ARTICLE

pubs.acs.org/crystal

Pyrazinamide-Diflunisal: A New Dual-Drug Co-Crystal

vora, Ricardo A. E. Castro, Teresa M. R. Maria, M
ario T. S. Rosado, M. Ramos Silva,#
Ant
onio O. L. E
A. Matos Beja, Jo~ao Canotilho,*, and M. Ermelinda S. Eus
ebio*,
#

Department of Chemistry, Faculty of Pharmacy, and #CEMDRX, Department of Physics, University of Coimbra, Portugal
bS Supporting Information
ABSTRACT: A 1:1 co-crystal involving pyrazinamide, one of
the rst-line drugs recommended by the World Health Orga-
nization for tuberculosis treatment, and diunisal, a nonster-
oidal anti-inammatory substance, has been synthesized for the
rst time. From a combination drug perspective, this is an
interesting pharmaceutical co-crystal because of the known side
eects of pyrazinamide therapy. Preliminary studies by compu-
tational methods on the relative stability of homodimers versus
the two probable heterodimers indicated dierences that could
easily be overcome by the network of intermolecular interac-
tions in a possible co-crystal structure. The co-crystal synthesis
was rst attempted by manually grinding equimolar mixtures.
This procedure yields a physical mixture of the components, whose dierential scanning calorimetry (DSC) curve indicates possible
conditions for generating the co-crystal. The pyrazinamide-diunisal co-crystal can be obtained from an equimolar mortar ground
mixture by thermal activation at T = 80
C. The co-crystal synthesis was also successfully achieved from equimolar mixtures by two
other methods: ethanol-assisted ball mill grinding and room temperature annealing of a low crystalline mixture obtained by neat ball
mill grinding. The new species was characterized by DSC (Tfus = (147.4 ( 0.2)
C, which lies between those of the pure
components), polarized light thermal microscopy, X-ray powder diraction, and Fourier transform infrared spectroscopy. The
infrared spectra show evidence of pyridine-acid association.

INTRODUCTION
Pharmaceutical co-crystals crystalline adducts comprising
an active pharmaceutical ingredient (API) and a co-crystal
former have recently emerged as an innovative strategy to
improve the performance of medicines by modifying their
physical properties without changing any covalent bonds in
either of the species.1
4 The co-crystal former may be another
API or, if not, it should ideally be a generally recognized as safe
(GRAS) substance.5 As co-crystals represent unique solid forms
of the parent APIs with dierent physical and chemical proper- Figure 1. (a) Pyrazinamide and (b) diunisal molecular structures.
ties, multi-API co-crystals are also potential solid forms for the
delivery of combination drugs that can be tested to overcome
problems associated with traditional combination drugs.6 An- 40% of the patients, nongouty polyarthralgia is observed as a side-
other obvious benet of a multi-API co-crystal is the improve- eect, with aspirin or an NSAID being the prophylaxis adopted.10,12
ment of patients long-term medication compliance in long-term The synthesis of a pyrazinamide-diunisal co-crystal therefore
drug therapy, since fewer pills need to be taken.7,8 represents an attractive alternative, which has the potential for
The work presented here involves investigation of co-crystal development of combination drug therapy formulations.
formation between pyrazinamide (PZA), Figure 1a, an antitu- In this work, a rst insight on the feasibility of co-crystal for-
berculosis drug, and diunisal (DFL), Figure 1b, a nonsteroidal mation between diunisal and pyrazinamide is addressed by
anti-inammatory compound (NSAID), which belongs to class computational quantum chemistry methods applied to homodimers
II of the Biopharmaceutical Classication System (low aqueous found in the API crystalline structures and to hypothetical hetero-
solubility, high membrane permeability, as most NSAIDs).9 dimers. Dierent experimental approaches have been attempted for
Tuberculosis is a global pandemic with a huge number of new
cases every year,10,11 and pyrazinamide is one of the rst-line Received: March 7, 2011
drugs recommended by the World Health Organization for Revised: September 16, 2011
treatment of the disease.12 However, it is reported that in up to Published: September 20, 2011

