
Chemical
Formula
C8H10N4
C8H10N4
O2,C6H5Cl
N2O2
C8H10N4O2, C8H10N4O2, C8H10N4
C6H5IN2O2 C6H5FN2O2 O2,C6H5Cl
N2O2
C8H10N4O2,C6 C8H10N4O2, C8H10N4O2,
H5IN2O2
C7H4N2O6 C7H4FNO4
Formula
weight
Cryst syst. Monoclinic
Space group P21/c
ꢀ
332.33
350.32
366.77
458.22
350.32
366.77
458.22
406.32
379.31
Orthorhombic Monoclinic
Pna21
15.8624(19)
13.5643(15)
Monoclinic Monoclinic
P21/c
8.0323(5)
13.7265(8)
15.3774(9)
90
93.5480(10) 92.806(2)
90 90
1692.19(18) 1562.3(2)
1.799
1.926
1.99–27.0
4
Monoclinic
P21/c
13.585(6)
13.9085(6)
17.5266(8)
90
104.8920(10) 97.473(3)
90
3200.4(2)
1.522
0.274
Monoclinic
P21/n
8.1283(5)
13.8659(7)
14.9447(8)
90
Triclinic
P ꢁ 1
Monoclinic
P21/c
12.5652(6)
8.1475(4)
P21/c
P21/c
a/A
ꢀ
10.5157(7)
10.7574(7)
7.7950(6)
13.5627(9)
14.9920(10)
90
95.6570(10)
90
1577.25(19)
1.545
0.278
2.63–26.98
4
5.8784(5)
33.258(3)
8.0008(7)
90
8.5624(4)
11.8197(6)
b/A
ꢀ
c/A
13.6464(10) 7.3360(9)
90 90
100.1790(10) 90
90 90
1519.41(18) 1578.4(3)
18.7587(10) 16.5266(8)
88.2690(10) 90
77.0890(10) 93.688(2)
72.2120(10) 90
1760.53(15) 1688.41(14)
1.533
0.127
1.81–27.0
4
a (ꢀ)
b (ꢀ)
g (ꢀ)
90
3
ꢀ
Vol/A
1670.05(16)
1.822
1.952
2.01–26.99
4
Dc/g cmꢁ3
1.453
0.110
1.474
0.119
1.98–27.0
4
1.489
0.120
2.62–27.0
4
1.492
0.125
2.47–27.0
4
m/mmꢁ1
q range (ꢀ) 1.97–27.0
1.89–27.0
8
Z
4
Range h
Range k
Range l
Reflns
collected
ꢁ13 to + 13 ꢁ20 to + 20 ꢁ9 to + 6
ꢁ10 to + 10 ꢁ7 to + 7
ꢁ17 to + 17
ꢁ10 to + 10
ꢁ17 to + 17
ꢁ19 to + 18
41560
ꢁ10 to + 10 ꢁ15 to + 16
ꢁ15 to + 15 ꢁ10 to + 10
ꢁ23 to + 23 ꢁ9 to + 20
ꢁ13 to + 13 ꢁ17 to + 17 ꢁ17 to + 17
ꢁ17 to + 17 ꢁ40 to + 42 ꢁ11 to + 17
ꢁ17 to + 17 ꢁ9 to + 2
ꢁ17 to + 19
ꢁ19 to + 19 ꢁ10 to + 9
ꢁ22 to + 22
23085
7079
13582
13862
12814
26368
28334
14412
Independent 3326
reflns
Obsd reflns 2798
2053
3420
3697
3384
6933
3644
7644
3678
1704
3181
3227
2911
6332
2992
5914
2902
T/K
R1
wR2
GOF
296(2)
0.0401
0.1192
1.054
100(2)
0.0429
0.1106
1.080
100(2)
0.033
0.0936
1.035
860124
296(2)
0.0256
0.0649
1.073
296(2)
0.0588
0.1406
1.134
100(2)
0.0298
0.0805
1.067
296(2)
0.0443
0.1015
1.208
296(2)
0.0558
0.1464
1.030
296(2)
0.0457
0.1274
1.026
CCDC No. 860127
860125
860123
860129
860126
860122
860128
860130
Differential scanning calorimetry (DSC)
asymmetric unit contains one molecule of each component. In
the structure, each molecule interacts via multiple hydrogen
bonds (H-bonds) that lead to a three dimensionally (3D) inter-
locked structure. Each caffeine molecule is connecꢀted with
DSC was conducted on a Mettler-Toledo DSI1 STARe instru-
ment. Accurately weighed samples (2–3 mg) were placed in
hermetically sealed aluminium crucibles (40 mL) and scanned
from 30 ꢀC to 300 ꢀC at a heating rate of 5 ꢀC minꢁ1 under a dry
nitrogen atmosphere (flow rate 80 mL minꢁ1). The data were
managed by STARe software.
