Phenazopyridine cocrystal and salts that exhibit enhanced solubility and stability

Article abstract of DOI:10.1021/cg300327x

One phenazopyridine monohydrate (1?H₂O), one cocrystal of phenazopyridine with phthalimide (2), and three salts of phenazopyridine with benzoic acid (3), 4-hydroxyphenylacetic acid (4), and scaaharin (5) were synthesized, and their structures w

Full text of DOI:10.1021/cg300327x

Article
pubs.acs.org/crystal
Phenazopyridine Cocrystal and Salts That Exhibit Enhanced
Solubility and Stability
Qian Tao,† Jia-Mei Chen,*,† Lei Ma,‡ and Tong-Bu Lu*,†,§
†School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
‡Center for Drug Evaluation, State Food and Drug Administration, Beijing 100038, China
§MOE Key Laboratory of Bioinorganic and Synthetic Chemistry/State Key Laboratory of Optoelectronic Materials and
Technologies/School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
S
* Supporting Information
ABSTRACT: One phenazopyridine monohydrate (1·H2O), one cocrystal of phenazopyridine with phthalimide (2), and three
salts of phenazopyridine with benzoic acid (3), 4-hydroxyphenylacetic acid (4), and scaaharin (5) were synthesized, and their
structures were determined by single crystal X-ray diffraction. The results of dissolution experiments indicate that the solubility of
phenazopyridine can be enhanced after the formations of cocrystal and salts, in which the apparent solubility value of 5
is approximately 9 times as large as that of phenazopyridine in water, and the apparent solubility value of 4 is approximately
10 times as large as that of phenazopyridine hydrochloride (1·HCl) in 0.1 M HCl aqueous solution. The results of the stability
study demonstrate that 2−5 are less hygroscopic than 1·H2O and 1·HCl at both 85% and 98% RH.
demonstrated that the cocrystallization of an API with coformers
can improve its physical properties such as hygroscopicity,
solubility, dissolution rate, and bioavailability, and can be used
especially for improving unfavorable physical properties of
nonionic APIs.23,24
INTRODUCTION
■
The active pharmaceutical ingredients (APIs) are preferred to
be administered as solid oral dosage forms such as tablets and
capsules because of their convenience, cost-effectiveness, and
high patient compliance.1−3 However, the usage of some drug
candidates with highly desirable pharmacological properties
might be limited by their unfavorable physical properties,
such as low solubility and severe hygroscopicity.4 For an API
which falls into Biopharmaceutical Classification Systems
(BCS) class II (low solubility and high permeability),5,6 enhanc-
ing the solubility is significant for improving its poor absorption.
Pharmaceutical scientists have exploited different approaches such
as micronization, solubilization in micellar solution, and forma-
tions of salts and solvates7−9 to improve the poor solubility and
stability of a given API. Some of these approaches can effectively
improve the solubility as well as the stability and crystallinity of
the APIs.10,11
Phenazopyridine (2,6-diamino-3-(phenylazo) pyridine, 1; see
Scheme 1) is a local anesthetic and analgesic drug which has