r 2011 American Chemical Society 4780 dx.doi.org/10.1021/cg200288b | Cryst. Growth Des. 2011, 11, 47804788
Crystal Growth & Design
Scheme 1. Isodesmic Reactions for the Calculation of the Relative Stability of the Heterodimers vs Homodimers. (a) Acid-Amide
Heterosynthon; (b) Acid-Pyridine Heterosynthon.
Table 1. B3LYP/aug-cc-pVDZ Energies of Diunisal and Pyrazinamide Homodimers and Heterodimersa
symmetry
(degeneracy) Eelec/Eh
DFL homodimer Ci(1)
1850.370
PZA homodimer Ci(1)
865.664
DFL-PZA acid-amide C1(2)
1358.019
DFL-PZA acid-pyridine C1(2)
1358.008
a
Eelec: electronic energy; E0: Eelec + zero point vibrational energy; H298 K: enthalpy at 298 K; G298 K: Gibbs energy at 298 K.
the co-crystal synthesis and their results interpreted using a combi-
nation of dierential scanning calorimetry (DSC), polarized light
thermal microscopy (PLTM), X-ray powder diraction (XRPD),
and infrared spectroscopy (FTIR).
EXPERIMENTAL PROCEDURES
Materials. Diflunisal was acquired from Sigma-Aldrich and pyrazi-
namide from Fluka, with specified purity greater than 99% (N). Both
compounds were used as received. Analytical grade solvents were
employed in the crystallization from solution experiments.
Computational Methods. All DFT calculations were carried out
at the B3LYP/aug-cc-pVDZ level.13
17 Starting geometries of PZA and
DFL homodimers were extracted from their crystalline X-ray diffraction
structures. Starting geometries were constructed from the molecular
species found in the same crystals for two hypothetical heterodimers
containing DFL and PZA, considering both acid-amide and acid-
pyridine synthons, as these are the supramolecular units expected in
the new structures.3 The full geometry optimization for all supramole-
cular species was followed by calculation of vibrational frequencies at the
same level of theory to elucidate the nature of the stationary points and
to allow the calculation of Gibbs energies at room temperature. The
calculations were performed using the GAMESS 12 JAN2009 (R3)
software18 running in a Linux-based cluster of six commodity PCs.
Co-Crystal Synthesis. Co-crystallization was attempted from
equimolar amounts of diflunisal and pyrazinamide, both by grinding
and by crystallization from solutions.
Grinding experiments were carried out manually in an agate mortar
using 0.05 mmol of each compound and no solvent. Mortar-ground solid
4781
ARTICLE
E0/ (kJ mol
1) H298 K/ (kJ mol
1) G298 K/ (kJ mol
1)

4857172
4857091
4857343

2272252
2272208
2272373

3564717
3564654
3564863

3564691
3564627
3564842
mixtures were also annealed at dierent temperatures, for various periods of
time. A Retsch MM400 mill was also used: 0.25 mmol of each substance
was ground in a 10 mL stainless steel jar for 30 min at 15 Hz frequency,
with two stainless steel 7 mm diameter grinding balls. The experiments
were carried out under two dierent conditions: without added solvent
or with the addition of 10 L of ethanol.
In the solution crystallization experiments, ethyl acetate, tetrahydro-
furan, ethanol, methanol, ethyl acetate-ethanol (1:1 v/v), isopropanol
were used as solvents. The original materials (0.05 mmol of each API)
were dissolved in 6 mL of the solvent, at room temperature, the solutions
were ltered to a Petri dish, and the solvent was evaporated at room
temperature (ca. 20
C). Additional experiments were performed
with the same solution composition, by slow evaporation at ca. 20
C
(until a solid phase was obtained) from ethanol and ethyl acetate, the
solvents that produced the least contaminated co-crystal in the previous
experiments.
X-ray Powder Diffraction (XRPD). A glass capillary was filled
with the powder obtained by grinding the solids. The samples were
mounted on an ENRAF-NONIUS powder diffractometer (equipped
with a CPS120 detector by INEL) and data were collected for 5 h using
Debye
Scherrer geometry. Cu K1 radiation was used ( = 1.540598
). Silicon was chosen as an external calibrant.
Infrared Spectroscopy (FTIR). The infrared spectra of the solids
in KBr pellets were recorded at room temperature using a FTIR
spectrometer, ThermoNicolet IR300, at 1 cm
1 resolution.
Polarized Light Thermal Microscopy (PLTM). The solids
obtained were characterized by PLTM using a hot stage Linkam system,
model DSC600, with a Leica DMRB microscope and a Sony CCD-IRIS/
RGB video camera. Real Time Video Measurement System software by
dx.doi.org/10.1021/cg200288b |Cryst. Growth Des. 2011, 11, 47804788
Crystal Growth & Design ARTICLE

