Approach of Cocrystallization to Improve the Solubility and

Article pubs.acs.org/crystal

Approach of Cocrystallization to Improve the Solubility and Photostability of Tranilast Na Geng,† Jia-Mei Chen,*,† Zi-Jian Li,‡ Long Jiang,‡ and Tong-Bu Lu*,†,‡ †

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510275, China MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China

‡

S Supporting Information *

ABSTRACT: The cocrystals and salts of an antiallergic drug, tranilast, were synthesized to improve its solubility and photostability. Two tranilast cocrystals with urea (1) and nicotinamide (2), as well as two salts with cytosine (3) and sodium ion (4), were obtained and characterized by infrared spectra, thermogravimetric analyses, differential scanning calorimetry, and powder and single crystal X-ray diffractions. The results of single crystal structure analyses of 1−3 indicate that tranilast combines amide groups in coformers via R22(8) synthon, resulting in a 1:1 stoichiometry. The complexes showed advantages in terms of solubility and photostability in comparison to pure tranilast. The maximum solubility values of 1−3 in phosphate buffer of pH 6.8 are approximately 1.6, 1.9, and 2.0 times as large as that of tranilast, and the residual of tranilast is 79.5, 92.9, 88.5, 86.2, and 87.4% for tranilast and 1−4, respectively, under the fluorescent lamp irradiation for 96 h.

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INTRODUCTION Active pharmaceutical ingredient (API) can exist in a variety of distinct solid forms, including polymorphs, solvates, hydrates, salts, cocrystals, and amorphous solids.1 Crystal engineering approach can supply numerous crystalline materials to modify the physicochemical properties of an API through robust and reliable supramolecular synthons, which is of great importance in the pharmaceutical industry.2,3 According to the previous reports, salts and cocrystals have been shown to be effective in improving the physicochemical solid-state properties of API such as aqueous solubility,4−10 intrinsic dissolution,11,12 stability,13 and mechanical property.14,15 Salt formation is commonly employed in API, and the reaction between such components involves proton transfer from the acid to the base, while the salt option can only be used for ionizable drug candidates. In contrast to the salts, cocrystals have been recently demonstrated as a pharmaceutical development option for neutral drug.16 A pharmaceutical cocrystal is defined as a stoichiometric multiple component substance formed by API and coformers in their pure solid form.17−22 The API and coformers are connected by noncovalent intermolecular interactions, such as hydrogen bonding,23,24 halogen bonding,25 π···π,26,27 and other noncovalent interactions.28−30 © XXXX American Chemical Society

Tranilast (TL, Figure 1), N-(3,4-dimethoxycinnamoyl) anthranilic acid, is an antiallergic drug and comes in oral and transdermal formulations.31−33 An inherent drawback of TL is its low aqueous solubility, approximately 14.5 μg/mL in water and 0.7 μg/mL in buffer solution of pH 1.2, which leads to relatively high daily dose of 300 mg/day.34 Besides, TL has a photochemically unstable cinnamoyl group that undergoes two degradation pathways including isomerization and dimerization under photoirradiation.35 Though several structures of TL and its solvates have been reported,36 a few methods have been reported to improve the solubility and photostability of TL. Kawabata and co-workers attempted to improve the solubility and photostability by developing crystalline solid dispersion of TL.34 Hori reported that the addition of UV absorbers into TL in an oily gel may be useful for the reduction of TL photodegradation.37 Recently, a series of pharmaceutically acceptable carboxylic acid and amide compounds were chosen to cocrystallize with Received: April 9, 2013 Revised: June 20, 2013

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dx.doi.org/10.1021/cg400518w | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 1. Chemical structures of TL, urea, nicotinamide, and cytosine (from left to right).

