Polymorphs and cocrystals of nalidixic acid

Article abstract of DOI:10.1021/cg300895c

Only one X-ray crystal structure of the parent quinolone antibiotic nalidixic acid is known in the published and patent literature. A systematic search for new solid-state forms of the drug yielded two polymorphs (forms II and III) and six cocrystals with resorcinol, catechol, hydroquinone, pyrogallol, orcinol, and phloroglucinol. Of these, X-ray crystal structures were determined for polymorph II and cocrystals with resorcinol, catechol, hydroquinone, and pyrogallol, whereas the remaining solid forms were identified by their unique powder X-ray diffraction patterns. Nalidixic acid is intramolecularly O-H...O hydrogen bonded in a six-member ring, and its molecular dimers are assembled via C-H...O synthon. The OH donors on phenolic coformers H bond with the α-keto acid moiety of the drug as connectors and spacers. Intermolecular drug-drug C-H...O interactions in polymorphs are replaced by strong drug-coformer O-H...O hydrogen bonds in cocrystals.

Full text of DOI:10.1021/cg300895c

Article
pubs.acs.org/crystal
Polymorphs and Cocrystals of Nalidixic Acid
Swarupa Gangavaram,† S. Raghavender,† Palash Sanphui,‡ Sharmistha Pal,*,§ Sulur G. Manjunatha,§
Sudhir Nambiar,§ and Ashwini Nangia*,†,‡
†Technology Business Incubator, and ‡School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Central University PO,
Gachibowli, Hyderabad 500 046, India
§Pharmaceutical Development, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560 024, India
S
* Supporting Information
ABSTRACT: Only one X-ray crystal structure of the parent
quinolone antibiotic nalidixic acid is known in the published
and patent literature. A systematic search for new solid-state
forms of the drug yielded two polymorphs (forms II and III)
and six cocrystals with resorcinol, catechol, hydroquinone,
pyrogallol, orcinol, and phloroglucinol. Of these, X-ray crystal
structures were determined for polymorph II and cocrystals
with resorcinol, catechol, hydroquinone, and pyrogallol,
whereas the remaining solid forms were identified by their
unique powder X-ray diffraction patterns. Nalidixic acid is
intramolecularly O−H···O hydrogen bonded in a six-member
ring, and its molecular dimers are assembled via C−H···O
synthon. The OH donors on phenolic coformers H bond with the α-keto acid moiety of the drug as connectors and spacers.
Intermolecular drug−drug C−H···O interactions in polymorphs are replaced by strong drug−coformer O−H···O hydrogen
bonds in cocrystals.
of a new polymorph (form II) upon slow evaporation. The bulk
material form II was grown from a dichloromethane−n-hexane
solvent−antisolvent mixture (1:4 ratio). Their unit cell
parameters and molecular packing are significantly different,
but the melting points are very close (difference 0.2 °C).
Attempted salt formation of nalidixic acid by crystallization
from methanesulfonic acid afforded a third polymorph of the
drug. The product was crystalline but single crystals for X-ray
diffraction could not be obtained. The melting point of form III
is 2 °C lower than that of form I and II. Along with
polymorphs, cocrystals of nalidixic acid were obtained with
phenolic coformers by liquid-assisted ball-mill grinding.12,13
Crystallographic parameters of polymorphs and cocrystals in
this study (Scheme 1) are listed in Table 1.
The intramolecular O−H···O hydrogen bond in the α keto
acid moiety of the molecule (form I: 2.53 Å, 153°; Form II:
2.57 Å, 155°), the anti conformation of COOH group, and the
conformation of terminal N−CH2CH3 group are identical in
the crystal structures of form I and II. Since strong hydrogen
bonding groups are engaged in the solitary intramolecular O−
H···O hydrogen bond, molecular packing in the crystal
structure is directed by mutual recognition and weaker C−
H···O interactions. The molecules adopt a herringbone motif in
the unit cell of form I (Figure 1a) with a dimer assembled via
INTRODUCTION
■
Nalidixic acid is one of the earliest quinolone antibiotics used in
the treatment of urinary tract infections.1a The drug is effective
against both Gram-positive and Gram-negative bacteria. It is
the only FDA approved quinolone drug for pediatric
formulation. The drug is insoluble in water at <100 mg/L
solubility and with a dose of 500 mg to 4 g/day, its dose
number Do is 20.1b,c High doses of the drug can occasionally
trigger convulsions and hyperglycemia.1d Our objective was to
study polymorphs and cocrystals of nalidixic acid for improving
its solubility and bioavailability, a topic that is receiving
increasing focus2 in the pharmaceutical development of drugs.