Figure 2. Infrared spectra: (1) Mortar ground equimolar diunisal-I + pyrazinamide- mixture; (2) diunisal, polymorph I; (3) pyrazinamide,
polymorph .

Figure 4. DSC heating runs; scanning rate 10
C/min: (1) mortar

Figure 3. Experimental X-ray powder diraction spectra: (1) Mortar ground equimolar diunisal-I+pyrazinamide- mixture, m = 1.57 mg;
ground equimolar diunisal-I + pyrazinamide- mixture; (2) diunisal, (2) diunisal-I, m = 1.69 mg; (3) pyrazinamide-, m = 2.13 mg; inset a:
polymorph I;21 (3) pyrazinamide, polymorph .20 expansion of curve 1.

Linkam was used for image analysis. The images were obtained Differential Scanning Calorimetry (DSC). The studies were
by combined use of polarized light and wave compensators, using a performed in a Pyris1 power compensation calorimeter from Perkin Elmer,
200 magnification. with an intracooler cooling unit at
10
C - ethylenglycol-water, 1:1 (v/v),

4782 dx.doi.org/10.1021/cg200288b |Cryst. Growth Des. 2011, 11, 47804788

Crystal Growth & Design ARTICLE

Figure 5. Thermomicroscopy images obtained in a heating run performed at 10
C/min on a mortar ground equimolar diunisal-I+pyrazinamide-
mixture, scanning rate 10
C min
1; amplication 200.

cooling mixture. The samples were hermetically sealed in aluminum

pans and an empty pan was used as reference. A 20 mL/min nitrogen
purge was employed. Temperature and enthalpy calibration were
performed as described in previous work.19