Table 1. Crystallographic Data for 1−4 empirical formula formula weight space group temperature (K) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) Z V (Å3) theta range (deg) μ (mm−1) reflections collected unique reflections data/restraints/parameters R1 [I > 2σ(I)]a wR2 [all data]b goodness-of-fit a

1

2

3

4

C19H21N3O6 387.39 P21/n 293(2) 8.1957(2) 14.9197(3) 16.1595(3) 90 104.386(2) 90 4 1913.98(7) 4.09−62.50 0.850 7371 3042 3242/0/276 0.0370 0.0988 1.035

C24H23N3O6 449.45 P21/n 150(2) 5.1527(3) 19.4205(11) 21.9733(10) 90 90 90 4 2198.8(2) 3.04−65.37 0.821 11345 3653 3653/0/305 0.0374 0.0966 1.024

C22H22N4O6 438.44 P21/c 150(2) 5.4481(5) 21.0571(12) 17.8991(13) 90 94.142(7) 90 4 2048.0(3) 3.25−65.11 0.880 7121 3414 3414/23/359 0.0614 0.1550 1.014

C18H28NNaO11 457.40 P1̅ 150(2) 7.1939(4) 11.1238(7) 14.8985(10) 73.134(6) 89.524(5) 71.422(6) 2 1076.86(12) 3.11−65.31 1.169 7145 3571 3571/0/337 0.0532 0.0951 1.030

R1 = Σ||Fo| − |Fc||/ΣFo|. bwR2 = [Σ[w(Fo2 − Fc2)2]/Σw(Fo2)2]1/2; w = 1/[σ2 (Fo)2 + (aP)2 + bP ], where P = [(Fo 2) + 2Fc2]/3.

Figure 2. Structures of (a) chain and (b) sheet in 1.

APIs.30,37,38 As shown in Figure 1, TL consists of amide and carboxylic acid groups, which can act as good hydrogen bond sites to interact with some compatible coformers, and amides

are good candidates as coformers to form cocrystals or salts with TL. Herein, we report the preparation of two cocrystals and two salts of TL: urea cocrystal (1), nicotinamide cocrystal B



Article

Figure 3. Structures of (a) chain and (b) sheet in 2. geometry. The Cu-Kα (1.5406 Å) X-ray radiation source was operated at 40 V and 40 mA. Each sample was measured between 5 and 40° 2θ at a step size of 0.12°(2θ) and a step time of 0.12 s. TL Urea Cocrystal (1:1), 1. TL (327 mg, 1 mmol) and urea (60 mg, 1 mmol) were added in 3 mL of acetone, the resulting suspension was treated with ultrasonic waves for 30 min and was further stirred for 15 h. After centrifugation, the resulting supernatant liquid was filtered, and the filtrate was evaporated slowly at room temperature. One day later, rod-shaped colorless crystals were harvested. IR data (KBr, cm−1): 3431, 3325, 3239, 3149, 3005, 1666, 1614, 1510, 1463, 1260, 770. TL Nicotinamide Cocrystal (1:1), 2. This compound was prepared by a similar procedure to that of 1 except using nicotinamide (122 mg, 1 mmol) instead of urea. IR data (KBr, cm−1): 3307, 3122, 3000, 2954, 2839, 1663, 1513, 1451, 1263, 758. TL Cytosine Salt (1:1), 3. This compound was prepared by a similar procedure to that of 1 except using cytosine (111 mg, 1 mmol) instead of urea. IR data (KBr, cm−1): 3433, 3382, 3168, 3082, 2997, 1661, 1510, 1439, 1263, 764. TL Sodium Salt, 4. TL (327 mg, 1 mmol) was added to 10 mL of NaOH aqueous solution (1.0 M); the suspension was treated with ultrasonic waves for 30 min and was further stirred for 1 day. The resultant suspension was filtered, and the isolated solid of 4 was dried under vacuum for 24 h at ambient temperature. The block-shaped crystals of 4 were obtained by slow evaporation of an acetone solution

(2), cytosine salt (3), and sodium salt (4). We employed solidstate material characterization techniques such as single crystal X-ray diffraction, powder X-ray diffraction (PXRD), and infrared spectra (IR), as well as differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA), to characterize these cocrystals and salts. Their powder dissolution and photostability were also investigated in this study.

