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Enhancing the Solubility of 6‑Mercaptopurine by Formation of Ionic Cocrystal with Zinc Trifluoromethanesulfonate: Single-Crystal-to-Single-Crystal Transformation Published as part of the Crystal Growth & Design virtual special issue IYCr 2014 - Celebrating the International Year of Crystallography Jia Yao,† Jia-Mei Chen,*,‡ Yi-Bo Xu,† and Tong-Bu Lu*,†,‡ †

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China ‡ School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China S Supporting Information *

ABSTRACT: An antitumor drug, 6-mercaptopurine monohydrate (MP·H2O), has a low oral bioavailability due to its poor aqueous solubility. In order to improve its solubility, two ionic cocrystals of 6-mercaptopurine with zinc trifluoromethanesulfonate (Zn(CF3SO3)2), [Zn(MP)2(H2O)2](CF3SO3)2·2H2O (1) and [Zn(MP)2](CF3SO3)2 (2), were prepared. Slow evaporation of the methanol solution containing 1 gave the crystals of [Zn(MP)2(H2O)(MeOH)](CF3SO3)2·H2O (1a). Single-crystal-to-single-crystal transformation occurred under certain conditions, in which 1a transformed to 1 in the open air around 10 °C, and 1 further transformed to [Zn(MP)2(H2O)](CF3SO3)2 (1b) at room temperature (∼25 °C) and low RH%. The structures of 1, 1a, and 1b were determined by single crystal X-ray diffraction, in which MP and Zn(CF3SO3)2 were assembled via coordination bonds and hydrogen bonds, and the coordination geometry of Zn(II) changed from octahedron in 1 and 1a to square pyramid in 1b. After the formation of ionic cocrystals of 1 and 2, both the apparent solubility and dissolution rate were increased.

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INTRODUCTION

combination of an API with alkali or alkaline earth metal salts. It is well-known that alkali or alkaline earth metal ions prefer to interact with oxygen atoms, and they do not easily form ICCs with an API that does not contain oxygen atoms. 6-Mercaptopurine (MP) is used as a clinically important antimetabolite and antineoplastic drug for the treatment of human leukemia, system lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease.16,17 The commercially available form, 6-mercaptopurine monohydrate (MP·H2O), has low oral bioavailability (about 16%) due to its poor solubility in water.18 Therefore, increasing the solubility of MP and consequently

Recently, cocrystals have been identified as viable solid forms for improving the physicochemical properties of active pharmaceutical ingredients (APIs).1−6 A pharmaceutical cocrystal is defined as a stoichiometric multiple component substance of an API with one or more coformers, in which the API and coformers are connected by noncovalent intermolecular interactions, typically hydrogen bonds.7−10 Very recently, ionic cocrystals (ICCs), formed by an organic molecule and a metal salt instead of two organic molecules, have shown new potentialities.11−15 Besides hydrogen bonds, coordination bonds are also involved in ICCs. It has been proven that the physicochemical properties of an API, such as melting point, dissolution behavior, and pharmacokinetics can be modified by the formation of ICCs. Up to now, all the reported ICCs are a © 2014 American Chemical Society

Received: April 24, 2014 Revised: September 5, 2014 Published: September 18, 2014 5019