RESULTS AND DISCUSSION

Identification of Polymorphic Forms of Starting Materials.
The pyrazinamide sample used in this work was previously
characterized in our group as the -polymorph19,20 (Figure S1a,
Supporting Information). In the crystalline structure of -pyrazin-
amide, monoclinic, P21/a, Z = 4, two molecules are linked
together forming amide
amide dimers (dN
H 3 3 3 O = 2.905 ;
N
H 3 3 3 O = 179
), with each dimer connected to two other
molecules by N
H 3 3 3 Nring hydrogen bonds (dN
H 3 3 3 N =
3.138 ; N
H 3 3 3 N = 136
). From XRPD experiments, Figure
S1b, Supporting Information, diflunisal was identified as form I,
which was first structurally characterized by Cross et al.21 In
diflunisal I, triclinic, P1, Z = 2, acid
acid dimers are present
(dO
H 3 3 3 O= = 2.699 ; O
H 3 3 3 O= = 170
) and vanishing weak
intermolecular O
H 3 3 3 O
H bonds connect the dimers. The
same kind of acid
acid homodimers are present in all known
diflunisal crystalline structures,21
24 and partial molecular dis-
order is reported with the ortho fluorine atom equally distributed
over two sites.
Computational Results. The formation of co-crystals is
dependent on the ability of the constituent molecules to associate
in a new mixed supramolecular species, due to the establishment
of favorable noncovalent intermolecular interactions. The sim-
plest entity that can simulate this association in the co-crystal
synthon, retaining the main intermolecular interactions involved,
is a heterodimer comprising one molecular unit of each starting
substance. However, the existence of the heterodimer as a stable
species is not sufficient to ascertain the possibility of co-crystal
formation. It is a necessary condition that the heterodimers have
greater stability than the corresponding homodimers, since the
molecular units of the substances will associate in the thermo-
dynamically most stable form. Since there are other molecular
interactions present, the use of dimers as model species cannot be
a complete representation of the crystalline chemical environ-
ment and structures. However, it seems to represent the most
important aggregate to simulate the crystals because of the diffe-
rent scale of interactions present, as indicated by the intermolecular
4783
Figure 6. DSC heating curves of mortar ground equimolar mixtures of
diunisal/pyrazinamide annealed for dierent periods of time, t, at T =
80
C; scanning rate 10
C/min: (1) t = 0, m = 1.30 mg; (2) t = 1 day, m
= 1.90 mg; (3) t = 2 days, m = 1.30 mg; (4) t = 3 days, m = 1.50 mg; (5) t
= 4 days, m = 1.52 mg; (6) t = 5 days, m = 1.24 mg. Inset a: expansion of
curves 1 and 6.
distances in the crystalline structures of pure APIs. This method
gives a first insight into the practical feasibility of a co-crystal.
To minimize potential errors the relative stability of the
heterodimers vs homodimers can be evaluated from the calcu-
lated reaction free energies in the isodesmic reactions (a) and
(b), Scheme 1.
Results obtained for the dimeric structures are presented in
Table 1.
Geometry optimization of homodimers did not lead to
signicant dierences in the structure. The analysis of the relative
stabilities of heterodimers and homodimers provides an indica-
tion of the feasibility of formation of pyrazinamide-diunisal
adducts at least in acid-amide synthons (Go298 K =
5 kJ mol
1)
corresponding to the isodesmic reaction (a) in Scheme 1). The
calculations indicate that the acid-pyridine association is 16 kJ mol
1
less stable than the homodimers of initial substances (Go298 K
of the isodesmic reaction (b) in Scheme 1). These relatively small
stability dierences obtained for the dimers point to a delicate
dx.doi.org/10.1021/cg200288b |Cryst. Growth Des. 2011, 11, 47804788
Crystal Growth & Design ARTICLE

Figure 7. PLTM images obtained in the heating process of a mortar ground equimolar diunisal/pyrazinamide mixture, after annealing at T = 80
C, for
5 days; scanning rate 10
C/min, amplication 200.

Figure 8. X-ray powder diraction patterns: (1) Experimental for an equimolar diunisal/pyrazinamide mixture annealed at 80
C for 5 days. (2)
Simulated for (a) diunisal, polymorph I;21 (b) diunisal, polymorph III;21 (c) diunisal, polymorph V.22

balance of equilibria among the homodimers and any of the
possible heterosynthons, and that this can eventually be tipped
toward one or another, depending on the physicochemical envi-
ronment of the API and coformer mixture.
Co-Crystal Synthesis and Characterization. The co-crystal
synthesis was initially attempted by manual grinding of equimo-
lar amounts of pyrazinamide, polymorph , and diflunisal, form I,
in an agate mortar. X-ray diffraction, infrared spectroscopy, and
differential scanning calorimetry were used to characterize the
resulting mixture and identify possible co-crystal formation.
4784
The infrared spectra and the XRPD patterns of the initial com-
pounds and of the ground mixture are shown in Figures 2 and 3,
respectively.
The infrared spectra and the X-ray powder diractograms
clearly show that no co-crystal formation took place, since the
results for the ground mixture correspond to the sum of the
individual characteristics of the separate compounds. However,
interesting results were obtained by dierential scanning calorimetry/
thermomicroscopy as shown in Figures 4 and 5. In Figure 4 the
DSC traces obtained for the pure compounds and for the mixture
dx.doi.org/10.1021/cg200288b |Cryst. Growth Des. 2011, 11, 47804788
Crystal Growth & Design ARTICLE