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EXPERIMENTAL SECTION

Materials and General Methods. TL was purchased from Suizhou Hongqi Chemical Co., Ltd., and the coformers were purchased from Aladdin reagent Inc. All other chemicals and solvents were received from various commercial sources and used without further purification. Bruker EQUINOX 55 FT-IR spectrometer was used for collecting the IR spectra of the samples. A total of 64 scans were collected over a range of 4000 to 400 cm−1 with a resolution of 0.2 cm−1 for each sample. Differential scanning calorimetry (DSC) was performed on a Netzsch STA 409 PC instrument. Sample powders were placed in aluminum pans under nitrogen atmosphere. The sample was equilibrated at 30 °C, with a heating rate of 10 °C/min. Thermogravimetric analysis (TGA) was performed on a TG-209 (Netzsch) with an open aluminum pan under nitrogen atmosphere, and a heating rate of 10 °C/min. Powder X-ray diffraction data were collected on a Bruker D8 Advance diffractometer with a Bragg−Brentano C



Article

Figure 4. Structures of (a) chain and (b) 3D framework in 3. of 4. IR data (KBr, cm−1): 3547, 3337, 3064, 2984, 2943, 2842, 1657, 1589, 1437, 792, 764. Single Crystal X-ray Diffraction. The single crystal data for 1−4 were collected on an Agilent Technologies Gemini A Ultra system with graphite monochromated Cu Kα radiation (λ = 1.5418 Å). Cell refinement and data reduction were applied using the program of CrysAlis PRO.39 The structures were solved by the direct method and refined by the full-matrix least-squares method on F2. All the nonhydrogen atoms were refined anisotropically. Hydrogen positions on nitrogen and oxygen were located in Fourier-difference electron density maps. Hydrogen atoms associated with carbon atoms were refined in geometrically constrained riding positions. The cytosine molecule and one methoxyl group of TL in 3 exhibit orientational disorder over two sets of positions and can be modeled by the splitting method. Restraints (DFIX, FLAT, ISOR, SIMU, and DELU) and constraints (AFIX) were applied for disordered methoxyl group and cytosine molecule in 3, and the disordered components were refined with 0.504(10):0.496(10) occupancies. All the calculations were performed using the SHELX-97 programs.40 X-ray crystallographic parameters and details of refinements of 1−4 are summarized in Table 1, and the hydrogen bonding distances and angles are given in Table S1, Supporting Information. Powder Dissolution Experiments. The powder dissolution experiments were conducted in pH 6.8 phosphate buffer solution. All the powders were sieved by standard mesh sieves, which provide samples with the particle size ranges of 75−150 μm. Then, 200 mg of powdered sample was added in 50 mL of buffer solution, and the resulting suspension was stirred continuously in a water bath maintained at 37 °C and 250 rpm for 1440 min. Aliquots were filtered with

0.22 μm nylon filters after 2, 4, 6, 8, 10, 15, 20, 25, 30, 60, 120, 180, 300, 420, 540, 660, 1440, and 2880 min. Each filtered aliquot was diluted with appropriate volume of buffer solution. The concentration of TL was assayed by a Cary 50 UV spectrometer (Cary 50, Varian, American) based on the absorbance at 333 nm (λmax of TL without interference from coformers). For TL, a standard curve produced by dilutions and absorbance readings at 333 nm was used to establish a linear regression. All experiments were repeated for three times to evaluate the standard deviation. After the dissolution experiments, the pH values of the solutions were measured, and the remaining solids were collected by filtration, dried, and measured by PXRD. Photostability Experiments. For oily stated stability test, each TL formulation (50 mg) was weighted exactly and distributed uniformly in the vehicle. For TL, whose mass ratio was controlled to 2.5−3%, was grinded with white petrolatum (WP) and liquid paraffin (LP) complicatedly in each sample. The mass ratio of WP and LP was controlled to 95.8−96.3% and 1.2%, respectively. The oily gel sample was placed on a glass plate and each gel layer was controlled less than 2 mm. Photostability experiments were conducted in the stability chamber (Labonce-250 PS, China), which were carried out at 25 °C and 60% humidity with an illuminance of 4000 1×. The samples were exposed to fluorescent lamp radiation for 4, 24, 48, 72, and 96 h. At a specified time, 5 mg of sample was taken out and dissolved in 2 mL of chloroform, and the contents of TL were determined by high performance liquid chromatography. High Performance Liquid Chromatography (HPLC) Analysis. The contents of TL were analyzed by a Shimadzu LC-20A HPLC system at a UV detection wavelength of 333 nm using a C18 column D