dx.doi.org/10.1021/cg5005819 | Cryst. Growth Des. 2014, 14, 5019−5025

Crystal Growth & Design

Article

solvents are commercially available and were used as received. Elemental analyses (EA) were carried out by Elementar Vario EL elemental analyzer. 1H NMR spectra were recorded at room temperature in methanol-d on a Bruker AVANCE III 400 MHz. ESI−MS were recorded on Thermofisher TSQ Quantum Ultra. Thermogravimetric analyses (TG) were recorded on a Netzsch TG209 instrument and alumina crucibles in nitrogen atmosphere, with a heating rate of 10 °C/min. Differential scanning calorimetry (DSC) was recorded on a Netzsch DSC 200 F3 instrument and aluminum sample pans in nitrogen atmosphere, with a heating rate of 3 °C/min. Room temperature X-ray powder diffraction (XRPD) patterns were obtained on a Bruker D2 PHASE with Cu Kα radiation (30 kV, 10 mA). Variable temperature XRPD patterns were obtained on a Bruker D8 Advance with Cu Kα radiation (40 kV, 40 mA). [Zn(MP)2(H2O)2](CF3SO3)2·2H2O (1). A mixture of MP·H2O (680 mg, 4 mmol) and Zn(CF3CO3)2·7H2O (978 mg, 2 mmol) in ethanol (20 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure. The resulting solid of 1 was washed with acetone, and dried under ambient conditions. Yield: 1.30 g, 87.9%. Anal. (%) Calcd for ZnS4F6C12H16N8O10: C, 19.47; H, 2.18; N, 15.14. Found: C, 19.34; H, 2.00; N, 14.89. 1H NMR (CD3OD): 8.60 (H1, s, br), 8.41 (H2, s, br). ESI-MS: m/z 366.8 ([Zn(MP)2]+), 407.9 ([Zn(MP)2(H2O)2]+). [Zn(MP)2(H2O)(MeOH)](CF3SO3)2·H2O (1a) and [Zn(MP)2(H2O)](CF3SO3)2 (1b). The solid of 1 was dissolved in methanol, and the solution was left to evaporate at room temperature in a sealed glass desiccator. After a few days, plate single crystals of 1a were obtained. When the crystals of 1a were left in the open air around 10 °C, single-crystal-to-single-crystal transformation occurred, and the crystals of 1a transformed to 1. When the crystals of 1 were left at room temperature (∼25 °C) and low RH% (less than 20%, see the details of the dynamic vapor sorption (DVS) results), single-crystal-to-singlecrystal transformation also occurred, and the crystals of 1 further transformed to 1b, in which two lattice and one coordinated water molecules in 1 lost. Zn(MP)2(CF3SO3)2 (2). The solid of 1 was heated to 150 °C and held at this temperature for 4 h. After being cooled to room temperature, the anhydrous solid of 2 was obtained. Anal. (%) Calcd for ZnS4F6C12H8N8O6: C, 21.58; H, 1.21; N, 16.78. Found: C, 21.27;

improving its bioavailability is of interest for the development of new dosage forms of MP. It has been reported that the solubility and bioavailability of MP can be improved by the formation of PEG-MP prodrug.18 Though a hydrochloride salt of MP has been reported,27 the research did not refer to its solubility. We have previously reported that the solubility of MP can be improved via cocrystals and salts,22 and now we are interested to see if the solubility of MP can also be enhanced by the formation of ICCs. MP only contains N and S as coordinated atoms, and it is difficult to form ICCs with alkali or alkaline earth metal salts. Thus, zinc salts were chosen to prepare ICCs with MP, as zinc(II) can coordinate to both N and S atoms in MP.28 Moreover, zinc is an essential element which is included in the Generally Recognized as Safe (GRAS) list. Scheme 1. Structure of 6-Mercaptopurine

In this paper, the hydrous and anhydrous forms of ICCs of MP with zinc trifluoromethanesulfonate were obtained. Their structures, interconversion, solubility, and dissolution properties were investigated.

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EXPERIMENTAL SECTION

Materials and General Methods. MP·H2O was purchased from Suizhou Hongqi Chemical Co., Ltd. All of the other chemicals and

Table 1. Crystallographic Data for 1a, 1, and 1b formula formula weight temperature/K crystal system space group a, Å b, Å c, Å α, deg β, deg γ, deg V, Å3 Z Dc/g·cm−3 F(000) crystal size/mm range of indices

Rint GOF R1 [I > 2σ(I)]a wR2a [all data] a

1a

1

1b

ZnS4F6C13H16N8O9 735.95 150(2) monoclinic P21/c 12.2295(3) 18.1053(6) 11.9682(3) 90 97.479(2) 90 2627.44(13) 4 1.860 1480 0.10 × 0.08 × 0.05 −11 ≤ h ≤ 13 −21 ≤ k ≤ 20 −9 ≤ l ≤ 13 0.0311 1.024 0.0583 0.1842