Solid dispersions of nalidixic acid were recently reported.3
Although nalidixic acid has been in use for almost 50 years as
one of the earliest quinolone antibiotics, no polymorphs,
solvates, hydrates, and/or cocrystals of nalidixic acid are
disclosed. Only one crystal structure of nalidixic acid is
reported4 to date. Salts of nalidixic acid with sodium (crystalline
alkali metal salts) and 1,2-ethanediamine were disclosed in
patents.5 A few recent reports deal with polymorphs,6
hydrates,7 salt hydrates,8 cocrystals,9 and salts10 of fluoroqui-
nolone antibiotics, e.g., norfloxacin and ciprofloxacin.
RESULTS AND DISCUSSION
■
The current update of the CCDC contains a single entry for
nalidixic acid (Refcode NALIDX01).11 The commercial
material (designated form I) was dissolved in a methanol−
nitromethane mixture (3:1 ratio, 8 mL) to afford single crystals
Received: July 3, 2012
Revised: August 20, 2012
Published: August 20, 2012
© 2012 American Chemical Society
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Scheme 1. Nalidixic Acid Drug and Coformers Used to Obtain Novel Cocrystals
Table 1. Crystallographic Data on Polymorphs and Cocrystals of Nalidixic Acid
nalidixic acid−
resorcinol cocrystal
(1:1)
nalidixic acid−
catechol cocrystal
(1:1)
nalidixic acid−
hydroquinone
(1:0.5)
nalidixic acid form I CSD nalidixic acid
nalidixic acid−pyrogallol
refcode NALIDIX01
form II
cocrystal hemihydrate (1:1:0.5)
empirical
formula
C12H12N2 O3
C12H12N2O3
C18H18N2O5
C18H18N2O5
C15H15N2O4
C18H19N2O6.50
formula
weight
232.23
232.23
342.34
342.34
287.29
367.35
crystal
system
monoclinic
monoclinic
orthorhombic
triclinic
monoclinic
monoclinic
space group
a (Å)
b (Å)
c (Å)
P21/c
8.921(1)
13.156(2)
9.369(1)
90
P21/n
P212121
7.9735(11)
8.0661(11)
25.497(3)
90
P1
P1
C2/c
̅
̅
10.0895(16)
7.0684(14)
15.296(2)
90
7.581(5)
7.9735(11)
13.437(12)
74.230(10)
84.306(15)
74.627(11)
2
7.559(4)
9.765(4)
10.036(4)
87.82(3)
87.78(4)
67.56(4)
2
33.756(5)
7.1890(11)
14.479(2)
90
α (°)
β (°)
γ (°)
Z
vol. (Å3)
100.04
90
96.282(14)
90
90
106.874(16)
90
90
4
4
4
8
1082.7
1.42
1085.2(3)
1.42
1639.8(4)
1.38
819.5(11)
1.38
684.0(5)
1.39
3362.4(9)
1.45
Dcalc
(mg/mm3)
R1
0.039
0.0613
0.0888
0.890
0.0522
0.0961
1.047
0.0503
0.1299
1.038
0.0637
0.1488
1.009
0.0609
0.1539
1.056
wR2
GOF
bifurcated C−H···O hydrogen bonds between DDA fragments
(D = C−H donor, A = O acceptor).