ꢀ
neighbouring 4NA molecules via N–H/O]C (d/A, q/ : 2.16(2)
ꢀ
ꢀ
ꢀ
ꢀ
A, 165(2) ; synthon-3) and N–H/N (2.32(2) A, 174(2) ) inter-
actions (synthon-2, R ¼ H; Scheme 1), and with neighbouring
ꢀ
ꢀ
caffeine molecule via C–H/O]C (2.229(19) A, 157.4(16) )
interaction (Fig. 1).
Thermogravimetric analysis (TGA)
TGA was performed on a Mettler-Toledo TGA/SDTA 851e
instrument. Approximately 10–15 mg of the sample was added to
an aluminium crucible and heated from 30 to 350 ꢀC at a rate of
10 ꢀC minꢁ1 under continuous nitrogen purge.
Caffeine/4-fluoro-3-nitroaniline
Caffeine and 4-fluoro-3-nitroaniline (4F3NA) co-crystallize from
methanol solvent in the orthorhombic space group Pna21. The
asymmetric unit contains one molecule of each component. Two
carbonyl groups of each caffeine molecule are involved in two
IR spectroscopy
ꢀ
ꢀ
ꢀ
ꢀ
intermolecular N–H/O]C (2.13 A, 156 ; 2.04 A, 164 ) inter-
actions (synthons-3, Scheme 1) with the amino groups of two
adjacent 4F3NA molecules, leading to the formation of two
zigzag molecular tapes parallel to (011) and (0–11) planes that
have an intersecting angle of nearly 50ꢀ between them (Fig. 2).17
Molecules from similar tapes stack down along the c-axis to
optimize the p/p interactions.18
Transmission infrared spectra of the solids were obtained using
a Fourier–transform infrared spectrometer (Shimadzu). KBr
samples (2 mg in 20 mg of KBr) were prepared and 10 scans were
collected at 4 cmꢁ1 resolution for each sample. The spectra were
measured over the range of 4000–400 cmꢁ1
.
Results and discussion
Caffeine/4-nitroaniline
Caffeine/4-chloro-3-nitroaniline
Caffeine (CAF) and 4-nitroaniline (4NA) co-crystallize from
Caffeine and 4-chloro-3-nitroaniline (4Cl3NA) co-crystallize
methanol solution in the monoclinic space group P21/c. The
from methanol solution in the monoclinic space group P21/c. The
2446 | CrystEngComm, 2012, 14, 2444–2453
This journal is ª The Royal Society of Chemistry 2012

Fig. 1 Caffeine/4-nitroaniline co-crystal. (a) Interaction of each CAF
molecule with two 4NA and two CAF molecules via intermolecular H-
bonds. (b) Crystal packing view along a-axis. Note that the molecules
shown are not in the same plane. (c) Crystal packing view along c-axis to
show the 3D interlocked structure in the co-crystal.
asymmetric unit contains one molecule of each component. Two
carbonyl groups of each caffeine molecule are involved in two
ꢀ
ꢀ
ꢀ
intermolecular N–H/O]C (2.098(18) A, 168.4(16) ; 2.11(2) A,
162(2)ꢀ) interactions with the amino groups of two adjacent
4Cl3NA molecules that lead to the formation of 2D planar sheets
parallel to (101) (Fig. 3). In ꢀaddition, there is a weak C–H/O
ꢀ
hydrogen bond (2.50 A, 151 ) in the two component supramo-
lecular assembly. The Cl-atom from 4Cl3NA is not involved in
any significant intermolecular interaction, hence it is merely
a spectator in the layer formation. The arrangement of caffeine
(A) and co-former (B), 4Cl3NA, within the sheet may be shown
as in Fig. 3b. Two perpendicular tapes19 of ABAB type may be
identified within a layer. The sheets stack antiparallel to optimize
p/p interactions where the molecules of type A and B stack one
over the other with some offset. The separation between the two
Fig. 2 Caffeine/4-fluoro-3-nitroaniline. (a) Side view (along b-axis) and
(b) top view (down c-axis) of the antiparallel tapes in the structure. (c) 3D
interlocking of the antiparallel tapes that are stacked down along the
c-axis.
ꢀ
consecutive layers is 3.016 A.