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. 5020



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H, 1.62; N, 16.31. 1H NMR (CD3OD): 8.55 (H1, s, br), 8.28 (H2, s, br). ESI-MS: m/z 366.9 ([Zn(MP)2]+), 407.8 ([Zn(MP)2(H2O)2]+). Single Crystal X-ray Diffraction. Single crystal X-ray diffraction data for 1a, 1, and 1b were collected using an Agilent Technologies Gemini A Ultra system. Data reduction and cell refinement were performed with the CrysAlis PRO program.19 The structures were solved by the direct method using the SHELXS-97 programs20 and refined by the full-matrix least-squares method on F2. All non-hydrogen atoms were refined with anisotropic displacement parameters. The CF3SO3 anions in 1a, 1, and 1b, and lattice water molecules in 1a and 1 are disordered, which were refined with different occupancy ratios. The hydrogen atoms of disordered lattice water molecules in 1a and 1 were not added. All 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 leastsquares refinement. Crystallographic data and details of refinements of 1a, 1 and 1b are listed in Table 1, and the hydrogen bonding distances and angles are given in Table 2.

Table 2. Hydrogen Bonding Distances and Angles for 1a, 1, and 1b D−H···A 1aa N1−H1N···O8#1 N3−H3N···N6#2 O(1)−H(2W)···O(7)#2 O(2)−H(2O)···O(9)#2 N(5)−H(5N)···O(5)#3 N(7)−H(7N)···N(2)#4 O(1)−H(1W)···O(3) 1b N(1)−H(1N)···O(3)#1 N(3)−H(3N)···N(2)#2 O(5)−H(5O)···O(6)#3 O(4)−H(4O)···O(2) 1bc N(3)−H(3)···N(2)#1 O(4)−H(4)···O(1)#2 N(1)−H(1)···O(2)

D···A (Å)

D−H···A (deg)

2.754(8) 2.972(6) 2.728(7) 2.85(3) 2.716(8) 2.976(6) 2.698(7)

163.4 157.8 160.0 167.6 169.1 158.3 163.4

2.756(10) 2.994(4) 2.445(17) 2.779(8)

171.9 158.6 139.4 159.5

2.996(7) 2.622(8) 2.736(10)

157.8 166.3 168.2

a Symmetry codes. #1 x + 1, −y + 3/2, z + 1/2; #2 x + 1, y, z; #3 x, −y + 3/2, z − 1/2; #4 x − 1, y, z. b#1 x, −y + 1, z − 1/2; #2 −x, y, −z + 3/2; #3 x, y + 1, z. c#1 −x, y, −z + 3/2; #2 x, −y + 1, z + 1/2.

Powder Dissolution Experiments. Concentrations of 1, 2, and MP·H2O in water at 25 °C were determined by a Cary 50 UV spectrophotometry, and the absorbance values were related to solution concentrations using a calibration curve. The solids were milled to powders and sieved using standard mesh sieves to provide samples with approximate particle size ranges of 75−150 μm. In a typical experiment, 125 mg of sample was added to a flask containing 50 mL of water, and the resulting mixture was stirred at 25 °C and 500 rpm. At each time interval, an aliquot of the slurry was withdrawn from the flask and filtered through a 0.22 μm nylon filter. And appropriate dilutions were made to maintain absorbance readings within the standard curve. The resulting solution was measured with the UV/vis spectrophotometer. After the dissolution experiment, the remaining solids were collected by filtration, dried, and analyzed by XRPD. Dissolution Rate Studies. The dissolution rate studies of solid materials were carried out on ZQY-2 Dissolution Tester (Shanghai Huanghai Yaojian instrument distribution Co., Ltd.). The solid materials were milled to powders and sieved using standard mesh sieves to provide samples with approximate particle size ranges of 75−150 μm. In each experiment, the sample of 16 mg of MP (corresponding to, for MP·H2O, 1 and 2) was added to 200 mL of deionized water at 37 °C, with the paddle rotating at 50 rpm. At different intervals, 2 mL of the dissolution medium was withdrawn and