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Figure 5. Structures of (a) chain and (b) 3D framework in 4. (Inertsil ODS-3, 5 μm × 4.6 mm × 150 mm column, GL Sciences Inc., Japan). The mobile phase consisted of methanol/0.3% formic acid 75/25 (v/v) under isocratic elution with a flow rate of 1.0 mL/min.

The asymmetric unit of 4 contains one independent TL anion, two half occupied sodium cations, and six water molecules. In 4, each Na+ is coordinated with six water molecules to form a slightly distorted octahedral geometry, and the sodium cations are connected by μ2-OH2 to form a chain of [Na(OH2)4]nn+. The [Na(OH2)4]nn+ chains are further connected by TL anions through multiple intermolecular hydrogen bonds to form the three−dimensional (3D) framework of 4 (Figure 5b). It is significant to make a distinction between a cocrystal and a salt for a solid-form drug. In this article, hydrogen position between carboxylic acid of TL and the pyrimidine group of cytosine is identified by difference Fourier maps. On the basis of the two C−O distances of a carboxyl group, a distinction between a salt and a cocrystal can be made by the fact that the carboxylate anion possesses two close d(C−O) values (Δd(C−O) ≤ 0.03 Å), whereas a neutral carboxyl group possesses two distinctively different d(C−O) values (Δd(C−O) > 0.08 Å).41 The Δd(C−O) values are 0.018 Å in 3 and 0.009 Å in 4, confirming that 3 and 4 are salts rather than cocrystals (Table 2).

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RESULTS AND DISCUSSION Crystal Structures. In 1, two urea molecules form a dimer through two N3−H1N3···O6 hydrogen bonds (Figure 2a), with the N3···O6 distance of 2.919 Å. The urea dimer then links two TL molecules through three hydrogen bonds of N2−H1N2···O4, N3−H2N3···O4, and N3−H2N3···O3 to form a chain, with the hydrogen bonding distances of 3.108, 3.100, and 3.063 Å, respectively. The adjacent chains are further connected via N2−H2N2···O2 intermolecular hydrogen bond to generate a sheet (Figure 2b) with the N2···O2 distance of 3.114 Å. The adjacent sheets are further linked through intersheet hydrogen bonds to generate the three-dimensional (3D) structure of 1. As shown in Figure 3a, two nicotinamide molecules in 2 form a dimer through two N4−H4A···O6 hydrogen bonds, with the O6···N4 distance of 2.816 Å. The dimers then alternately link TL molecules through N4−H4B···O3 intermolecular hydrogen bonds to generate a chain. The adjacent chains are further connected by TL molecules through O1−H1···N2 interchain hydrogen bonds to form a sheet (Figure 3b). As shown in Figure 4a, a proton transfers from the carboxylic acid group of TL in 3 to the amino group of cytosine (Figure 4a). The TL anion is connected by the cytosine cation through two N3−H3B···O1 and N4−H4C···O2 intermolecular hydrogen bonds to form a dimer, and the dimers are further linked by interdimer N4−H4B···O3 hydrogen bond to generate a chain along the b axis. All the chains are packed along the b axis to generate the structure of 3 (Figure 4b).