polymorph phase by PXRD match. Form III exhibited a
different PXRD line pattern (Figure 3). The IR spectra and
DSC thermograms (Figures 4 and 5) show small differences in
peak positions for polymorphs I−III; e.g., the carbonyl peak is
at 1715.8, 1711.7, 1719.8 cm−1 and the weak O−H band is at
3419.5, 3431.6, and 3453.6 cm−1 in the three polymorphs,
respectively. FT-IR vibrational frequencies are summarized in
Table 3. A comparison of the heat of fusion values and melting
points of the polymorphs from DSC (heating rate 5 °C min−1,
Figure 5) suggests that the new found polymorphs are
monotropically related to form I. While the melting points of
form I and II are similar, form III has a slightly lower melting
temperature (by 2 °C). The enthalpy of fusion for form I, II,
and III are 37.9, 36.1, and 31.8 kJ mol−1.14 Additionally, the
absence of any new endo/exotherm peaks at a faster heating
rate (20 °C min−1, Figure S9, Supporting Information) implies
that no minor phase transitions were overlooked in the thermal
analysis. Thus, according to the heat of fusion rule14 the free
energy order of polymorphs is form 1 (most stable) < form 2 <
form 3 (least stable). The stability order of polymorphs at room
In contrast to the edge-to-face orientation of phenyl rings in
form I, the molecules are π−π stacked in form II crystal
structure (Figure 2a). The same C−H···O dimer synthon
(Figure 2b) is present in both polymorphs (Form I: 2.37 Å,
162°; 2.43 Å, 148°; Form II: 2.51 Å, 154°; 2.36 Å, 143°).
Hydrogen bonding metrics are given in Table 2. The pyridine
nitrogen does not participate in hydrogen bonding because of
steric screening by the flanking N-ethyl and ortho-methyl
groups.
The bulk material of form I was easily obtained by routine
crystallization. The new form II of nalidixic acid was crystallized
in larger quantity by dissolving the compound in dichloro-
methane by sonication and heating, cooling to room temper-
ature, and then n-hexane was added as antisolvent. Dissolution
of nalidixic acid in methanesulfonic acid by gentle heating,
cooling to room temperature, and addition of water as
antisolvent afforded crystals of a new form III. The bulk
material of form I and II matched with the single crystal
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Figure 1. (a) Herringbone packing of fused heteroaromatic cores in the crystal structure of nalidixic acid form I, and (b) bifurcated C−H···O dimer
synthon between inversion related molecules.
Figure 2. (a) Stacking of heteroaromatic rings down the b-axis in crystal structure of form II, and (b) bifurcated C−H···O synthon.
temperature was established by grinding and slurry experi-
ments. An equimolar mixture of form I and II was ground in
mortar-pestle for 1 h to give stable form I. Transformation in a
slurry of n-heptane and cyclohexane at room temperature again
gave form I exclusively within 24 h. Slurry crystallization of
form I and III in the same conditions gave stable form I. PXRD
patterns are shown in Figure S5, Supporting Information. The
system may be defined as monotropic because no phase
transition was observed in the temperature range studied, and
form I is the stable modification. However, both form II and
form III transformed to form I in independent slurry
experiments at RT. Such a difference in polymorph trans-
formation behavior and stability relation in DSC vs slurry
conditions was recently noted for pyrazinamide and pheno-
barbital polymorphs.15
NA−catechol (1:1), and NA−hydroquinone (1:0.5) cocrystals,
and NA−pyrogallol hemihydrate (1:1:0.5). New PXRD line
patterns were observed for NA−orcinol and NA−phlorogluci-
nol (hydrate) cocrystals.
In all four X-ray crystal structures (Figure 6), the hydroxy
group of carboxylic acid on nalidixic acid is oriented in anti
conformation and forms an intramolecular hydrogen bond with
the carbonyl oxygen, similar to that in its polymorphs. Both O
atoms of the COOH group are geometrically in the correct
arrangement to interact with OH and CH donors of a phenol
donor molecule. Thus a two point O−H···O + C−H···O
synthon is consistently observed in all four structures, the so-
called DD:AA motif.17 The intermolecular hydrogen bond
synthon in NA polymorphs (DDA/ADD) is completely
different from that in cocrystals (DD:AA). Secondary level
differences such as helices of dimers in resorcinol cocrystal,
whereas centrosymmetric finite units in hydroquinone cocrystal
were noted. Catechol connects NA molecules in a linear array.