Caffeine/2-fluoro-5-nitroaniline
Caffeine/4-iodo-3-nitroaniline
Caffeine and 2-fluoro-5-nitroaniline (2F5NA) co-crystallize from
methanol solution in the monoclinic space group P21/c with one
molecule of each component in the asymmetric unit. In this case
also the two carbonyl groups of the caffeine molecule are
Caffeine and 4-iodo-3-nitroaniline (4I3NA) co-crystallize
from methanol solution in the monoclinic space group P21/c. The
co-crystal is isostructural to CAF/4Cl3NA. However, the longer
C–I bond in 4I3NA allows the iodo-group to reach to the nitro-
ꢀ
ꢀ
ꢀ
involved in two intꢀermolecular N–H/O]C (2.06(3) A, 164(3) ;
group of adjacent 4I3NA for forming the C–I/O (3.412 A,
ꢀ
2.24(3) A, 166(3) ) interactions with amino groups of two
174.4ꢀ) halogen bond (Fig. 4).
This journal is ª The Royal Society of Chemistry 2012
CrystEngComm, 2012, 14, 2444–2453 | 2447

Fig. 4 Caffeine/4-iodo-3-nitroaniline. (a) Top view of the 2D sheet
parallel to (101). (b) Stacking of the 2D sheets.
(Z0 ¼ 2). Two carbonyl groups of each caffeine molecule are
ꢀ
ꢀ
ꢀ
involved in intermolecular N–H/O (2.04(18) A, 168.7(16) )
ꢀ
with the amino group and C–H/O (2.37(3) A, 153 ) interactions
between caffeine molecules that lead to the formation of
2D wave-like corrugated sheets. There is a weak Cl/O(nitro)
(3.211 A, 143.43 ) interaction connecting two 2Cl5NA mole-
cules. The arrangement of the caffeine (A) and co-former (B),
2Cl5NA, within the sheet is completely different in this case
(Fig. 6). The perpendicular tapes within the layers are ABAB and
AAAA/BBBB types.19 The sheets stack along [10–5] to optimize
Fig. 3 Caffeine/4-chloro-3-nitroaniline. (a) 2D sheet formed by two
component assembly. (b) Representation of perpendicular ABAB type
tapes formed by CAF (A) and 4Cl3NA (B) molecules, within a 2D sheet.
(c) Stacking of the 2D sheets in an antiparallel fashion.
ꢀ
ꢀ
adjacent 2F5NA molecules, leading to the formation of 2D
sheets (Fig. 5). But interestingly, in this case the 2D sheets have
a wave-like corrugation. The arrangement of caffeine (A) and co-
former (B), 2F5NA, within the 2D sheet may be shown as
perpendicular ABAB type tapes (Fig. 3b). The sheets stack along
the b-axis to optimize the p/p interactions (Fig. 5b). The
the p/p interactions,18 with an interplanar distance of 3.331 A.
ꢀ
Caffeine/2-iodo-4-nitroaniline
Caffeine and 2-iodo-4-nitroaniline (2I4NA) co-crystallize in the
monoclinic space group P21/n with Z0 ¼ 1. Each caffeine mole-
cule interacts with neighbouring caffꢀeine and 2I4NA molecules
ꢀ
distance between the two consecutive layers is 3.391 A.
Caffeine/2-chloro-5-nitroaniline
ꢀ
via a strong C–I/N (3.03 A, 170.66 ) halogen bond and some
Caffeine and 2-chloro-5-nitroaniline (2Cl5NA) co-crystallize
from methanol solution in the monoclinic space group P21/c.
The asymmetric unit contains two molecules of each component
other supporting weak interactions (Fig. 7). Interestingly both
nitro and amino groups from 2I4NA are aligned in the same
plane, face to face (Fig. 7a). The arrangement of caffeine (A) and
2448 | CrystEngComm, 2012, 14, 2444–2453
This journal is ª The Royal Society of Chemistry 2012

Fig. 5 Caffeine/2-fluoro-5-nitroaniline. (a) Top view of the wave like 2D
layer parallel to (ꢁ102). (b) Stacking of the 2D wave-like sheets.
co-former (B), 2I4NA, within the sheet may be shown as in
Fig. 7b. Three types of tapes may be identified within the layer,
AAAA, BBBB and ABAB. The latter is zigzag and perpendicular
to the former two, which are parallel to each other. The sheets
stack along [10ꢁ3] to optimize the p/p interactions.