Table 2. Δd(C−O) of the C−O Bond Lengths of TL and 1−4 C−O (long) C−O (short) Δd(C−O)

TL

1

2

3

4

1.339 1.201 0.138

1.302 1.227 0.075

1.317 1.223 0.094

1.272 1.254 0.018

1.266 1.257 0.009

In addition, the melting points for 1 and 2 are between those of TL and the corresponding coformers, while the melting point of 3 is higher than that of TL and cytosine (see the PXRD and Thermal Properties section), further demonstrating that 1 and 2 are cocrystals, while 3 is a salt. E



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PXRD and Thermal Properties. The PXRD was used to check the crystalline phase purity of 1−4. The results show that the patterns of the products are different from either that of TL or those of the corresponding coformers (Figure 6). In addition, all the peaks displayed in the measured patterns closely match those in the simulated patterns generated from single crystal diffraction data, confirming the formation of the corresponding molecular complexes 1−4. The thermal behaviors of TL and 1−4 were investigated by DSC and TGA, and the results are presented in Figure S1, Supporting Information. The melting points of urea, nicotinamide, and cytosine are 132.7, 122.1, and 111.1 °C, respectively. After the formation of cocrystals and salts, the melting points are 194.1, 174.0, and 217.7 °C for 1−3, respectively, which are different from those of TL (212.5 °C) and the corresponding coformers. The TGA curve of 4 shows a weightloss of 23.2% in the 40−100 °C temperature range, which is consistent with the loss of six water molecules (calcd 23.6%). After the loss of water molecules, compound 4 can be stable up to 250 °C and then begins to decompose upon further heating. Powder Dissolution and Photostability. The solubility of urea, nicotinamide, and cytosine in aqueous media is 1.21 g/ mL, 0.40 g/mL, and 7.70 mg/mL, respectively.42−44 Because of their relative high solubility, we supposed that the aqueous dissolution of TL would be increased after the formation of cocrystals and salts. Powder dissolution profiles for TL and 1−4 in phosphate buffer of pH 6.8 are shown in Figure 7. From Figure 7, it can be found that both the dissolution rate and apparent solubility values of 1−3 are larger than those of TL, indicating the solubility of TL can be indeed improved via forming the cocrystals 1 and 2 and salt 3. Though the dissolution rate and apparent solubility values of 4 are larger than those of TL at the beginning (within 20 min), the apparent solubility value of 4 is even less than that of TL after 20 min. The maximum solubility values of 1−3 are approximately 1.6, 1.9, and 2.0 times as large as that of TL, respectively. The dissolution plots for all the complexes reach a maximum solubility (Smax) within 30 min (Figure 7a), and the maximum solubility can keep constant at least 2 h, indicating the complexes did not transform into the TL sodium salt. From Figure 7b, it can be found that 1−3 transformed into TL sodium salt very slowly, and the complexes have completely transformed into the TL sodium salt until 48 h. After the dissolution experiments, the undissolved solids were filtered and dried under vacuum for 12 h, the results of PXRD analyses indicate all the complexes transformed to 4 after the dissolution experiments (Figure S2, Supporting Information). The petrolatum and liquid paraffin were used as a vehicle of formulation in the photostability experiments. During the course of 96 h, all complexes and TL were photodecomposed at different degrees (Figure 8), while the cocrystals and salts were relatively more stable than TL under fluorescent lamp irradiation. The residual of TL was 79.5, 92.9, 88.5, 86.2, and 87.4% for TL and 1−4, respectively. The results of photostability experiments demonstrate that the photostability of TL can be improved after the formation of cocrystals and salts. From the structures of 1−4, it can be found that the shortest centroid···centroid distances between CC groups on the adjacent TL molecules are 4.575, 5.153, 5.448, and 4.069 Å for 1−4, respectively, and these distances are longer than that of 3.972 Å in pure TL molecule,36 indicating the distances between CC atoms on the adjacent TL molecules are

Figure 6. PXRD patterns for 1 (a), 2 (b), 3 (c), and 4(d).

increased after the formation of 1−4. The above results demonstrate that that the degradation of TL molecules in 1−4 F



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CONCLUSIONS We investigated the cocrystallization behavior of TL using a crystal engineering approach, with the purpose of identifying new crystal forms that could potentially be used to improve its poor solubility and photostability. Two cocrystals of TL with urea (1) and nicotinamide (2), as well as two salts of TL with cytosine (3) and sodium ion (4) were obtained, and their structures were determined by the single crystal X-ray diffraction. The solubility experiments conducted in pH 6.8 phosphate buffer solution revealed that the maximum solubility of 1−3 are approximately 1.6, 1.9, and 2.0 times as large as that of TL, and the results of photostability experiments demonstrate that the photostability of TL can also be enhanced after the formation of cocrystals and salts.