The cocrystal of nalidixic acid and pyrogallol was crystallized as
a hemihydrate. It is likely that the water molecule was included
from the hydrate form of pyrogallol, the commercial material as
it was used in crystallization. The water molecule resides on a 2-
fold axis in the C2/c crystal system, accepting H bonds from
phenol donor and donating H bonds to an adjacent OH. Two
of the three phenol OHs are bonded to drug molecules. The
observation that bis-phenol coformers (e.g., resorcinol,
catechol, hydroquinone) formed 1:1 cocrystals whereas tris-
phenol coformers (such as pyrogallol, phloroglucinol) formed
Nalidixic acid salts with alkali metals (e.g., Na+) and 1,2-
ethanediamine are reported.5 We attempted cocrystallization of
nalidixic acid with phenolic coformers with the thought that the
OH and CO groups on the API will hydrogen bond with
donor groups on the coformer. This expectation was based on
our recent success with curcumin cocrystals.16 Several different
functional group coformers were attempted, e.g., amino acids
(L-lysine, L-glutamine, L-histidine, L-proline, L-threonine, etc.),
carboxylic acids (benzoic acid, nicotinic acid, salicylic acid,
ferulic acid, etc.), carboxamides (nicotinamide, isonicotinamide,
acetamide, urea, etc.), and a few nucleobases (adenine, cytosine,
thymine). Results with phenols were most encouraging. Single
crystals were obtained for nalidixic acid (NA)−resorcinol (1:1),
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Table 2. Hydrogen Bonds in Crystal Structures (Neutron-Normalized Distances)
crystal forms
interaction
H···A (Å)
D···A (Å)
∠D−H···A (°)
symmetry code
intramolecular
nalidixic acid form I
O2−H12···O1
C2−H4···O3
C3−H6···O3
O2−H2···O1
C9−H9···O3
C2−H2B···O2
O2−H2···O1
O4−H4···O1
O4−H4···O5
C7−H7···O5
C15−H15···O2
C15−H15···O2
O3−H3···O1
O4−H4···O2
O5−H5···O1
C3−H3A···O4
C14−H14···O3
O2−H2···O1
O4−H4···O3
O5−H5···O4
O5−H5···O1
O6−H6···O5
O6−H6···O7
O7−H7B···O5
C18−H18···O3
O2−H2···O1
O4−H4···O3
C7−H7···O4
C14−H1···O2
1.61
2.37
2.43
1.65
2.36
2.51
1.59
2.01
2.25
1.80
2.37
2.35
1.60
1.76
1.77
2.42
2.29
1.61
1.80
2.27
1.88
2.19
2.06
2.64
2.47
1.57
1.82
2.25
2.35
2.5280
153
162
148
155
143
154
156
129
108
159
162
156
151
151
166
170
166
151
175
109
155
111
149
124
130
153
155
145
159
3.4186
1 − x, 1 − y, 1 − z
1 − x, 1 − y, 1 − z
intramolecular
3.3949
nalidixic acid form II
2.571(3)
3.289(4)
3.524(4)
2.521(3)
2.733(3)
2.712(3)
2.738(3)
3.417(4)
3.370(4)
2.500(4)
2.707(4)
2.732(4)
3.488(4)
3.357(5)
2.518(3)
2.784(3)
2.750(3)
2.797(3)
2.704(3)
2.951(2)
3.188(2)
3.268(4)
2.486(3)
2.745(3)
3.202(4)
3.384(4)
−x, 1 − y, −z
2 − x, 1 − y, 2 − z
intramolecular
nalidixic acid−catechol
−1 + x, y, z
intramolecular
x, −1 + y, z
1 + x, y, z
x, −1 + y, z
intramolecular
nalidixic acid−resorcinol
x, −1 + y, z
−1/2 + x, 1/2 − y, −z
1 − x, 1/2 + y, 1/2 − z
x, −1 + y, z
nalidixic acid−pyrogallol hydrate
intramolecular
1/2 − x, 1/2 + y, 1/2 − z
intramolecular
x, 1 − y, −1/2 + z
intramolecular
−x, 1 − y, −z
1 − x, y, 3/2 − z
1/2 − x, 1/2+ y, 1/2 − z
intramolecular
nalidixic acid−hydroquinone
1 − x, −y, 1 − z
1 − x, 1 − y, 1 − z
1 − x, −y, 1 − z
cocrystal hydrates with nalidixic acid is due to the extra OH
phenol being able to form hydrogen bond with water and
complete the O−H···O network in the crystal structure.