Scheme 1. Structure of Phenazopyridine (1)
been used for treatment of urinary tract disorders in con-
junction with an antibacterial agent.25 Phenazopyridine belongs
Recently, cocrystals have been identified by pharmaceutical
scientists as viable solid forms for improving the physicochem-
ical properties of the APIs.12−17 A pharmaceutical cocrystal is a
molecular complex that contains an API and one or more
coformers in the same crystal lattice.18−22 It has been
Received: March 8, 2012
Revised: April 24, 2012
Published: May 7, 2012
© 2012 American Chemical Society
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Table 1. Crystallographic Data and Detail of Refinements for 1−5
1·H2O
2
3
4
5
formula
formula weight
crystal system
space group
T/K
C11H13N5O
231.26
orthorhombic
Pca21
C19H16N6O2
360.38
monoclinic
P21/c
C18H19N5O3
353.38
monoclinic
P21/c
C19H19N5O3
365.39
monoclinic
C2/c
C18H18N6O3S
398.45
triclinic
P1
̅
293(2)
11.5256(5)
18.2862(6)
5.5638(2)
90
293(2)
15.3617(4)
7.1053(2)
16.8264(5)
90
293(2)
6.1302(4)
24.1397(12)
11.8866(6)
90
293(2)
13.2789(2)
10.3034(2)
26.0066(4)
90
293(2)
7.4108(5)
7.8292(5)
17.7574(9)
84.729(5)
85.353(5)
63.728(7)
2
a/Å
b/Å
c/Å
α/deg
β/deg
90
104.220(3)
90
103.251(5)
90
97.728(2)
90
γ/deg
90
Z
V/Å3
4
4
4
8
1172.62(8)
1.31
1780.32(9)
1.345
1712.16(16)
1.419
3525.85(10)
1.377
919.02(10)
1.440
Dc/g cm−3
μ/mm−1
refln collected
unique reflns
observed reflns
0.739
0.756
0.796
0.794
1.861
4438
7490
7020
7102
6166
2044
3380
3286
3319
3344
1702
2707
2095
2567
2716
a
R1 [I > 2σ(I)]
0.0442
0.1163
0.0541
0.1743
0.0783
0.2636
1.092
0.0433
0.1247
1.041
0.0487
a
wR2 [all data]
0.1438
GOF
1.018
1.072
1.059
a
2
2
2
R1 = Σ||Fo| − | Fc||/Σ|Fo|. wR2 = [Σ[w(Fo − Fc2)2]/Σw(Fo )2]1/2, w = 1/[σ2(Fo)2 + (aP)2 + bP ], where P = [(Fo ) + 2Fc2]/3.
to BCS class II drug, with a poor aqueous solubility value of 0.02
mg/mL and a high LogP value of 2.31.26,27 To get a higher
solubility, phenazopyridine was commercially available as hydro-
chloride salt (1·HCl) tablets (Pyridium),28,29 with an aqueous
solubility value of 8.5 mg/mL for 1·HCl.26 However, the results of
relative bioavailability study show that the maximum plasma level
is only 60−70 ng/mL with the highest prescribed dose of 200 mg
of 1·HCl,30−32 indicating phenazopyridine is still poorly absorbed.
Furthermore, it has been reported that pharmaceutical salts,
especially hydrochlorides, are often inherently more hygroscopic
than their corresponding free base,33 and we found that 1·HCl
indeed absorbs moisture and displays hygroscopicity.
The poor solubility of 1 and hygroscopicity of 1·HCl might
limit the treatment effect of phenazopyridine. In addition,
although 1 and 1·HCl have been applied in clinical treatment
for a long time, their polymorphic forms and crystal structures
have not been reported so far. To improve the solubility and
stability of phenazopyridine, a series of coformers were used to
cocrystallize with phenazopyridine, and one cocrystal and three
salts of 1 were obtained. In addition, a hydrate form of phena-
zopyridine, 1·H2O, was unexpectedly isolated. Their crystal
structures, powder dissolutions, and hygroscopicity were inves-
tigated in this study.
