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DOI: 10.1002/cjoc.201300217

New Crystalline Forms of Mebendazole with n-Alkyl Carboxylic Acids: Neutral and Ionic Status
Jiamei Chena and Tongbu Lu*,b
b

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, 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, Guangdong 510275, China

Structural information on the crystalline forms of mebendazole, an anti-parasitic drug, is limited, although three polymorphic forms of this drug have been reported. The present work investigates the structures and properties of different crystalline forms of mebendazole with a series of n-alkyl carboxylic acids, including trifluroacetic acid (1), formic acid (2), acetic acid (3), propanoic acid (4), butanoic acid (5), valeric acid (6) and hexanoic acid (7). These compounds were characterized by thermogravimetric analysis, IR spectra, as well as powder and single-crystal X-ray diffraction analysis. The R22(8) structural motif was detected in all the seven products, which was formed by a pair of NHO/OHN hydrogen bonds between mebendazole and carboxylic acid. Forms 37 were found to be neutral solvate, while in forms 1 and 2, proton transfer was observed from carboxylic acid to mebendazole. Keywords crystal engineering, hydrogen bond, supramolecular synthon, crystalline form, mebendazole

Introduction
The majority of active pharmaceutical ingredients (APIs) exist in the crystalline forms due to reasons of stability and ease of handling during the various stages of drug development.[1] Crystal engineering technologies make it possible to obtain many types of crystalline forms for APIs, such as polymorphs,[2] solvates, salts[3,4] and cocrystals.[5,6] Polymorphs are different crystal structures of the same API arising from different arrangements and/or conformations of the molecules in the crystal lattice.[4,5] API molecule may coexist with a guest molecule, and the crystalline forms are designated as a solvate or a cocrystal,[4,5] when the guest molecule is a liquid or solid at room temperature, respectively. Salts are distinguished from all other solid forms by being stabilized by ionic bonding between API and guest molecule.[3,4] All these forms exhibit varying physicochemical properties[7-10] and represent a broad patent space[11] since their design and preparation involve several elements of non-obviousness and they generally have novel and useful properties. In the pharmaceutical field, it is crucial to generate different crystalline forms of an API, which can offer altered/ improved physical properties of the API without changing its chemical identity or biological activity, and subsequently select a suitable form for the intended use.[12] Mebendazole (5-benzoyl-2-benzimidazolecarbamic

acid methyl ester, MBZ) is a broad-spectrum anthelmintic drug producing high cure rates in infestations by ascaris, threadworms, hookworms and whipworms, and administered orally as a tablet formulation and suspension.[13] It has been known that mebendazole exists in three polymorphs (A, B and C), and form C is the most efficacious one.[14,15] Mebendazole has low solubility (0.035 mg/mL in water at 25 for form C) and poor flowability,[16-18] thus it is significant to develop new solid forms of mebendazole for improvement of its physical and/or chemical properties. The crystal structure of mebendazole form C (refcode YULGIW) has been reported and shows that two mebendazole molecules form a dimer through a supramolecular homosynthon I (Scheme 1),[19] thus for mebendazole cocrystallization with coformers, this supramolecular synthon motif must be interrupted. Carboxylic acids are chosen as potential coformers with mebendazole by forming supramolecular heterosynthon II (Scheme 1). We have successfully prepared several salts and cocrystals of mebendazole with dicarboxylic acids through supramolecular heterosynthon II, and several of them show significantly improved solubility.[20] In the present work, mebendazole was reacted with a series of n-alkyl carboxylic acids, including trifluroacetic acid, formic acid, acetic acid, propanoic acid, butanoic acid, valeric acid and hexanoic acid. All coformers produced new crystalline forms 17, in

* E-mail: lutongbu@mail.sysu.edu.cn; Tel.: 0086-020-84112921; Fax: 0086-020-84112921 Received March 21, 2013; accepted May 2, 2013; published online May 14, 2013. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300217 or from the author.
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Scheme 1 Hydrogen bonding synthons of mebendazole
O O H N N H N N H I N H N O II O O O H N N H O N H O

Chen & Lu

which two of them are ionic and the remaining five are neutral.

