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Chiang Mai J. Sci. 2011; 38(3)
405
Chiang Mai J. Sci. 2011; 38(3) : 405-411
http://it.science.cmu.ac.th/ejournal/
Contributed Paper
Supramolecular Structure of Cocrystallized
J-Amino Butyric Acid and Oxalic Acid
Nongnaphat Khosavithitkul*[a] and Kenneth J. Haller**[b]
[a] The Center for Scientific and Technological Equipment, Suranaree University of Technology,
Nakhon Ratchasima 30000, Thailand.
[b] School of Chemistry, Institute of Science, Suranaree University of Technology,
Nakhon Ratchasima 30000, Thailand.
Authors for correspondence; *e-mail: [email protected], **e-mail: [email protected]
Received: 27 October 2010
Accepted: 29 November 2010
ABSTRACT
Pharmaceutical cocrystals are crystalline molecular complexes that contain
therapeutically active molecules. In many cases properties important to the bioavailability
or processing of pharmaceutical solids have been demonstrated to be improved upon via
cocrystallization. The structural elements (strong hydrogen bond donor, strong hydrogen
bond acceptor, and nonpolar region) of J-amino butyric acid, GABA, are typical of small drug
molecules, and GABA is a major neurotransmitter inhibitor of the central nervous system.
GABA and oxalic acid, OX, were cocrystallized as part of a study on formation of cocrystals
of pharmaceutically interesting molecules via hydrogen bonding. The crystal structure of
the resulting transparent colorless 2GABA:OX cocrystal was studied by single crystal X-ray
R
analysis (monoclinic; P21/c; a = 7.4153(9), b = 10.2052(13), c = 9.7584(12) A, E = 108.396(3) , V
= 700.72(15) A3, Z = 2, T = 298 K). The supramolecular structure contains extensive OH˜˜˜O,
NH˜˜˜O and CH˜˜˜O interactions leading to an elaborate three-dimensional hydrogen
bonded network. The ammonium cation participates in three separate O˜˜˜HîNîH˜˜˜O
motifs (half of the R42(8) synthon), but the R42(8) synthon itself is not found. Notable features
in the structure include an S33(10) string containing a serpentine carboxylic acid-carboxylate
motif alternating with the ammonium motif. Additional strings and other concerted hydrogen
bond motifs are also present.
Keywords: supramolecular structure, cocrystal, GABA.
1. INTRODUCTION
Cocrystals are crystalline molecular complexes containing two or more species with
essentially molecular properties. The species
can, at least in principle, be separated into
pure components with similar chemical nature
to those they possess in the cocrystal. Phar-
maceutical cocrystals are, therefore, crystalline
molecular complexes containing therapeutically active molecules, usually in conjunction
with molecules that do not have therapeutic
value. In many cases properties, including
solubility and physical stability, important
406
to the bioavailability or processing of pharmaceutical solids have been demonstrated
to be improved upon via cocrystallization.
Traditionally, the major modification of active
pharmaceutical ingredients, API, to obtain good
crystalline products has been the formation
of salts. In contrast to the limited number of
salt-forming counter ions in use today [1],
cocrystallization provides extensive alternative solid-state modification possibilities
through the groups of compounds approved
as additives, and those classified as GRAS
(generally regarded as safe) by the food and
drug association [2]. Thus, with the inherent
advantages
of property improvement,
pharmaceutical cocrystallization should play
a significant role in the development of
tomorrow’s medicines.
J-Amino butyric acid, GABA, itself is an
important substance as a major neurotransmitter inhibitor of the central nervous
system. In addition the structural elements
(strong hydrogen bond donor, strong hydrogen bond acceptor, and nonpolar region) of
GABA are typical of small drug molecules,
making GABA a good model compound for
pharmaceutical cocrystallization studies. In
this work GABA and oxalic acid, OX, were
cocrystallized as part of a study on formation
of cocrystals of pharmaceutically interesting
molecules via hydrogen bonding. The
material was previously reported by
Wenger and Bernstein [3] in a study of fourcomponent synthons involving two amine
donor groups and two carbonyl acceptor
groups, but the supramolecular structure has
not been analyzed in detail.
2. MATERIALS AND METHODS
2:1 GABA/Oxalic Acid was prepared by
both solution crystallization and solid-state
grinding. Single crystal X-ray diffraction
quality 2GABA:OX cocrystals were grown
from ethanol solution by slow evaporation
Chiang Mai J. Sci. 2011; 38(3)
at room temperature. The structure was
determined by single crystal X-ray analysis.