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ASSOCIATED CONTENT

S Supporting Information *

Hydrogen bonding distances and angles and TG/DSC curves for 1−4, and PXRD pattern of 4 after the dissolution experiment. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

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

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by 973 Program of China (2012CB821705), NSFC (Grant Nos. 91127002, 21101173, and 21121061), and NSF of Guangdong Province (S2012030006240).

Figure 7. Powder dissolution profiles for TL and 1−4 in phosphate buffer of pH 6.8 for (a) 2 and (b) 48 h.

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REFERENCES

(1) Morissette, S. L.; Almarsson, Ö .; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. Adv. Drug Delivery Rev. 2004, 23, 275−300. (2) Blagden, N.; Matas, M.; Gavan, P. T.; York, P. Adv. Drug Delivery Rev. 2007, 59, 617−630. (3) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 1013−1021. (4) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P. J. Am. Chem. Soc. 2004, 126, 13335−13342. (5) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950− 2967. (6) Chen, J. M.; Wang, Z. Z.; Wu, C. B.; Li, S.; Lu, T. B. CrystEngComm 2012, 14, 6221−6229. (7) Tao, Q.; Chen, J. M.; Ma, L.; Lu, T. B. Cryst. Growth Des. 2012, 12, 3144−3152. (8) Xu, L. L.; Chen, J. M.; Yan, Y.; Lu, T. B. Cryst. Growth Des. 2012, 12, 6004−6011. (9) Yan, Y.; Chen, J. M.; Geng, N.; Lu, T. B. Cryst. Growth Des. 2012, 12, 2226−2233. (10) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2011, 8, 1867−1876. (11) Paluch, K. J.; Tajber, L.; Elcoate, C. J.; Corrigan, O. I.; Lawrence, S. E.; Healy, A. M. J. Pharm. Sci. 2011, 100, 3268−3283. (12) Cherukuvada, S.; Babu, N. J.; Nangia, A. J. Pharm. Sci. 2011, 100, 3233−3244. (13) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Int. J. Pharm. 2006, 320, 114−123.

Figure 8. Profiles of retention ration of TL versus irradiation time.

undergoes a dimerization pathway rather than a isomerization pathway, as only the dimerization pathway can be significantly affected by increased distances between the adjacent TL molecules, while the isomerization pathway could be unaffected or even made worse along with the increasing distances between the adjacent TL molecules. G