Caffeine/2,4-dinitrobenzoic acid
Caffeine and 2,4-dinitrobenzoic acid (24DNB) co-crystallize from
acetonitrile solution in the triclinic space group P ꢁ 1, with two
molecules of each component (Z0 ¼ 2) in the asymmetric unit. The
constituent molecules forman interesting flat layer structurein this
case. Four molecules of CAF and four molecules of 24DNB form
tetramers via multiple C–H/O hydrogen bonds (Fig. 8) with an
angle >140ꢀ at the donor groups. This indicates their significance
when considering the angle criteria for the bond strengths.20 Each
caffeine molecule interacts with twoꢀneighbouring caffeine mole-
Fig. 6 Caffeine/2-chloro-5-nitroaniline (1 : 1) co-crystal. (a) 2D layer
formation by involving caffeine and 2Cl5NA molecules. (b) Schematic
representation of the perpendicular tapes, ABAB and AAAA/BBBB type
in the 2D layers. (c) Side view of the stacked layers.
ꢀ
ꢀ
ꢀ
cules, via C–H/O (2.43(2) A, 145(2) ; 2.41(2) A, 141.7(19) ), and
ꢀ
ꢀ
two 24DNB molecules, via O–H/N (1.82(4) A, 173 ; synthon-1),
to form AABB type perpendicular tapes. The 24DNB molecules
form C–H/O interactions among them. As a result, within the 2D
sheet, the four caffeine and four 24DNB molecules, each form
a square type tetramer as shown in Fig. 8b.
interactions, one each with neighbouring caffeine and 2F5NB
molecules, leading to molecular tapes which run paralꢀlel to (110)
ꢁ
or (110) planes with an intersecting angle of nearly 30 (Fig. 9a).
Caffeine/2-fluoro-5-nitrobenzoic acid
This leads to 3D interlocked packing of the molecules (Fig. 9b).
Caffeine and 2-fluoro-5-nitrobenzoic acid (2F5NB) co-crystallize
from methanol solution in the monoclinic space group P21/c with
one molecule of each co-former in the asymmetric unit. The two
Mechanical properties
ꢀ
molecular componentsinteract via the strong O–H/N (1.67(4) A,
175(3)ꢀ; synthon-1) hydrogen bond. Two carbonyl groups of each
Mechanical properties of molecular crystals strongly depend on
the features of underlying crystal packing.7 Based on the
mechanical behaviour the molecular crystals are classified into
caffeine molecule are involved in the two intermolecular C–H/O
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Fig. 7 Caffeine/2-iodo-4-nitroaniline (1 : 1) co-crystal. (a) 2D sheet
formed by two component assembly. (b) Molecular tapes, AAAA, BBBB
and zigzag ABAB. (c) Offset stacking of molecular sheets.
Fig. 8 Caffeine/2,4-dinitrobenzoic acid (1 : 1) co-crystal. (a) 2D layer
involving multiple interactions between CAF and 24DNB molecules. (b)
Representation of the layer with perpendicular AABB type tapes. (c)
Packing of the 2D flat layers.
soft (shearing and bending) and brittle types. Anisotropic crys-
tals with 2D layer packing or with strong and weak (nonspecific)
interactions in perpendicular directions are known to show
plastic shearing or bending behaviour, respectively. While
isotropic crystals with similar interactions in all the dimensions
generally show brittle nature. In this series the co-crystals adopt
either 2D layer or 3D interlocked packing. Mechanical studies
performed on the single crystals, using forceps and needle under
a stereomicroscope, revealed that the co-crystals, namely CAF/
24DNB, CAF/2Cl5NA and CAF/2I4NA are of the shearing
type, while all the others in this series are brittle. Among the
shearing type co-crystals, CAF/24DNB was found to be
extremely soft and showed smooth shear deformation on
application of a mechanical stress parallel to the 2D layers in the
crystal (Fig. 10). In this structure the 2D layers are formed via
strong O–H/N and multiple (Ar)C–H/O H-bonds between the
molecules (see Fig. 8a). This is consistent with our previously
proposed model: the formation of robust layers with weak
interlayer interactions is necessary for smooth shearing in 2D
layer crystals.14d,e 2D layer crystals with comparable interlayer
and intralayer interactions do not show such shearing and simply
break (i.e. shear stress > cleavage stress). Hence, the shearing
behaviour in CAF/24DNB is a clear proof for the robustness of
intralayer interactions and non-specificity of the interlayer
interactions.
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Fig. 10 Shearing in crystals of caffeine/2,4-dinitrobenzoic acid on
application of a mechanical stress. (a) Crystal before application of the
mechanical stress. (b) To (d) show the stages of crystal shearing. Notice
the striations due to shearing and cleavage of crystal layers on application
of continuous stress.