Changes in CO stretching frequencies (10−15 cm−1) as
well as in OH region (Table 3) gave a preliminary indication of
new solid phases.
phloroglucinol in equimolar ratio with a few drops of EtOH
added gave a cocrystal hydrate of 1.2−1.4 water stoichiometry.
Water is introduced in the crystal lattice from the atmosphere
or from EtOH during grinding and handling. The cocrystals of
nalidixic acid with tris-phenols, such as pyrogallol and
phloroglucinol, are hydrates of 0.5 and 1.2−1.4 water
stoichiometry, respectively. IR spectra suggest new solid-state
forms (Figure S4, Supporting Information). The stoichiometry
of the cocrystal part is 1:1 based on equimolar quantity mixed
in cocrystallization as well as 1H NMR spectrum of the
crystalline product (see Figures S6 and S7, Supporting
Information). Growing single crystals of nalidixic acid−orcinol
and nalidixic acid−phloroglucinol is under progress. Attempted
salt formation with carboxylic acids and sulfonic acids did not
yield any new adducts.
The bulk cocrystals prepared by liquid-assisted grinding13,18
matched perfectly with the single crystal phase based on a peak-
to-peak comparison of experimental and calculated XRD lines
(Figure 7). The PXRD plots and IR spectra of API, coformer
and cocrystal are displayed in Figures S1 and S2, Supporting
Information. The melting endotherm temperature of cocrystal
is different from that of the pure components (see Table 4 and
Figure 8). TGA confirmed weight loss of NA−pyrogallol
hemihydrate crystals consistent with half of a water molecule
(obsd. 2.23%, calc. 2.45%). Powdering of the sample gave lower
water content in TGA (1.27%) and KF titration (1.42%) due to
partial water loss during grinding.
CONCLUSIONS
■
Nalidixic acid is one of the earliest fluoroquinolone antibiotics,
but there is no reported study of its polymorphs and cocrystals.
A structural landscape20 of nalidixic acid is shown as two new
polymorphs and six cocrystals. The drug being an acceptor rich
molecule is able to form cocrystals with hydrogen bond donor-
rich molecules. This suggests a larger exploration for NA
cocrystals with GRAS molecules. One of the earliest solubility
improvement examples using additives is that of digoxin−
hydroquinone.21 Physicochemical studies on NA cocrystals for
solubility enhancement are ongoing. The success with phenolic
coformers opens the possibility for antioxidant naturally
occurring acids partner molecules.
Two new multicomponent products were obtained by
grinding whose single crystals could not be grown, but
remaining solid-state characterization suggested that they are
cocrystals. Liquid-assisted grinding of nalidixic acid and orcinol
gave a PXRD pattern (Figure 7) different from that of the
starting components and orcionol hydrate, a possible byproduct
in grinding. IR spectral differences (Figure S3, Supporting
Information) and a sharp DSC endotherm indicate cocrystal
formation. The lower melting point of the product (see DSC in
Figure 8) compared to either of the starting materials could also
mean an eutectic phase,19 but the differences in PXRD line
pattern favor a cocrystal phase. Grinding of NA and
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Figure 4. FT-IR spectra of nalidixic acid polymorphs.
Figure 5. DSC of three polymorphs of nalidixic acid shows that the
melting endotherm for two polymorphs is at the same temperature
(227.9 and 228.1 °C, difference in Tpeak < 0.2 °C) for forms I and II.