Figure 1. Structures of (a) asymmetric unit, (b) 1D chain, (c) 2D layer, and (d) 3D framework in 1a. replaced by an equal volume of fresh medium to maintain a constant volume. After appropriate dilutions, the solution was measured with the UV/vis spectrophotometer. Dynamic Vapor Sorption. A dynamic vapor sorption (DVS) study was performed on a DVS Intrinsic instrument (Surface Measurement Systems, UK). All samples were initially dried for several hours under a stream of nitrogen to establish the equilibrium dry mass at 25 °C. Then the relative humidity (RH) was increased in 10% RH steps to 90% RH. Finally, the RH was decreased in a similar fashion for desorption phase. The temperature was maintained at a constant 25 ± 0.1 °C. The sorption/desorption isotherms were calculated from the equilibrium mass values.

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RESULTS AND DISCUSSION Crystal Structures. The result of X-ray structural analysis reveals that 1a crystallizes in P21/c space group. The asymmetric unit of 1a contains one [Zn(MP)2(H2O)(MeOH)]2+

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Figure 3. (a) Coordination environment of Zn and (b) the structures of 3D framework in 1b.

bonds, with O···O distances of 2.698(7) and 2.728(7) Å, respectively. The [Zn(MP)2(H2O)(MeOH)](CF3SO3)2 units are linked by two N(3)−H(3N)···N(6)#2 and N(2)···H(7N) #2−N(7N)#2 intermolecular hydrogen bonds to form a onedimensional (1D) chain (Figure 1b), with N···N distances of 2.972(6) and 2.976(6) Å, respectively. The adjacent chains are further connected via N(1)−H(1N)···O(8)#1 interchain hydrogen bonds to generate a two-dimensional (2D) layer (Figure 1c), with a N···O distance of 2.754(8) Å. All the 2D layers are connected via hydrogen bonds between the lattice water molecules and coordinated methanol molecules to generate the threedimensional (3D) framework of 1a (Figure 1d). When the crystals of 1a were left in the open air around 10 °C, single-crystal-to-single-crystal transformation occurred, and the crystals of 1a transformed to 1, in which the coordinated methanol molecule in 1a was replaced by a coordinated water molecule in 1, and there is a 2-fold axis in the cation of [Zn(MP)2(H2O)2]2+ in 1. Similar to the structure of 1a, the zinc(II) ion in 1 also shows an octahedral coordination geometry, by coordinating with two nitrogen and two sulfur atoms from two MP molecules at equatorial plane, and two water molecules at axial positions (Figure 2a). The [Zn(MP)2(H2O)2](CF3SO3)2 units are linked through similar intermolecular hydrogen bonds to those of 1a, to form a similar 1D chain (Figure 2b), 2D layer (Figure 2c), and 3D framework (Figure 2d) of 1. However, 1 cannot transfer to 1a in an methanol vapor atmosphere, as the interaction between Zn(II) and water molecule is stronger than the interaction between Zn(II) and methanol molecule. When the crystals of 1 were left at room temperature (∼25 °C) and low RH (∼0%), single-crystal-to-single-crystal transformation also occurred, and the crystals of 1 further transformed to 1b, in which two lattice and one coordinated water molecule in 1 lost, and the asymmetric unit of 1b contains one

Figure 2. (a) Coordination environment of Zn and the structures of (b) 1D chain, (c) 2D layer, and (d) 3D framework in 1.

cation, two CF3SO3− anions, and one lattice water molecule. In each cation, the zinc(II) ion displays an octahedral coordination geometry, by coordinating with two nitrogen and two sulfur atoms from two MP molecules at equatorial plane, and two oxygen atoms from one methanol and one water molecule at axial positions (Figure 1a). The two CF3SO3− anions are connected to the coordinated water molecule through two O(1)−H(1W)···O(3) and O(1)−H(2W)···O(7)#2 hydrogen 5022



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Figure 4. (a) TG and DSC curves for 1, and (b) TG curve for 2.