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(14) Karki, S.; Frišcǐ ć, T.; Fábián, L.; Laity, P. R.; Day, G. M.; Jones, W. Adv. Mater. 2009, 21, 3905−3909. (15) Sun, C. C.; Hou, H. Cryst. Growth Des. 2008, 8, 1575−1579. (16) Kojima, T.; Onoue, S.; Murase, N.; Katoh, F.; Mano, T.; Matsuda, Y. Pharm. Res. 2006, 23, 806−812. (17) Aakeröy, C. B.; Champness, N. R.; Janiak, C. CrystEngComm 2010, 12, 22−43. (18) Almarsson, Ö .; Zaworotko, M. J. Chem. Commun. 2004, 1889− 1896. (19) Vangala, V. R.; Nangia, A.; Lynch, V. M. Chem. Commun. 2002, 1304−1305. (20) Shan, N.; Zaworotko, M. J. The Role of Cocrystals in Pharmaceutical Science. Drug Discovery Today 2008, 13, 440−446. (21) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499−516. (22) Arora, K. K.; Zaworotko, M. J. Pharmaceutical Co-crystals: A New Opportunity in Pharmaceutical Science for a Long-known but Little Studied Class of Compounds. In Polymorphism in Pharmaceutical Solids; Brittain, H. G., Ed.; Informa Healthcare: London, 2009; pp 282−317. (23) Braga, D.; Dichiarante, E.; Palladino, G.; Grepioni, F.; Chierotti, M. R.; Gobetto, R.; Pellegrino, L. CrystEngComm 2010, 12, 3534− 3536. (24) Basavoju, S.; Boström, D.; Velaga, S. P. Pharm. Res. 2008, 25, 530−541. (25) Liantonio, R.; Metrangolo, P.; Pilati, T.; Resnati, G.; Stevenazzi, A. Cryst. Growth Des. 2003, 3, 799−803. (26) Fabelo, O.; Delgado, L. C.; Delgado, F. S.; Luis, P. L.; Laz, M. M.; Julve, M.; Ruiz-Pérez, C. Cryst. Growth Des. 2005, 5, 1163−1167. (27) Orola, L. V. M; Mutikainen, V. I.; Sarcevica, I. Cryst. Growth Des. 2011, 11, 4009−4016. (28) Olenik, B.; Boese, R.; Sustmann, R. Cryst. Growth Des. 2003, 3, 175−181. (29) Sanphui, P.; Goud, N. R.; Khandavilli, U. B. R.; Nangia, A. Cryst. Growth Des. 2011, 11, 4135−4145. (30) Das, B.; Baruah, J. B. Cryst. Growth Des. 2011, 11, 5522−5532. (31) Suzawa, H.; Kikuchi, S.; Arai, N.; Koda, A. Jpn. J. Pharmacol. 1992, 60, 91−96. (32) Uno, M.; Kurita, S.; Misu, H.; Ando, H.; Ota, T.; MatsuzawaNagata, N.; Kita, Y.; Nabemoto, S.; Akahori, H.; Zen, Y.; Nakanuma, Y.; Kaneko, S.; Takamura, T. Hepatology 2008, 48, 109−118. (33) Yamada, H.; Tajima, S.; Nishikawa, T.; Murad, S.; Pinnell, S. R. J. Biochem. 1994, 116, 892−897. (34) Kawabata, Y.; Yamamoto, K.; Debari, K.; Onouea, S.; Yamada, S. Eur. J. Pharm. Sci. 2010, 39, 256−262. (35) Kakegawa, H.; Mitsuo, N.; Matsumoto, H.; Satoh, T.; Akagi, M.; Tasaka, K. Chem. Pharm. Bull. 1985, 33, 3738−3744. (36) Vogt, F. G.; Cohen, D. E.; Bowman, J. D.; Spoors, G. P.; Zuber, G. E.; Trescher, G. A.; Dell’orco, P. C.; Katrincic, L. M.; Debrosse, C. W. J. Pharm. Sci. 2005, 94, 651−665. (37) Hori, N.; Fujii, M.; Ikegami, K.; Momose, D.; Saito, N.; Matsumoto, M. Chem. Pharm. Bull. 1999, 47, 1713−1716. (38) Ando, S.; Kikuchi, J.; Fujimura, Y.; Ida, Y.; Higashi, K.; Moribe, K.; Yamamoto, K. J. Pharm. Sci. 2012, 101, 3214−3221. (39) CrysAlisPro, version 1.171.35.20; Agilent Technologies Inc.: Santa Clara, CA, 2011 (40) Sheldrick, G. M. SHELXT\L-97, program for crystal structure solution and refinement; University of Gottingen: Gottingen, Germany, 1997. (41) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4, 323−338. (42) Lee, F. M.; Lahti, L. E. J. Chem. Eng. Data 1972, 17, 304−306. (43) Rasool, A. A.; Hussain, A. A.; Dittert, L. W. J. Pharm. Sci. 1991, 80, 387−393. (44) Nitsch, K.; Šubertová, E. Czech. J. Phys. 1977, 27, 1181−1186.

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Approach of Cocrystallization to Improve the Solubility and

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