The melting endotherm for form III is 2 °C lower (Tpeak 226.6 °C).
DSC recorded at 5 °C heating rate. Faster heating rate thermogram at
20 °C is shown in Supporting Information (Figure S9).
Table 3. FT-IR Stretching Vibration Modes (νs, cm−1) for
Nalidixic Acid Polymorphs and Cocrystals
O−H
CO aromatic CC enol C−O
NA-FORM I 3419.5 (broad)
1715.8
1711.7
1615.9
1621.4
1443.8
1440.5
NA-FORM
II
3431.6 (broad)
NA-FORM
III
3453.6 (broad)
1719.8
1620.2
1440.9
NA-CAT
NA-RES
3425.2 (broad)
3371.5, 3234.1
1699.8
1705.0
1708.4
1621.4, 1600.7
1616.3
1448.5
1445.8
1448.7
NA-PYR-
H2O
3651.1, 3530.8,
3220.1
1622.6
NA-HYQ
3276.7
1700.9
1709.0
1620.7
1616.7
1445.3
1444.3
Figure 3. Overlay of PXRD line pattern (black) and calculated lines
from the X-ray crystal structure (red) for nalidixic acid (a) form I, (b)
form II, and (c) form III (experimental pattern only).
NA-PHG-
H2O
3469.0, 3425.0,
3222.6
NA-ORC
CAT
3475.3, 3378.7
3450.6, 3323.5
3259.3
1712.3
1616.2
1444.5
1470.1
1490.1
1482.1
1477.4
1417.0
1475.5
1619.8, 1601.8
1608
EXPERIMENTAL SECTION
■
RES
Nalidixic Acid, NA. Crystallizations from methanol, acetone, and
nitromethane solvents yieled exclusively block shaped crystals, whereas
in dichloromethane gave parallelogram shaped thin crystals. This is
NA form I. M.p. 227−229 °C.
PYR
3527.4, 3357.7
3267.4
1621.9
HYQ
PHG
ORC
1618.3, 1597.3
1619.8
3475.3
3320.1
1629.8, 1600.6
Nalidixic Acid Form II. Thirty milligrams (0.13 mmol) of nalidixic
acid form I was dissolved in 8 mL of CH3OH−CH3NO2 mixture (3:1
ratio) by heating and the solution was kept for slow evaporation at
room temperature. Single crystals of two different typesblocks and
plateswere obtained. These two types were analyzed by X-ray
diffraction, DSC, and IR. The blocks were identified as a reported form
of nalidixic acid (form I), and crystals of plate morphology were
detected as a new polymorph (form II, see Figure S8, Supporting
Information) by its unit cell parameters and molecular packing.
100 mg (0.4 mmol) of nalidixic acid was added to 10 mL of CH2Cl2
followed by sonication and heating. After cooling to room temper-
ature, 40 mL of n-hexane was added as antisolvent and the solid
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Figure 6. Crystal structure of (a) nalidixic acid (NA)−resorcinol (1:1), (b) NA−catechol (1:1), (c) NA−hydroquinone (1:0.5) cocrystals, and (d)
NA−pyrogallol hemihydrate (1:1:0.5).
residue that crystallized was filtered, dried, and analyzed by IR, DSC,
and PXRD.
Nalidixic Acid−Hydroquinone Cocrystal, NA−HYQ (1:0.5).
Nalidixic acid (117 mg, 0.5 mmol), hydroquinone (28 mg, 0.25
mmol), and EtOH (1 drop) were taken in a ball mill and the mixture
was ground for 1 h. The product was characterized by IR, DSC, and
PXRD.
The above ground material was kept for crystallization in
chlorobenzene (5 mL) at room temperature. Single crystals obtained
after two days were characterized by X-ray diffraction. M.p. 140−144
°C.
Nalidixic Acid−Resorcinol Cocrystal, NA−RES (1:1). Nalidixic
acid (117 mg, 0.5 mmol), resorcinol (56 mg, 0.5 mmol), and EtOH (1
drop) were taken in a ball mill and the mixture was ground for 1 h.