MP molecule, half zinc ion and half water molecule, and one CF3SO3− anion. In contrast to the structures of 1a and 1, the coordination geometry of Zn(II) changes from octahedron in 1a and 1 to square pyramid in 1b (Figure 3a). The [Zn(MP)2(H2O)](CF3SO3)2 units are linked by the same intermolecular hydrogen bonds as those of 1, to form similar 1D chain and 2D layer. As water molecules escaped, 1D channels along the c axis, with about 11.4% volume calculated by PLATON,21 were left in 3D framework of 1b (Figure 3b). An attempt to obtain the crystals of anhydrous 2 failed, as the crystals collapsed after removing all the coordinated water molecules in 1. Thermal Stability and XRPD. The results of TG and DSC measurements indicate that the dehydration of 1 proceeds in two steps (Figure 4a). In the first step, 1 had a weight loss of 6.9% up to 65 °C, being consistent with the removal of three water molecules (calcd 7.3%) to convert to 1b. In the second step, 1b had a weight loss of 2.4% in the 105−140 °C temperature range, corresponding to the removal of one

coordinated water molecule (calcd 2.4%) to transform to 2. There is no weight loss for 2 before 270 °C in the TG curve (Figure 4b), indicating no solvate molecules are included in 2. The result of variable temperature XRPD measurements of 1 is consistent with those of TG. All the peaks displayed in the measured patterns at 30 °C match those in the simulated patterns generated from single crystal diffraction data, confirming the formation of single phase of 1. In the 50−100 °C temperature range, the position of the peaks at 21.80° and 28.93° for 1 moved to higher angles, which match the simulated patterns generated from single crystal diffraction data of 1b, demonstrating the transformation from 1 to 1b after the loss of three water molecules. At 120 °C, all the peaks in the pattern matched those of either 1b or 2, indicating the sample was a mixture of 1b and 2, which was consistent with the transformation from 1b to 2. From Figure 5, it also can be found that 1b completely transformed to 2 up to 160 °C, and 2 can be stable up to 270 °C. 5023



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Scheme 2. Transformations between 1a, 1, and 1b

Solubility. Apparent solubility and dissolution rate of solids are of importance in pharmaceutical development and quality control, and higher apparent solubility and shorter dissolution time may result in more absorption. Powder dissolution profiles for MP·H2O, 1 and 2 in water are shown in Figure 7. From

Figure 5. Variable temperature XRPD patterns of 1.

Dynamic Vapor Sorption (DVS). The water sorption kinetics of 2 was studied by DVS measurements at 25 °C, and the curves are shown in Figure 6. From Figure 6, it can be found

Figure 7. Powder dissolution profiles for MP·H2O, 1, and 2 in water.

Figure 7 it can be found that 1 and 2 show an increase in apparent solubility values. Complexes 1 and 2 reach a maximum apparent solubility within 8−10 min and then decrease over that time. This specific type of profile is a product of the “spring and parachute effect”, which has been exhibited by many pharmaceutical cocrystals.22−26 The maximum apparent solubility values for 1 and 2 are approximately 2.6 and 2.0 times as large as that of MP·H2O, and these values are comparable to those of MP-4-hydroxybenzoic acid (1.6 times) and MP-2,4dihydroxybenzoic acid cocrystals (2.0 times),22 and lower than those of MP-piperazinium salts (14 and 4.2 times for 1:1 and 2:1 salts respectively).22 The undissolved solids were filtered and dried under a vacuum, and the results of XRPD analyses indicate both 1 and 2 transformed to MP·H2O after the experiments (Figure S4, Supporting Information). Previously studies reveal that the undissolved solids of MP-4-hydroxybenzoic acid cocrystal, MP-2,4-dihydroxybenzoic acid cocrystal, and MP-piperazinium salts also transformed to MP·H2O after the dissolution experiments, demonstrating MP·H2O is the most stable form in aqueous solution. The curves of dissolution rate measurements performed in unsaturated aqueous solution are shown in Figure 8, which can be seen that both 1 and 2 display a faster dissolution rate than MP·H2O. For instance, 70% of 1 and 98% of 2 were dissolved within the primary 5 min, while only 38% of MP·H2O was dissolved within the same time. The above results demonstrate that the solubility and dissolution rate of APIs can be increased by the formation of ionic cocrystals.