Table 2. Hydrogen Bonding Distances and Angles for 1−5
H···A
(Å)
D−H···A
compound
H bond
D···A (Å)
(deg)
a
1·H2O
O1W−H1B···O1W#1
O1W−H1A···N4
N3−H3A···N1
N6−H1···N4
N5−H5···O2#1
N3−H2···O2
2.02
1.95
1.94
1.87
2.04
2.23
2.18
2.02
1.92
1.84
2.01
2.24
1.98
1.87
2.03
1.89
2.63
2.11
1.85
2.00
1.95
2.04
2.18
1.96
2.03
1.85
2.07
2.803(6)
2.820(3)
2.653(3)
2.842(2)
2.993(2)
3.155(2)
3.079(2)
2.686(2)
2.748(5)
2.713(4)
2.862(4)
3.075(4)
2.801(4)
2.710(4)
2.638(4)
2.775(17)
3.310(19)
2.956(19)
2.583(19)
2.859(19)
2.783(17)
2.646(19)
3.029(3)
2.813(2)
2.897(3)
2.777(3)
2.663(3)
145
177
133
178
172
174
175
130
175
162
174
165
160
178
127
173
137
169
147
179
163
127
170
171
169
173
171
b
2
N5−H4···O1
N3−H3···N1
c
3
O3−H6B···O2#1
O3−H5A···O1
N5−H4BA···O3#2
N5−H4AA···O3
N3−H3AA···O2
N4−H3···O1
N3−H3BA···N1
N4−H4N···O2
N3−H3B···O2
N5−H5A···O3#2
O3#1−H3A#1···O2
N5−H5B···O1#3
N3−H3B···O1
N3−H3C···N1
N5−H5AA···O2
N5−H5BA···O3#1
N3−H3AA···O3
N4−H4NA···N6
N3−H3BA···N1
d
4
EXPERIMENTAL SECTION
e
■
5
Materials and General Methods. 1·HCl was purchased from
Wuhan Yuancheng Chemical Co. Ltd. 1 was obtained by neutralizing
an aqueous solution of 1·HCl with a NaOH solution, and the resulting
precipitate of 1 was filtered, washed with water, and dried under a
vacuum. All the coformers were purchased from Aladdin reagent Inc.
All of the other chemicals and solvents were commercially available
and used as received. Elemental analyses were determined using an
Elementar Vario EL elemental analyzer. The infrared spectra were
recorded in the 4000−400 cm−1 region using KBr pellets and a Bruker
EQUINOX 55 spectrometer. Differential scanning calorimetry (DSC)
was recorded on a Netzsch STA 409 PC instrument and aluminum
sample pans in nitrogen atmosphere, with a heating rate of 10 °C/min.
a
Symmetry codes: #1 −x + 0.5, y, z − 0.5; #2 −x + 0.5, y, z + 0.5; #3
b
c
−x + 1, −y + 2, z − 0.5. #1 x, −y + 0.5, z + 0.5. #1 x − 1, y, z; #2 −x
d
+ 1, −y + 1, −z + 2. #1 −x + 1.5, y + 0.5, −z + 1.5; #2 −x + 1.5, y −
e
0.5, −z + 1.5; #3 z − 0.5, y − 0.5, z. #1 x + 1, y − 1, z.
X-ray powder diffraction (XRPD) patterns were obtained on a Bruker
D8 Advance with Cu Kα radiation (40 kV, 40 mA).
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Phenazopyridine Monohydrate (1·H2O). A mixture of 1 (426
mg, 2 mmol) and glycine (151 mg, 2 mmol) was dissolved in 40 mL of
water and ethanol (1:1). The resulting solution was stirred at room
temperature for one day, and then evaporated slowly at room
temperature. After about one week, yellow needle-shaped crystals of
1·H2O were isolated from the solution, which were filtered, washed with
water, and dried in air. Yield: 380 mg, 89%. Anal. Calcd for C11H13N5O
(1·H2O): C, 57.13; N, 30.28; H, 5.67%. Found: C, 57.08; N, 30.44;
H, 5.41%. IR data (KBr, cm−1): 3448, 3376, 3327, 3163, 1581, 1496,
760, 711.
Scheme 2. Possible Hydrogen Bonding Synthons of 1 with
Co-Formers
Phenazopyridine Phthalimide Cocrystal (2). A mixture of
1 (426 mg, 2 mmol) and phthalimide (294 mg, 2 mmol) was dissolved
in 40 mL of ethanol and stirred at 60 °C for one day. Single crystals of
2 were obtained by slowly evaporating the filtrated solution at room
temperature. Yield: 580 mg, 80%. Anal. Calcd for C19H16N6O2: C,
63.32; N, 23.32; H, 4.48%. Found: C, 63.38; N, 22.84; H, 4.71%. IR
data (KBr, cm−1): 3408, 3378, 3235, 2984, 1714, 1659, 1598, 1546,
1458, 739, 713.
