Phenazopyridine Cocrystal and Salts That Exhibit Enhanced Solubility

May 7, 2012 - Synopsis. One phenazopyridine monohydrate (1·H2O), one cocrystal of phenazopyridine with phthalimide (2), and three salts of phenazopyr...
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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.

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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 enhancing the solubility is significant for improving its poor absorption. Pharmaceutical scientists have exploited different approaches such as micronization, solubilization in micellar solution, and formations 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 Recently, cocrystals have been identified by pharmaceutical scientists as viable solid forms for improving the physicochemical 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 © 2012 American Chemical Society

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 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 conjunction with an antibacterial agent.25 Phenazopyridine belongs Received: March 8, 2012 Revised: April 24, 2012 Published: May 7, 2012 3144

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Table 1. Crystallographic Data and Detail of Refinements for 1−5 formula formula weight crystal system space group T/K a/Å b/Å c/Å α/deg β/deg γ/deg Z V/Å3 Dc/g cm−3 μ/mm−1 refln collected unique reflns observed reflns R1 [I > 2σ(I)]a wR2 [all data]a GOF a

1·H2O

2

3

4

5

C11H13N5O 231.26 orthorhombic Pca21 293(2) 11.5256(5) 18.2862(6) 5.5638(2) 90 90 90 4 1172.62(8) 1.31 0.739 4438 2044 1702 0.0442 0.1163 1.018

C19H16N6O2 360.38 monoclinic P21/c 293(2) 15.3617(4) 7.1053(2) 16.8264(5) 90 104.220(3) 90 4 1780.32(9) 1.345 0.756 7490 3380 2707 0.0541 0.1743 1.072

C18H19N5O3 353.38 monoclinic P21/c 293(2) 6.1302(4) 24.1397(12) 11.8866(6) 90 103.251(5) 90 4 1712.16(16) 1.419 0.796 7020 3286 2095 0.0783 0.2636 1.092

C19H19N5O3 365.39 monoclinic C2/c 293(2) 13.2789(2) 10.3034(2) 26.0066(4) 90 97.728(2) 90 8 3525.85(10) 1.377 0.794 7102 3319 2567 0.0433 0.1247 1.041

C18H18N6O3S 398.45 triclinic P1̅ 293(2) 7.4108(5) 7.8292(5) 17.7574(9) 84.729(5) 85.353(5) 63.728(7) 2 919.02(10) 1.440 1.861 6166 3344 2716 0.0487 0.1438 1.059

R1 = Σ||Fo| − | Fc||/Σ|Fo|. wR2 = [Σ[w(Fo2 − Fc2)2]/Σw(Fo2)2]1/2, w = 1/[σ2(Fo)2 + (aP)2 + bP ], where P = [(Fo2) + 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 hydrochloride 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 phenazopyridine, 1·H2O, was unexpectedly isolated. Their crystal structures, powder dissolutions, and hygroscopicity were investigated in this study.

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Table 2. Hydrogen Bonding Distances and Angles for 1−5 compound

H bond

H···A (Å)

D···A (Å)

D−H···A (deg)

1·H2Oa

O1W−H1B···O1W#1 O1W−H1A···N4 N3−H3A···N1 N6−H1···N4 N5−H5···O2#1 N3−H2···O2 N5−H4···O1 N3−H3···N1 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

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

2b

3c

4d

EXPERIMENTAL SECTION

5e

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.

Symmetry codes: #1 −x + 0.5, y, z − 0.5; #2 −x + 0.5, y, z + 0.5; #3 −x + 1, −y + 2, z − 0.5. b#1 x, −y + 0.5, z + 0.5. c#1 x − 1, y, z; #2 −x + 1, −y + 1, −z + 2. d#1 −x + 1.5, y + 0.5, −z + 1.5; #2 −x + 1.5, y − 0.5, −z + 1.5; #3 z − 0.5, y − 0.5, z. e#1 x + 1, y − 1, z. a

X-ray powder diffraction (XRPD) patterns were obtained on a Bruker D8 Advance with Cu Kα radiation (40 kV, 40 mA). 3145

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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. 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. Phenazopyridine 4-Hydroxyphenylacetate (4). A mixture of 1 (426 mg, 2 mmol) and 4-hydroxyphenylacetic acid (304 mg, 2 mmol)

Scheme 2. Possible Hydrogen Bonding Synthons of 1 with Co-Formers

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 refinement and data reduction were applied using the program of CrysAlis PRO. The structures were solved by the direct method using the

Figure 1. (a) The molecular structure of 1·H2O; (b) 1D hydrogen bonding linked chain; (c) the 3D structure of 1·H2O. 3146

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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.

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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 amidepyridine (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 3147

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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 distance 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 threedimensional (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 hydrogen 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 phenazopyridine and one water molecules (Figure 1a). The water molecules in 1·H2O are linked through O1W−H1B···O1W#1 3148

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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-hydroxyphenylacetic 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′). 3149

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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, respectively. 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 phenazopyridine 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 temperature 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 3150

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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. 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 hygroscopic compared with 2−5.

The authors declare no competing financial interest.

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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).

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CONCLUSIONS One monohydrate, one cocrystal, and three salts of phenazopyridine were isolated, and their structures were determined by single X-ray diffraction. In 1·H2O, only the pyridine nitrogen atom of phenazopyridine forms a hydrogen bond with a water molecule, while almost all the hydrogen bond donors and acceptor of phenazopyridine in 2−5 form hydrogen bonds with coformer or organic anions. The solubility of phenazopyridine increased after the formation of 2−5 in both water and 0.1 M HCl aqueous solution, while the solubility of 1·HCl dramatically decreased in 0.1 M HCl aqueous solution compared to its solubility in water. In addition, the results of hygroscopicity experiments indicate that stability of phenazopyridine can also be improved by forming cocrystal and salts. The present study demonstrates that cocrystals and salts may offer a unique opportunity for developing new solid forms in which a variety of desired physical properties can be obtained through choosing suitable coformers. Since solubility and bioavailability are often related, we believe that 4 may be more bioavailable than 1 and 1·HCl.

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic information files. This material is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*Fax: +86-20-84112921. E-mail: [email protected] (J.-M.C.); [email protected] (T.-B.L.). 3151

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