Experimental
Materials and methods MBZ (form C) was purchased from Hubei Yuancheng Pharmaceutical Co., Ltd, China, with a purity of 99.0%, and was used without further purification. All other reagents and solvents obtained from commercial suppliers were used as received. Elemental analyses were performed on an Elementar Vario EL elemental analyser. FT-IR (KBr pellet) spectra were recorded on a Bruker EQUINOX 55 FT-IR spectrometer. TGA measurements were carried out in a nitrogen stream using a Netzsch TG-209 instrument with a heating rate of 10 /min. Preparation of mebendazole-trifluoroacetate salt (11) (1) MBZ form C (500 mg) was added to 20 mL of ethanol to obtain a white suspension. Approximately 15 mL of trifluroacetic acid was added incrementally until the suspension became clear. The resulted solution was filtered and evaporated slowly at room temperature. Block-shaped crystals of 1 were obtained after one month. Yield 82%. IR (KBr) : 3253 (vNH), 1748, 1660 (vCO) cm1. Anal. calcd for C18H14F3N3O5: C 52.82, H 3.45, N 10.27; found C 52.89, H 3.58, N 10.34. Preparation of mebendazole-formate salt (13) (2) MBZ form C (500 mg) was dissolved in 2 mL of formic acid by heating to 100 with constant stirring. The resulted solution was cooled to room temperature and filtered. The filtrate was evaporated slowly at room temperature. Plate-shaped crystals of 2 were obtained after 3 d. Yield: 65%. IR (KBr) v: 3368 (vNH), 1731, 1640 (vCO) cm1. Anal. calcd for C19H19N3O9: C 52.66, H 4.42, N 9.70; found C 53.02, H 4.23, N 9.96. Preparation of mebendazole-acetic acid solvate (11) (3) MBZ form C (100 mg) was dissolved in 5 mL of acetic acid by heating to 100 with constant stirring. The resulted solution was cooled to room temperature and filtered. The filtrate was evaporated slowly at room temperature. Needle-shaped crystals of 3 were obtained after one month. Yield: 73%. IR (KBr) v: 3353 (vNH), 1737, 1693 (vC O) cm1. Anal. calcd for C18H17N3O5: C 60.84, H 4.82, N 11.83; found C 61.03, H 4.71, N 11.77. Preparation of mebendazole-propanoic acid sol636
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vate (11) (4) MBZ form C (100 mg) was dissolved in 10 mL of propanoic acid by heating to 120 with constant stirring. The resulted solution was cooled to room temperature and filtered. The filtrate was evaporated slowly at room temperature. Needle-shaped crystals of 4 were obtained after one month. Yield 89%. IR (KBr) v: 3365 (vNH), 1737, 1684 (vCO) cm1. Anal. calcd for C19H19N3O5: C 61.78, H 5.18, N 11.38; found C 61.93, H 5.11, N 11.31. Preparation of mebendazole-butanoic acid solvate (11) (5) Needle-shaped crystals of 5 were obtained by a procedure similar to that of 4 except using butanoic acid instead of propanoic acid. Yield 87%. IR (KBr) : 3358 (vNH), 1737, 1684 (vCO) cm1. Anal. calcd for C20H21N3O5: C 62.65, H 5.52, N 10.96; found C 63.33, H 5.48, N 10.92. Preparation of mebendazole-valeric acid solvate (11) (6) Needle-shaped crystals of 6 were obtained by a procedure similar to that of 4 except using valeric acid instead of propanoic acid. Yield 52%. IR (KBr) v: 3361 (vNH), 1738, 1688 (vCO) cm1. Anal. calcd for C21H23N3O5: C 63.46, H 5.83, N 10.57; found C 63.55, H 5.79, N 10.50. Preparation of mebendazole-hexanoic acid solvate (11) (7) MBZ form C (15 mg) was dissolved in 3 mL of hexanoic acid by heating to 120 with constant stirring. The solution was cooled to room temperature and four drops of water were added. The resulted solution was filtered and evaporated slowly at room temperature. A few needle-shaped crystals of 7 were obtained after one month. Yield 6%. 7 was not further characterized due to insufficient quantity. Powder X-ray diffraction (PXRD) PXRD data were recorded using a Bruker D8 Advanced diffractometer (Bruker, Madison, WI). The diffractometer was operated with Cu K radiation (1.5418 ) at 40 kV and 40 mA. Data were collected over an angular range of 340 (2) value in continuous scan mode using a step size of 0.02 (2) and a step time of 0.12 s. Approximately 20 mg sample was weighed into glass sample holder, taking care not to introduce a preferential orientation of crystals. Calculated PXRD patterns were generated from the single-crystal structures using Mercury 2.4 (Cambridge crystallographic data center, UK) and compared with experimental patterns. Single-crystal X-ray diffraction Single-crystal X-ray diffraction data were collected on an Agilent Xcalubur Nova CCD diffractometer with graphite monochromated Cu K radiation (1.5418 ). Cell refinement and data reduction were applied using the program package CrysAlis PRO.[21] The structures were solved by the direct methods and refined by the fullmatrix least-squares method on F 2 . All the nonhydrogen atoms were refined anisotropically. Hydrogen atoms were refined in geometrically constrained riding positions. All the calculations were performed using the SHELX-97 program.[22] The crystallographic data are summarized in Tables 1 and 2, and the selected hydroChin. J. Chem. 2013, 31, 635640