Phenazopyridine Benzoate Monohydrate (3). A mixture of
1 (426 mg, 2 mmol) and benzoic acid (244 mg, 2 mmol) was
dissolved in 40 mL of ethanol and stirred at room temperature for one
day. Single crystals of 3 were obtained by slowly evaporating the
filtrated solution at room temperature. Yield: 620 mg, 92%. Anal.
Calcd for C18H19N5O3: C, 61.18; N, 19.82; H, 5.42%. Found: C,
61.05; N, 19.87; H, 5.66%. IR data (KBr, cm−1): 3350, 3160, 3062,
1690, 1649, 1578, 770, 729, 713.
was dissolved in 40 mL of ethanol. The resulting solution was stirred at
room temperature for one day, and then evaporated slowly to get the
crystals of 4. Yield: 620 mg, 85%. Anal. Calcd for C19H19N5O3: C,
62.53; N, 19.09; H, 5.28%. Found: C, 62.63; N, 19.22; H, 4.98%. IR
data (KBr, cm−1): 3378, 3277, 2932, 1669, 1595, 1574, 1511, 750, 687.
Phenazopyridine Saccharinate (5). Saccharin (183 mg, 1 mmol)
and 1 (213 mg, 1 mmol) were ground with two drops of ethanol for
30 min. The resulting mixture was dissolved in 20 mL of ethanol and
evaporated slowly at room temperature to get the crystals of 5. Yield:
376 mg, 95%. Anal. Calcd for C18H18N6O3S: C, 54.26; N, 21.09; H,
4.55%. Found: C, 54.26; N, 21.00; H, 4.41%. IR data (KBr, cm−1):
3363, 3328, 3107, 2808, 2744, 2576, 1682, 1610, 1578, 773, 750, 680.
Single Crystal X-ray Diffraction. The single crystal data for
1·H2O and 2−5 were collected on an Agilent Xcalubur Nova CCD
diffractometer with Cu−Kα radiation (λ = 1.54178 Å). Cell refine-
ment and data reduction were applied using the program of CrysAlis
PRO. The structures were solved by the direct method using the
Phenazopyridine 4-Hydroxyphenylacetate (4). A mixture of 1
(426 mg, 2 mmol) and 4-hydroxyphenylacetic acid (304 mg, 2 mmol)
Figure 1. (a) The molecular structure of 1·H2O; (b) 1D hydrogen bonding linked chain; (c) the 3D structure of 1·H2O.
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Figure 2. (a) Side view of 1D hydrogen bonding linked chain of 2; (b) top view of 1D scissor-like chain along the c-axis; (c) the 3D structure of 2.
SHELXS-97 programs34 and refined by the full-matrix least-squares
method on F2. All non-hydrogen atoms were refined with anisotropic
displacement parameters. The hydrogen atoms of protonated pyridine
N4 of phenazopyridine in 3−5 and the water molecules in 1·H2O and
3 were located in the difference Fourier maps and refined isotropically.
All the other hydrogen atoms were placed in calculated positions with
fixed isotropic thermal parameters and included in the structure factor
calculations in the final stage of full-matrix least-squares refinement.
Crystallographic data and details of refinements of 1−5 are listed
in Table 1, and the hydrogen bonding distances and angles are given
in Table 2.
Powder Dissolution Studies. Concentrations of 1·H2O, 2−5,
and 1·HCl in water and 0.1 M HCl aqueous solution (pH = 1) were
determined by a Cary 50 UV spectrophotometry at 427 nm; the
absorbance values were correlated to solution concentrations using a
calibration curve. All the solids were milled to powders and sieved
using standard mesh sieves to provide samples with the particle size
ranges of 65−150 μm. In a typical experiment, a flask containing 300−
700 mg of powder was added 100 mL of water or 0.1 M HCl aqueous
solution, and the resulting suspension was stirred at 25 °C and 500
rpm. At each time interval (see Figure 7), the solution was withdrawn
from the flask and filtered through a 0.22 μm nylon filter. A 1.0 mL
portion of filtered aliquot was diluted to 10.0 mL with water or 0.1 M
HCl aqueous solution and measured with UV/vis spectrophotometry.