Fig.
9 Caffeine/2-fluoro-5-nitrobenzoic acid (1 : 1) co-crystal. (a)
Packing diagram to show the arrangement of perpendicular tapes. (b) 3D
interlocked structure of the co-crystal (H-bonds are not shown for clarity).
The other two soft co-crystals, CAF/2Cl5NA and CAF/
2I4NA, also show shearing behavior, but also crystal breakage
occur easily along the layers (Fig. S20, S21†). Although both the
crystals adopt 2D layer packing, in the case of CAF/2Cl5NA, the
layers, to a small degree, are wave-like (Fig. 6c), hence possibly
lead to easy breakage. Whereas, in the case of CAF/2I4NA,
although molecules within the 2D layer form stronger N–H/O
and C–I/N bonds, the support from other interactions is not
significant, for instance, the aromatic C–H groups from 2I4NA
Fig. 11 Brittle crystals of caffeine/2-fluoro-5-nitroaniline on application
of a mechanical stress. (a) Crystal before application of the mechanical
stress. (b) To (d) show the stages of crystal breakage in the process.
show any clear sign of shearing. Whereas the co-crystal, CAF/
2F5NA has corrugated type layers with significant interlayer
interactions, hence is brittle (Fig. 11). The brittle nature in the
case of CAF/NA, CAF/2F5NB and CAF/4F3NA is associated
with their 3D interlocked structure.
ꢀ
ꢀ
are not engaged at all, while the N–H/O (2.49 A, 106.17 )
hydrogen bond (between NH2 and NO2 which are co-planar,
face to face) is not robust which is clear from its H-bond matrices
(Fig. 7a). Similarly, in case of the two isostructural co-crystals,
CAF/4Cl3NA and CAF/4I3NA, which adopt 2D flat layer
structures, the aromatic C–H groups are not involved in any
hydrogen bonding, hence there is no contribution to the layer
strength. Hence these crystals are brittle in nature and do not
Thermal properties
Detailed DSC and TGA experiments on the co-crystals helped to
establish their thermal stabilities with respect to the commercial
sample of free caffeine (Form II or b phase). The DSC traces and
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thermogram in the case of CAF/2I4NA showed a small
additional endotheꢀrm at 154 ꢀC, which is very close to the major
endotherm at 157 C. This indicates the presence of an uniden-
tified new phase, which we could not obtain for characterisation
by single crystal XRD. DSC plots reveal that the thermal
stability of all the co-crystals is lower than that of the commercial
caffeine. The least stable among the co-crystals is CAF/2Cl5NA.
Conclusions
In conclusion, the successful formation of co-crystals by the least
explored anilines, with caffeine demonstrates the potential of
NH2 group based synthons for achieving new pharmaceutically
acceptable co-crystals, for example drug–drug solid forms. Out
of the seven CAF/aniline co-crystals in this series, six of them
form synthon-3 (strong N–H/O H-bonds), while this is not
observed only in the case of CAF/2I4NA. This demonstrates
the reliability of the previously unexplored NH2 group based
synthons for synthesizing new caffeine co-crystals. This
approach may also be applicable to theophylline and uric acid
which also have very similar chemical structures. Interestingly
synthon-2 is not seen in any of these co-crystals. Notably,
although 4F3NA, 4Cl3NA, 4I3NA are isomeric compounds,
only the latter two form the isostructural co-crystals, while we
could not synthesize their bromo-analogue. The series of crystals
allowed us to establish a structure–mechanical property rela-
tionship by using a simple mechanical deformation (qualitative)
method. The 2D flat layer crystals (CAF/24DNB, CAF/2Cl5NA
and CAF/2I4NA), with robust layers and weak interlayer inter-
actions show shear deformation behaviour, while those with
comparable intralayer and interlayer interactions (CAF/4Cl3NA
and CAF/4I3NA) showed brittle fracture on application of
a mechanical stress. This suggests that the presence of flat 2D
layer packing is only a requirement, but not the sufficient
condition, i.e., shearing requires relatively stronger intralayer
and weaker interlayer interactions. The structures with corru-
gated layers (CAF/2F5NA) or 3D interlocked packing (CAF/
NA, CAF/2F5NB and CAF/4F3NA) show brittle behaviour.
Acknowledgements
We thank Mr. S. Singhal (IISER-Kolkata) for assistance with
crystallization. SG thanks the CSIR (New Delhi) for fellowship.
CMR acknowledges financial support from the DST (SR/FT/CS-
074/2009).
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