The product was characterized by IR, DSC, and PXRD.
The above ground material was kept for crystallization in
chloroform (5 mL) at room temperature. Single crystals obtained
after one day were characterized by X-ray diffraction. M.p. 116−119
°C.
Nalidixic Acid Form III. 100 mg of nalidixic acid was dissolved in a
10 mL mixture of acetone−DMF (1:1) by sonication and heating.
After cooling to RT, 40 mL of water was added as antisolvent. The
precipitated solid was filtered, dried, and analyzed by IR, DSC, and
XRPD.
200 mg of nalidixic acid was dissolved in 2−3 mL of
methanesulfonic acid (in an attempt to obtain a salt of NA) by slight
heating. After cooling the solution to RT, 10 mL of water was added as
antisolvent, and the resulting precipitate was filtered, dried, and
analyzed by IR, DSC, and PXRD. The distinct powder diffraction lines
1
indicated a new polymorph (form III). H NMR confirmed that the
compound is pure nalidixic acid and there is no methanesulfonic acid
present (i.e., salt form was excluded). The same form III was obtained
from strong mineral acids, such as conc. HCl or H2SO4 in aqueous
medium. Growing single crystals of form III is currently in progress.
Nalidixic Acid−Catechol Cocrystal, NA−CAT (1:1). Nalidixic
acid (117 mg, 0.5 mmol), catechol (56 mg, 0.5 mmol), and EtOH
(one drop) as solvent were taken in a ball mill and the mixture was
ground for 1 h. The resulting crystalline product was analyzed by IR,
DSC, and PXRD.
The ground material above was kept for crystallization in
chloroform (5 mL) at room temperature. Single crystals were obtained
after one day which were characterized by X-ray diffraction. M.p. 124−
125 °C.
Nalidixic Acid−Orcinol Cocrystal, NA−ORC (1:1). Nalidixic
acid (117 mg, 0.5 mmol) and orcinol (63 mg, 0.5 mmol) were taken in
a RB flask and kept overnight in slurry of 1 mL of EtOH. The solid
residue was analyzed by DSC, IR, and PXRD and the composition was
1
ascertained by H NMR. M.p. 57−61 °C.
Nalidixic Acid−Phloroglucinol Cocrystal Hydrate, NA−PHG
(1:1:1.2−1.4). Nalidixic acid (117 mg, 0.5 mmol) and phloroglucinol
(64 mg, 0.5 mmol) were ground in a mortar pestle for 30 min in the
presence of EtOH (few drops). The crystalline material was analyzed
1
by DSC, IR, and PXRD and the composition was ascertained by H
Nalidixic Acid−Pyrogallol Cocrystal Hydrate, NA−PYR−H2O
(1:1:0.5). Nalidixic acid (117 mg, 0.5 mmol), pyrogallol (64 mg, 0.5
mmol), and EtOH (one drop) were taken in a ball mill and the
mixture was was ground for 1 h. The product was assayed by IR, DSC,
TGA, and PXRD.
The above crystalline material was dissolved in chloroform (5 mL)
at room temperature and left for crystallization. Single crystals
obtained after one day were characterized by X-ray diffraction. M.p.
131−134 °C, dehydration at 81−86 °C.
NMR. M.p. 141−144 °C. Dehydration temperature 70−75 °C.
Powder X-ray Diffraction. Bulk samples were analyzed by
powder X-ray diffraction on a Bruker D8 Advance diffractometer
(Bruker-AXS, Karlsruhe, Germany). Experimental conditions: Cu−Kα
radiation (λ = 1.54056 Å); 40 kV; 30 mA; scanning interval 5−50° 2θ
at a scan rate of 1° min−1; time per step 0.5 s. The experimental PXRD
patterns and calculated X-ray lines from the single crystal structure
were compared to confirm the purity of the bulk phase using Powder
Cell.22
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Figure 7. Overlay of the experimental powder X-ray diffraction pattern (black trace) on the PXRD lines caluclated form the crystal structure (red
trace). (a) Nalidixic acid (NA)−resorcinol, (b) NA−catechol, (c) NA−hydroquinone, and (d) NA−pyrogallol hemihydrate. PXRD comparison of
(e) NA−PHG and (f) NA−ORC indicates new solid phases. The minor peaks at 2θ 11.7 and 24.2° in (c) are due to unreacted nalidixic acid and at
7.0° in (d) from unreacted pyrogallol.