Hygroscopicity Studies. Relative humidity conditions were
achieved at 25 °C within a sealed glass desiccator containing a
saturated K2SO4 aqueous solution for 98% RH value and a saturated
KCl aqueous solution for 85% RH value. Samples of 1·HCl, 1·H2O,
and 2−5 were evaluated for hygroscopicity at 85% and 98% RH for
time periods of 1, 3, 5, 7, 14, 21, and 28 days. Open glass vials
containing 50 mg of powder sample in each vial were stored in the RH
chamber. Each vial was weighed at each time interval. The following
equation was used to obtain hygroscopicity data for all the samples.
hygroscopicity = (Wn − Ws)/(Ws − Wo) × 100%
where Wn is the weight of sample and vial at each time interval, Ws is
the weight of sample and vial at the beginning; Wo is the weight of
empty vial.
RESULTS AND DISCUSSION
■
The structure of 1 contains two amino groups as hydrogen
bond donors and one pyridine nitrogen as hydrogen bond
acceptor, and it is potential to form cocrystals through amide-
pyridine (I), acid-pyridine (II), and imine-pyridine (III)
synthons (see Scheme 2), in which acid-pyridine synthon is
the most popular and frequently occurring hydrogen bonding
motif in the Cambridge Structural Database.35 It is generally
accepted that the reaction of an acid with a base will be
expected to form a salt if ΔpKa (ΔpKa = pKa (base) − pKa
(acid)) is greater than 3, while either a cocrystal or a salt will
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Figure 4. (a) The 1D chain, (b) the 2D double layer with crossover
packing mode, and (c) the 3D structure of 4.
intermolecular hydrogen bonds to form a one-dimensional
(1D) (H2O)n chain (Figure 1b), with the O1W···O1W#1 dis-
tance of 2.803(6) Å. The phenazopyridine molecules are
arranged along the chain and linked to the chain through
O1W−H1A···N4 intermolecular hydrogen bonds (Figure 1b).
All the 1D chains are packed along the c axis to form the three-
dimensional (3D) structure of 1·H2O (Figure 1c).
In 2, one phthalimide molecule links one phenazopyridine
molecule through the synthon III to form a dimer (Figure 2a),
with the O1···N5, N6···N4, and O2···N3 distances of 3.079(2),
2.842(2), and 3.155(2) Å, respectively. The dimers are further
linked together through N5−H5···O2#1 intermolecular hydro-
gen bonds to form a 1D scissor-like chain (Figure 2a,b), with a
N5···O2#1 distance of 2.993(2) Å. All the 1D scissor-like
chains are packed along the c axis to form the 3D structure of
2 (Figure 2c). There are π···π interactions between the
phthalimide molecule in one chain and the phenazopyridine
Figure 3. (a) The molecular structure of 3. (b) The tetramer structure,
and (c) the 1D hydrogen bonding linked band of 3. (d) The 3D
structure of 3.
form when ΔpKa is between 0 and 3.36 As phenazopyridine is a
weak base (pKa = 5.10), it is possible to obtain the proton from
carboxylic acid to result in an organic salt instead of a cocrystal.
Indeed, the reactions of 1 with phthalimide (pKa = 8.30),
benzoic acid (pKa = 4.19), 4-hydroxyphenylacetic acid (pKa =
4.50), and saccharin (pKa = 1.31) gave one cocrystal of 2 and
three salts of 3−5. While the reaction of 1 with glycine
unexpectedly gave a hydrate of phenazopyridine, 1·H2O.
The asymmetric unit of 1·H2O contains one phenazopyr-
idine and one water molecules (Figure 1a). The water mole-
cules in 1·H2O are linked through O1W−H1B···O1W#1
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Figure 5. (a) The 1D chain, and (b) the 3D structure of 5.
molecule in the adjacent chain, with the centroid···centroid
distance of 3.531 Å.