Figure 6. Water sorption/desorption isotherms for 2 at 25 °C.

that 2 absorbed negligible water (0.38%) below 30% RH. Then it rapidly absorbed water above 30% RH and gradually transformed to hydrous form as the humidity increased. And the sample absorbed 13.78% of water at 90% RH and completely converted to 1, which was proven by XRPD measurements (Figure S1, Supporting Information). During the desorption process, 1 gradually lost water molecules as the humidity decreased and converted to 1b below 10% RH, which was confirmed by XRPD measurements (Figure S2, Supporting Information). In the second cycle, 1b transformed to 1 above 20% RH, while 1 converted back to 1b rather than anhydrous 2 when the humidity decreased below 10%, indicating the coordinated water molecule in 1b cannot be removed at room temperature. The above results display a humidity-induced transformation relationship between the hydrous and anhydrous forms at room temperature. On the basis of the above results, a schematic representation for the transformations between 1a, 1, and 1 is given in Scheme 2. 5024



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Y.; Wang, H. T.; Sun, F. X.; Zhao, X. J.; Jia, J. T.; Liu, J. R.; Guo, W.; Cui, X. Q.; Gu, J. K.; Zhu, G. S. Cryst. Growth Des. 2013, 13, 5261− 5266. (3) Yan, Y.; Chen, J. M.; Lu, T. B. CrystEngComm 2013, 15, 6457− 6460. (4) (a) Chen, J. M.; Wang, Z. Z.; Wu, C. B.; Li, S.; Lu, T. B. CrystEngComm. 2012, 14, 6221−6229. (b) Zhang, T. T.; Wang, H. T.; Jia, J. T.; Cui, X. Q.; Li, Q.; Zhu, G. S. Inorg. Chem. Commun. 2014, 39, 144−146. (5) (a) Geng, N.; Chen, J. M.; Li, Z. J.; Jiang, L.; Lu, T. B. Cryst. Growth Des. 2013, 13, 3546−3553. (b) Wang, J. R.; Zhou, C.; Yu, X. P.; Mei, X. F. Chem. Commun. 2014, 50, 855−858. (6) Shan, N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440− 446. (7) Aakeröy, C. B.; Chopade, P. D.; Desper, J. Cryst. Growth Des. 2011, 11, 5333−5336. (8) Bailey Walsh, R. D.; Bradner, M. W.; Fleischman, S.; Morales, L. A.; Moulton, B.; Rodríguez-Hornedo, N.; Zaworotko, M. J. Chem. Commun. 2003, 186−187. (9) Aakeröy, C. B.; Champness, N. R.; Janiak, C. CrystEngComm 2010, 12, 22−43. (10) Chen, J. M.; Wu, C. B.; Lu, T. B. Chem. J. Chin. Univ. 2011, 32, 1996−2009. (11) Braga, D.; Grepioni, F.; Maini, L.; Prosperi, S.; Gobetto, R.; Chierotti, M. R. Chem. Commun. 2010, 46, 7715−7717. (12) Braga, D.; Grepioni, F.; Lampronti, G. I.; Maini, L.; Turrina, A. Cryst. Growth Des. 2011, 11, 5621−5627. (13) Braga, D.; Grepioni, F.; Maini, L.; Lampronti, G. I.; Capucci, D.; Cuocci, C. CrystEngComm 2012, 14, 3521−3527. (14) Braga, D.; Grepioni, F.; Maini, L.; Capucci, D.; Nanna, S.; Wouters, J.; Aerts, L.; Quéré, L. Chem. Commun. 2012, 48, 8219− 5221. (15) Smith, A. J.; Kim, S.-H.; Duggirala, N. K.; Jin, J.; Wojtas, L.; Ehrhart, J.; Giunta, B.; Tan, J.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2013, 10, 4728−4738. (16) Wang, C. C.; Chiou, S. S.; Wu, S. M. Electrophoresis 2005, 26, 2637−2642. (17) Kato, Y.; Matsushita, T.; Yokoyama, T.; Mohri, K. Pharm. Res. 1992, 9, 697−699. (18) Zacchigna, M.; Cateni, F.; Luca, G. D.; Drioli, S. Bioorg. Med. Chem. Lett. 2007, 17, 6607−6609. (19) CrysAlis PRO, version 1.171.36.20; Agilent Technologies Inc.: Santa Clara, CA, USA, 2013. (20) Sheldrick, G. M. Acta Crystallogr. A 2008, 64, 112−122. (21) Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7−13. (22) Xu, L. L.; Chen, J. M.; Yan, Y.; Lu, T. B. Cryst. Growth Des. 2012, 12, 6004−6011. (23) Takata, N.; Takano, R.; Uekusa, H.; Hayashi, Y.; Terada, K. Cryst. Growth Des. 2010, 10, 2116−2122. (24) Stanton, M. K.; Tufekcic, S.; Morgan, C.; Bak, A. Cryst. Growth Des. 2009, 9, 1344−1352. (25) Stanton, M. K.; Bak, A. Cryst. Growth Des. 2008, 8, 3856−3862. (26) Cheney, M. L.; Shan, N.; Healey, E. R.; Hanna, M.; Wojtas, L.; Zaworotko, M. J.; Sava, V.; Song, S.; Sanchez-Ramos, J. R. Cryst. Growth Des. 2010, 10, 394−405. (27) Perez-Ruiz, E.; Delarbre, J. L.; Maury, L.; Selkti, M.; Tomas, A. Can. J. Anal. Sci. Spectrosc. 1998, 43, 59−67. (28) (a) Dubler, E.; Gyr, E. Inorg. Chem. 1988, 27, 1466−1473. (b) Amo-Ochoa, P.; Rodríguez-Tapiador, M. I.; Castillo, O.; Olea, D.; Guijarro, A.; Alexandre, S. S.; Gómez-Herrero, J.; Zamora, F. Inorg. Chem. 2006, 45, 7642−7650.