Figure 9. X-ray powder diraction patterns: (1) Experimental for an equimolar diunisal/pyrazinamide mixture annealed at 80
C for 5 days. (2)
Simulated for (a) pyrazinamide, polymorph ;20 (b) pyrazinamide, polymorph 0 ;26 (c) pyrazinamide, polymorph ;27 (d) pyrazinamide, polymorph
;19,25 (e) pyrazinamide, polymorph .28

are compared; heating runs were made from room temperature by melting of form at Tfus = (188.3 ( 0.1)
C, fusH = (28.1 (
up to the diunisal melting temperature. For this compound, a 0.3) kJ/mol.19 For the ground mixtures, an exothermic event is
single thermal event is observed, corresponding to the melting observed at T 110
C and is followed by an irregular endo-
process, Tfus = (211.8 ( 0.3)
C, fusH = (36 ( 1.6) kJ/mol, thermic peak. Thermomicroscopy images, shown in Figure 5 for
number of replicates, n = 6. For pyrazinamide, the endothermic a heating run at the same scanning rate, conrm the growth of a
transition from solid form to polymorph is observed at Ttrs = new phase in the exothermic process (see images from 113 to
(146.9 ( 0.5)
C (at a 10
C/min heating rate) and is followed 146
C) with the last event being the melting process. The results
4785 dx.doi.org/10.1021/cg200288b |Cryst. Growth Des. 2011, 11, 47804788
Crystal Growth & Design
Figure 10. Infrared spectra: (1) 1:1 diunisal/pyrazinamide co-crystal; (2) equimolar diunisal-I/-pyrazinamide physical mixture.
indicate that a new species is being formed in the exothermic
event observed in the DSC curve.
Following from these observations, the synthesis of this new
species was attempted by annealing manually ground equimolar
mixtures in closed containers in an oven. As the DSC experi-
ments were carried out in the scanning mode, it is anticipated that
the exothermic event will occur at a lower temperature when
isothermal conditions are employed. The rst annealing experi-
ments were therefore carried out at T = 65
C, well below the
onset recorded in the DSC experiments. However, even after two
days only residual sample evolution was observed. The oven
temperature was subsequently raised to 80
C and the solids
produced after dierent periods of time were analyzed by DSC.
After a 5 day period, the DSC curve shows a sharp single peak,
Figure 6 (Tfus = (147.4 ( 0.2)
C, fusH = (55.5 ( 0.9) kJ mol
1;
n = 4), which is assigned to co-crystal melting. Thermomicro-
scopy experiments conrm the single phase transition observed
as a melting process (see Figure 7).
The XRPD spectrum of the 1:1 mixture of pyrazinamide-
diunisal annealed at 80
C was obtained and compared with the
simulated spectra of the polymorphs of both APIs. Three
polymorphs of diunisal have been previously characterized by
single-crystal X-ray diraction. From Figure 8 it is seen that none
of them is present in the mixture. The crystalline structure of
pyrazinamide has been the object of research for a long time.19,25
29
4786
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The exhaustive work performed on this API led to four dierent
polymorphs being identied, , , , and -pyrazinamide, as well
as a possible fth polymorph, 0 , which is similar to . The
experimental XRPD spectrum of the 1:1 pyrazinamide-diunisal
mixture annealed for 5 days is compared in Figure 9 to those of
the dierent pyrazinamide polymorphs. The results are conclu-
sive: the presence of any of the pyrazinamide polymorphs is also
excluded.
Since there are no traces of any known polymorphs of the
original APIs in the ground mixture annealed at 80
C, a new
species must have been formed. The combined DSC, thermo-
microscopy, and XRPD results support the formation, in the
annealing process, of a 1:1 co-crystal involving pyrazinamide and
diunisal.
The infrared spectra of the co-crystal and of the 1:1 physical
mixture of diunisal and pyrazinamide are presented together in
Figure 10. There are dierences observed in the pyrazinamide
NH stretching bands: ass (NH2) = 3414 cm
1 (physical
mixture, p.m.) and ass (NH2) = 3409 cm
1 (co-crystal, c.c.);
s (NH2) = 3364 cm
1 (p.m.) and s (NH2) = 3370 cm
1 (c.c.);
in the amide II and ring vibration modes found between 1650 and