The asymmetric unit of 3 contains one phenazopyridine cation,
one benzoate anion, and one water molecule (Figure 3a), in which
a proton is transferred from benzoic acid to the pyridine N4 atom
of phenazopyridine. In 3, the phenazopyridine cation and benzoate
anion form a dimer through the synthon II (Figure 3a), with the
O1···N4 and O2···N3 distances of 2.710(4) and 2.801(4) Å,
respectively. Two dimers are linked by two water molecules
through two O3−H5A···O1, two N5−H4AA···O3, and two N5−
H4BA···O3#2 hydrogen bonds to form a tetramer (Figure 3b),
with the O3···O1, N5···O3, and N5···O3#2 distances of 2.713(4),
3.075(4), and 2.862(4) Å, respectively. The tetramers are further
linked together through O3−H6B···O2#1 hydrogen bonds and
π···π interactions between the adjacent tetramers to generate a
1D band (Figure 3c), with the O3···O2#1 and centroid···centroid
distances of 2.748(5) and 3.611 Å, respectively. All the 1D
bands are packed along the a axis to form the 3D structure of 3
(Figure 3d).
The asymmetric unit of 4 is comprised of a phenazopyridine
cation and a 4-hydroxyphenylacetate anion, in which a proton is
transferred from the carboxylic acid group of 4-hydroxyphenyl-
acetic acid to the pyridine N4 atom of phenazopyridine. Similar
to 3, the phenazopyridine cation and 4-hydroxyphenylacetate
anion in 4 also form a dimer through the synthon II (Figure 4a),
with the O2···N4 and O1···N3 distances of 2.775(17) and
2.783(17) Å, respectively. The dimers are further connected by
interdimer N5−H5B···O1#3 hydrogen bond to generate a 1D
chain (Figure 4a), with the O1#3···N5 distance of 2.859(19) Å.
The 1D chains are connected by N5−H5A···O3#2 and O3#1−
H3A#1···O2 hydrogen bonds with a crossover mode to form a
Figure 6. The measured XRPD patterns (1·H2O and 2−5) and
simulated patterns generated from the single-crystal diffraction data
(1′·H2O and 2′−5′).
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Figure 8. Hygroscopicity of 1·HCl, 1·H2O, and 2−5 at 25 °C, and (a)
85% RH, (b) 98% RH.
Figure 7. Powder dissolution profiles in water (top) and 0.1 M HCl
aqueous solution (bottom).
between the melting points of 1 (139 °C) and corresponding
coformers, which are 236, 122, 211, and 229 °C for phthalimide,
benzoic acid, 4-hydroxyphenylacetic acid, and saccharin, respec-
tively. In addition, the results of DSC measurements reveal that
1·H2O and 3 lost their water molecules below 73 and 115 °C,
respectively.
Powder Dissolution Studies. As shown in Figure 7,
the solubility values of 1 and 1·H2O in water are 0.022 and
0.020 mg/mL, respectively, whereas 2−5 dissolve more quickly
than 1 and 1·H2O, indicating the dissolution rate of phenazo-
pyridine can be increased by the formation of cocrystal and
salts. Indeed, the apparent solubility values of 4 (0.152 mg/mL)
and 5 (0.201 mg/mL) are approximately 7 and 9 times as large
as that of 1. After the dissolution experiments, the undissolved
solids were filtered and dried in air, and the results of XRPD
measurements demonstrate that the XRPD patterns of 2−5 did
not change, suggesting 2−5 are stable in water at least for 3 h.
Under the same conditions, the measured apparent solubility
value for 1·HCl is 6.5 mg/mL.
The powder dissolution experiments were also performed
in 0.1 M HCl aqueous solution (Figure 7). Interestingly, the
apparent solubility value of 1·HCl in 0.1 M HCl aqueous
solution (0.6 mg/mL) is much lower than that in water
(6.5 mg/mL), suggesting the poor solubility of 1·HCl in 0.1 M
HCl aqueous solution (gastric juice) might be the reason for
low absorption after the oral administration of the 1·HCl tablet.