Intensity data were collected using the
COLLECT software [4] on a Nonius Kappa
CCD diffractometer equipped with a fine
focus MoKD X-ray source, graphite monochromator, and 0.3 mm ifg capillary collimator.
Data were reduced to structure factors using
EvalCCD [5]. Crystallographic calculations
utilized MaXus [6], SIR97 [7], SHELX-97
[8], and ORTEP-III [9] (4925 data collected,
Rint = 0.0379, 1,606 unique data, 1,180 observed
o
data (Io > 2Ƴ(Io)), ƨmax = 26.37 ). In the final
cycles of refinement, nonhydrogen atoms
were included with anisotropic atomic
displacement parameters; all hydrogen atoms
were located and included in idealized
geometrical positions with varied average
distances d[X–H] for each type of hydrogen
atom (d[C–H] = 0.97 Å, d[N–H] = 0.92
Å, d[O–H] = 0.85 Å); and a single refined
isotropic atomic displacement parameter,
U[H], (0.053(3) Å2) for CH2 hydrogen atoms,
and another for NH and OH hydrogen
atoms (0.062(4) Å2). A summary of crystal
data and structure refinement parameters is
given in Table 1. The crystallographic data
for this paper has been deposited with The
Cambridge Crystallographic Data Centre as
deposition number CCDC 795844, and may
be obtained free of charge via the link www.
ccdc.cam.ac.uk/data_request/cif.
3. RESULTS AND DISCUSSION
The compound crystallizes in ionic form
in the monoclinic space group P21/c with
GABA as protonated ammonium cation and
oxalate dianions. Charge neutrality requires a
2:1 reaction ratio of GABA and oxalic acid. The
crystal structure of the title compound was
determined by single crystal X-ray diffraction.
The asymmetric unit is shown in Figure 1.
Chiang Mai J. Sci. 2011; 38(3)
407
Table 1. Crystal Data for 2GABA:OX.
Chemical formula
Chemical formula weight
Crystal color
Crystal system/Space group
Unit cell a =
b =
c =
Ƣ =
V =
Z =
Temperature =
dcalc =
F000 =
Radiation type =
ƬMo =
R1 =
wR(F2) =
Goodness of fit =
Electron density Ʊmax =
2(C4H10NO2+)˜(C2O42î)
296.28
Transparent colorless
Monoclinic P21/c
7.4153 (9) Å
10.2052 (13) Å
9.7584 (12) Å
108.396 (3)q
700.72(15) Å3
2
298 (2) K
1.404 Mg mî3
316
Mo Kơ
0.122 mmî1
0.0482
0.1141
1.141
0.18(4) e Åî3
Figure 1. A perspective view of the asymmetric unit of 2GABA:OX with atom labeling
scheme indicated thereon. Thermal ellipsoids are drawn at the 50% probability level.
408
Chiang Mai J. Sci. 2011; 38(3)
C(C=O)C, C(C=O)H, -NH3+, CNH2, NH4+,
and NNH2. This survey clearly indicates that
the highest incidence of participation in
the R24(8) synthon is for carboxylate anion
acceptors and ammonium cation donors.
The supramolecular structure of 2GABA:
OX contains extensive OH˜˜˜O, NH˜˜˜O,
and CH˜˜˜O interactions leading to an
elaborate three-dimensional hydrogen bonded
network. The ammonium cation participates
in three separate O˜˜˜HîNîH˜˜˜O motifs,
one to each of the three crystallographically
independent carboxylate C=O functional
groups. Each of these motifs is half of the
R42(8) synthon as shown in Figure 3 (d[CîH]
= 2.887, 2.777, and 2.786 Å), but the R42(8)
synthon itself is not found. Rather, the
O˜˜˜HîNîH˜˜˜O motifs are strings in larger
ring systems. The a and b hydrogen positions
(upper left in Figure 3) participate in centrosymmetric R66(20) rings (Figure 4) that also
include the carboxylic acid group of GABA
and one carboxylate group of the oxalate dianion in local serpentine arrangements. While
carboxylic acids generally form centrosymmetric R22(8) dimers (Figure 2), this robust
synthon is unavailable to a combination of
carboxylate with carboxylic acid. A common
motif for carboxylate with carboxylic acid is
An important part of the analysis of the
structures of cocrystals is the supramolecular
interconnectivity. A useful tool for this analysis
is graph set theory, introduced by Etter
et al. [10,11]. A typical graph set symbol is
R22(8) which is used to represent the typical
dimer formed in the solid state by two
carboxylic acid molecules as shown in
Figure 2a.