X-ray Crystallography. A single crystal obtained from the
crystallization solvent(s) was mounted on the goniometer of Oxford
Gemini (Oxford Diffraction, Yarnton, Oxford, UK) or Bruker Smart
(Bruker-AXS, Karlsruhe, Germany) X-ray diffractometer equipped
with Mo−Kα radiation (λ = 0.71073 Å) source and reflections were
collected at 298(2) K. Data reduction was performed using
CrysAlisPro 171.33.55 software.23 Crystal structures were solved and
refined using Olex2−1.024 with anisotropic displacement parameters
for non-H atoms. Hydrogen atoms were experimentally located
through the Fourier difference electron density maps in all crystal
structures. All O−H and C−H atoms were geometrically fixed using
HFIX command in SHELX-TL program of Bruker-AXS.25 A check of
the final cif file with PLATON26 did not show any missed symmetry.
Crystallographic parameters are summarized in Table 1. Hydrogen
bond distances in Table 2 are neutron-normalized to fix the D−H
distance to its accurate neutron value in the X-ray crystal structures
(O−H 0.983 Å, C−H 1.083 Å). Crystallographic .cif files (CCDC
Nos. 896858−896862) are available at www.ccdc.cam.ac.uk/data_
request/cif or as part of the Supporting Information.
Thermal Analysis. DSC and TGA were performed on a Mettler
Toledo DSC 822e module and a Mettler Toledo TGA/SDTA
851emodule, respectively. Samples were placed in open alumina pans
for TGA and in crimped but vented aluminum sample pans for DSC.
A typical sample size is 4−6 mg for DSC and 9−12 mg for TGA. The
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Article
IR Spectroscopy. A Thermo-Nicolet 6700 FT-IR spectrometer
(Waltham, MA, USA) was used to record IR and Raman spectra. IR
spectra were recorded on samples dispersed in KBr pellets.
Table 4. Melting Temperature (Tpeak) of Nalidixic Acid
Polymorphs and Cocrystals Compared with Coformers
a
mp of NA/
coformer (°C)
mp of cocrystal/hydrate/polymorph
(°C) (DSC, Tpeak)
ASSOCIATED CONTENT
■
NA-FORM I
NA-FORM II
NA-FORM III
NA-CAT
227−229
227.9
228.1
226.6
124.6
117.6
S
* Supporting Information
Additional PXRD, DSC, IR, NMR plots, and crystallographic
.cif files are available free of charge via the Internet at http://
pubs.acs.org/.
103−106
110−113
131−134
170−172
218−220
59−61
NA-RES
b
NA-PYR-H2O
NA-HYQ
106.5 , 132.2
AUTHOR INFORMATION
143.1
■
b
NA-PHG-H2O
NA-ORC
84.5 , 141.0
Corresponding Author
61.0
*E-mail: ashwini.nangia@gmail.com (A.N.), sharmistha.pal@
astrazeneca.com (S.P.).
a
Melting point of phenolic coformers are taken from the literature.
Dehydration endotherm.
b
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.N. thanks DST (JC Bose fellowship SR/S2/JCB-06/2009)
and CSIR (Project 01/2410)/10/EMR-II) for research funding.
DST (IRPHA) and UGC (PURSE grant) are thanked for
providing instrumentation and infrastructure facilities at UoH.
We thank Ch. Suryanarayan (PhD student, UoH) for
interpretation on DSCs of polymorphs. P.S. thanks the UGC
for a fellowship. Crystalin Research thanks AstraZeneca for
funding the research project at TBI-UoH.
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