Whereas 1−5 display higher solubility values in 0.1 M HCl
2D double layer (Figure 4b), with the N5···O3#2 and O3#1···O2
distances of 2.956(19) and 2.583(19) Å, respectively. The 2D
double layers are further packed through π···π interactions to
generate the 3D structure of 4, and the centroid···centroid distance
between two adjacent phenyl rings of phenazopyridine is 3.319 Å.
In 5, saccharin reacted with phenazopyridine to generate a salt,
in which saccharate anion and phenazopyridine cation form a
dimer through the synthon I (Figure 5a), with the N3···O3,
N4···N6, and N5···O2 distances of 2.897(3), 2.777(3), and
3.029(3) Å, respectively. The dimers are further connected by the
interdimer N5−H5BA···O3#1 hydrogen bond to generate a 1D
chain (Figure 5a), with the N5···O3#1 distance of 2.813(2) Å.
All the 1D chains are linked through the π···π interactions
between the adjacent phenazopyridine molecules to generate the
3D structure of 5 (Figure 5b), with the centroid···centroid distance
of 3.336 Å.
The X-ray Powder Diffraction and DSC Analyses. The
XRPD was used to detect the phase purity of 1·H2O and 2−5.
The results show that the patterns of the cocrystal and salts are
different from those of 1 and corresponding coformers, and all
the peaks displayed in the measured patterns at room temper-
ature closely match to those in the simulated patterns generated
from single-crystal diffraction data (Figure 6), indicating single
phases of 1·H2O and 2−5 were formed. The results of DSC
measurements show the melting points at 176.4, 128.6, 175.4,
and 209.2 °C for 2−5, respectively, and these values are
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Notes
aqueous solution than those in water, 4 shows the highest
apparent solubility value of 6.0 mg/mL. In addition, the color
of the powder of 1 changed quickly from yellow to dark red in
0.1 M HCl aqueous solution, and the solubility of 1 began to
decrease gradually after 1 h. After the dissolution experiments,
the undissolved solids were filtered, and the results of XRPD
measurements indicate that the XRPD patterns of 1·HCl and
2−5 did not change, while 1 transformed to 1·HCl.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by 973 Program of China
(2012CB821705), NSFC (20831005, 91127002, 21101173
and 21121061), and China Postdoctoral Science Foundation
(Grant No. 20110490919).
Hygroscopicity Studies. The results of hygroscopicity
experiments at 85% and 98% RH reveal that 1·H2O and 1·HCl
display serious hygroscopicity, which absorbed moisture to
almost reach the saturation within a short time (Figure 8).
However, the hygroscopicity of phenazopyridine has been
improved significantly by forming cocrystal 2 and salts 3−5
(Figure 8), indicating the stability of phenazopyridine can be
improved by forming pharmaceutical cocrystal and salts. From
the structures of 1·H2O and 2−5, it can be found that only the
pyridine nitrogen atom of phenazopyridine in 1·H2O forms an
intermolecular hydrogen bond with a water molecule, while
almost all the hydrogen bond donors (two amino groups) and
acceptor (pyridine nitrogen atom) of phenazopyridine in 2−5
form intermolecular hydrogen bonds with the coformer or
organic anions. Therefore, the phenazopyridine in 1·H2O can
still interact with water molecules by forming hydrogen bonds
with two amino groups of phenazopyridine, while the water
molecules are hard to further interact with phenazopyridine in
2−5, as almost all the hydrogen bond sites in phenazopyridine
form hydrogen bonds with coformer or organic anions.
Accordingly, 1·H2O and 1·HCl are much more prone to hygro-
scopic compared with 2−5.
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AUTHOR INFORMATION
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Corresponding Author
*Fax: +86-20-84112921. E-mail: chenjm37@mail.sysu.edu.cn
(J.-M.C.); lutongbu@mail.sysu.edu.cn (T.-B.L.).
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