A survey [2] of the Cambridge Structural
Database, CSD, has identified over 12,000
instances of the NH˜˜˜O synthon, virtually all
of which involve individual and nonconnected
(but not necessarily chemically different)
moieties in the solid state. Many of these
cases involve four chemically different moieties,
often resulting in the crystallographically
centrosymmetric or pseudo centrosymmetric
R42(8) pattern shown in Figure 2. Perhaps the
most remarkable feature about this synthon
in terms of cocrystal formation is that it
potentially involves the intermolecular recognition
of, and supramolecular synthesis from, four
different molecules in its construction. The
CSD survey gave 918 hits for structures
utilizing the R42(8) synthon in which the donor
is the amino group (NH2) and the acceptor is
the carbonyl group (C=O).These are broken
down into specific functional groups like
(C=O)O, N(C=O), N(C=O)N, (C=O)OH,
(a)
(b)
(c)
Figure 2. Graph set notation for simple synthons relating to carboxylates. a. The R22(8)
carboxylic acid dimer, b. the R42(8) synthon, and c. the R12(4) donor-carboxylate anion motif.
D represents a hydrogen bond donor and A represents a hydrogen bond acceptor.
Chiang Mai J. Sci. 2011; 38(3)
409
the R12(4) synthon (Figure 2) as seen in the O4˜˜˜H˜˜˜O3îC5 subrings in Figure 4. The strong
hydrogen bond parameters are given in Table 2.
Figure 3. The NH··· O hydrogen bonds of the ammonium cation. Thermal ellipsoids are
drawn at the 50% probability level.
Figure 4. The centrosymmetric R66(20) rings involving the a and b hydrogen positions of the
ammonium cation. Thermal ellipsoids are drawn at the 25% probability level.
Table 2. Strong hydrogen bonds.
DH
d(DH)
d(H˜˜˜A)
<DH˜˜˜A
d(D˜˜˜A)
A
symmetry operator
NHa
0.92
2.06
148.6
2.887
O1
[ -x, y+1/2, -z+1/2 ]
NHa
NHb
NHc
O2H2
0.92
0.92
0.92
0.86
2.56
1.91
1.89
1.68
113.5
156.5
164.8
171.3
3.042
2.777
2.786
2.534
O3
O3
O4
O4
[ x-1, -y+1/2, z-1/2 ]
[ x-1, y, z ]
[ -x, y-1/2, -z+1/2 ]
[ x, -y+1/2, z+1/2 ]
410
The O˜˜˜HîNîH˜˜˜O motifs involving
the a and c hydrogen positions (lower left in
Figure 3) and the b and c hydrogen positions
(right in Figure 3) are joined in the common
R54(15) rings shown in Figure 5. One of the
ammonium hydrogen atoms is also donated
Chiang Mai J. Sci. 2011; 38(3)
in a second (weaker) hydrogen bond connecting
GABA and OX through carboxylate oxygen
atoms. Additional strings and other concerted
hydrogen bond motifs are also present, further
augmented by a number of CîH˜˜˜O hydrogen
bonds.
Figure 5. The R54(15) rings involving the a and c, and the b and c hydrogen positions of the
ammonium cation. Thermal ellipsoids are drawn at the 20% probability level.
4. CONCLUSIONS
5. ACKNOWLEDGEMENTS
Strong OîH˜˜˜O and NîH˜˜˜O hydrogen
bonded strings and concerted motifs supported
by weaker CîH˜˜˜O hydrogen bonds from
two J-ammonium butyric acid monocations
and one oxalate dianion create an elaborate
three-dimensional supramolecular network.
While the ammonium ion features strongly in
the supramolecular structure, the anticipated
R42(8) synthon was not found. Instead, larger
nonsymmetric R54(15) and centrosymmetric
R55(20) rings connect adjacent ammonium
ions, oxalate dianions, and carboxylic acid
groups together.
This work was supported by Suranaree
University of Technology.
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Chiang Mai J. Sci. 2011; 38(3)
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