Figure 8. Dissolution rate profiles for MP·H2O, 1, and 2 in water.

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CONCLUSIONS The ionic cocrystal of 1 can be formed by the reaction of an API without containing oxygen atoms, MP·H2O, with a Zn(II) salt, Zn(CF3CO3)2·7H2O. Dissolving 1 in methanol generated the crystals of 1a. 1a transformed to 1 via single-crystal-tosingle-crystal transformation in the open air around 10 °C, and 1 further transformed to 1b via single-crystal-to-single-crystal transformation at room temperature (∼25 °C) and low RH%. The results of single crystal X-ray analyses indicate the coordination geometry of Zn(II) changes from octahedron in 1 and 1a to square pyramid in 1b. The apparent solubility and dissolution rate of MP are increased after forming ionic cocrystals of 1 and 2. The present study indicates that ionic cocrystal provides a new viable solid form for improving the solubility and dissolution rate of poorly soluble APIs.

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ASSOCIATED CONTENT

S Supporting Information *

XRPD patterns. This material is available free of charge via the Internet at http://pubs.acs.org

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AUTHOR INFORMATION

Corresponding Authors

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

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by NSFC (Grant Nos. 21101173, 91127002, and 21331007), NSF of Guangdong Province (S2012030006240), and Guangzhou Pearl River New Star Fund Science and Technology Planning Project (2013J2200054).

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REFERENCES

(1) Aakeröy, C. B.; Forbes, S.; Desper, J. J. Am. Chem. Soc. 2009, 131, 17048−17049. (2) (a) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2011, 8, 1867−1876. (b) Zhang, T. T.; Yang, 5025


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