1550 cm
1; in the amide III vibration around 1370 cm
1 and also
in the bands tentatively assigned to ring modes in ref 19, found in
the spectrum of physical mixtures at 1054 and 432 cm
1, and at
1062 and 444 cm
1, respectively, in the co-crystal. With diunisal,
dx.doi.org/10.1021/cg200288b |Cryst. Growth Des. 2011, 11, 47804788
Crystal Growth & Design
the OH stretching vibration mode in the 3100
2400 cm
1
region is modied considerably in the new crystalline environ-
ment. The same occurs with the CdO and the C
OH stretching
modes: s (CdO) = 1689 cm
1 (p.m.), s (CdO) = 1672 cm
1
(c.c.) and s (C
OH) = 1200 cm
1 (p.m.), s (C
OH) =
1233 cm
1 (c.c.).
It is well established that adducts containing carboxylic acid
OH 3 3 3 N hydrogen bonds exhibit typical broad infrared band
proles with characteristic maxima centered at approximately
2500 and 1910 cm
1.30
34 This feature is usually assigned to
Fermi resonance of OH stretching and overtones of bending
modes in OH 3 3 3 N complexes.31 These bands are identied in
the pyrazinamide-diunisal co-crystal spectrum and are absent in
the physical mixture. This observation provides clear evidence of
the establishment of this hydrogen bonding type, giving rise to
the acid-pyridine heterosynthon, which is only possible between
the two dierent APIs, thus conrming their association in a new
structure.
Co-Crystal Synthesis by Crystallization from Solutions
and by Ball Mill Grinding. The crystallization from solution
experiments performed so far, from 1:1 solutions of the compo-
nents, gave rise to mixtures of the co-crystal and pure APIs in
variable proportions. These observations are consistent with
different solubilities of diflunisal and pyrazinamide, giving rise
to noncongruently saturating systems.35
37 Despite all experi-
mental effort, no crystals could be obtained of appropriate size
and quality for structure determination.
Co-crystallization was also attempted by either ethanol as-
sisted or neat grinding of equimolar amounts of both compounds
in a ball mill. Ethanol (10 L) assisted grinding for 30 min at 15
Hz results in complete conversion to the co-crystal structure. The
neat process gives rise to a low crystalline material, and the co-
crystal is obtained from this material in about 60 min, at room
temperature.
CONCLUSIONS
Co-crystal formation involving the rst-line antituberculosis
drug, pyrazinamide, and diunisal, a nonsteroidal anti-inamma-
tory drug has been investigated.
A rst insight into the feasibility of co-crystal formation
involving the two APIs was obtained using computational
quantum chemistry methods. The thermodynamic stabilities of
the homodimers present in the APIs crystalline structures and
those of hypothetical heterodimers were compared using suitable
isodesmic reactions. The relatively small stability dierences
found indicate a delicate equilibrium among the possible inter-
molecular associations that can be tipped one way or another,
depending on the physicochemical environment of the mixture.
A 1:1 pyrazinamide-diunisal co-crystal was successfully pre-
pared by three dierent experimental methods: annealing a
mortar ground mixture at 80
C, room temperature annealing
of a low crystallinity mixture obtained by neat ball mill grinding,
and ethanol assisted ball milling.
The new species was characterized by dierential scanning
calorimetry, polarized light thermal microscopy, X-ray powder
diraction, and infrared spectroscopy.
The pyrazinamide-diunisal co-crystal is of considerable
interest because of its potential application in a combination
drug therapy, due to the side eects of pyrazinamide, and, in
addition, it oers the potential to improve diunisal aqueous
solubility.
4787
ARTICLE
ASSOCIATED CONTENT
bS Supporting Information. Figure S1a: pyrazinamide
X-ray powder diraction spectra; Figure S1b: diunisal X-ray
powder diraction spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: quierme@ci.uc.pt; jcano@ci.uc.pt.
ACKNOWLEDGMENT
We are grateful to FEDER/POCI 2010 for nancial support.
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