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New Crystalline Forms of Mebendazole with n-Alkyl Carboxylic Acids Table 1 Formula M T/K Crystal size/mm3 Crystal system Space group a/ b/ c/ /() /() /() V/3 Z dcalcd/(gcm ) /mm
1 3

Crystal data and refinement parameters for 13 1

b

Table 2 Formula M T/K

Crystal data and refinement parameters for 57 5b 383.40

3

2 433.37 100(2) 0.04 Triclinic P-1

3 355.35 295(2) 0.05 Triclinic P-1

6 397.40 150(2) 0.200.10 0.05 Triclinic P-1 5.8416(3)

7 411.45 150(2) 0.100.05 0.05 Triclinic P-1 5.7090(4) 11.4235(13) 78.875(11) 89.195(9) 84.379(8) 2 1.329 0.784 436 5h6

C18H14F3N3O5 C19H19N3O9 C18H17N3O7 409.32 150(2) 0.200.10 0.10 Monoclinic P21/n 7.6466(4) 9.3416(5) 24.7462(13) 90 95.692(5) 90 1758.94(16) 4 1.546 1.174 840 9h6 23l29

C20H21N3O7 C21H23N3O5 C22H25N3O5 295 (2) 0.300.10 0.08 Triclinic P-1 5.6632(2)

0.200.20 0.100.05

Crystal size/mm Crystal system Space group a/ b/ c/ /() /() /() V/ Z dcalcd/(gcm ) /mm1 F(000) range/() Index range
3 3

10.6837(5) 5.6351(2) 14.2008(10) 11.4265(6) 20.6149(17) 13.7931(7) 79.991(6) 76.749(5) 83.104(5) 2987.5(3) 6 1.445 0.999 1356 95.982(4) 98.586(4) 94.771(4) 868.98(7) 2 1.358 0.844 372

11.3741(8) 11.2511(6) 77.823(5) 81.620(4) 85.418(4) 970.17(9 2 1.312 0.794 404 6h4 79.729(5) 85.834(5) 84.349(5) 2 1.303 0.778 420 5h6

15.5946(9) 15.7680(10) 16.146(2)

1013.17(10) 1028.2(2)

2.9267.07 2.8567.07 2.7967.05 13k13 12k13 13k13 18l17 17l18 17l19

F(000) range/() Index ranges

3.5966.58 2.2366.59 2.9565.09 12h10 6h5 24l24 16l15 21938 0.0992] 98.7% 1.046 0.0913, 0.2157 0.1221, 0.2391 0.505, 0.355
2

11k11 15k16 11k13 Reflections collected Independent reflections Completenes Goodness-of-fit on F2 R1a, wR2b [I2(I)] R1, wR2 (all data) Largest diff. peak, hole/(e )
a 3

Reflection collected Independent reflection Completenes Goodness-of-fit on F2

7039 3101 [Rint 0.0465] 100.0% 1.054 0.0561, 0.1563 0.0694, 0.1714 0.435, 0.395
b

5490 0.0325] 99.4% 1.089 0.0431, 0.1139 0.0581, 0.1302 0.183, 0.201

6757 3472 [Rint 0.0253] 99.9%

7423 3607 [Rint 0.0338] 99.9%

6752 3673 [Rint 0.0468] 99.8%

10426 [Rint 3088 [Rint

Data/restraint/parameter 3472/0/260 3607/0/265 3673/0/274 1.035 1.059 1.073 0.0480, 0.0455, 0.0502, R1a, wR2b [I2(I)] 0.1302 0.1218 0.1253 0.0582, 0.0670, 0.0694, R1, wR2 (all data) 0.1421 0.1395 0.1591 Largest diff. peak, 0.223, 0.181, 0.259, hole/(e3) 0.243 0.179 0.308 a R1(FoFc)/Fo; b wR2[w(Fo2Fc2)2/w(Fo2)2]1/2.

Data/restraint/parameter 3101/0/263

10426/0/848 3088/0/238

R1(FoFc)/Fo;

wR2[w(Fo Fc2)2/w(Fo2)2]1/2.

gen bonding distances and angles are given in Table S1.

Results and Discussion

Crystal structures We have obtained the crystals suitable for single-crystal X-ray diffraction of all products,[23] with an exception of 4, whose crystal structure has been reported.[24] As shown in Figure 1, the asymmetric unit of
Chin. J. Chem. 2013, 31, 635640

1 contains one mebendazole cation and one trifluroacetate anion, in which a proton is transferred from the carboxyl group of trifluroacetic acid to the nitrogen atom of imidazole group in mebendazole. In 1, one mebendazole cation connects one trifluroacetate anion through two hydrogen bonds of N(1)H(1)O(4) and N(2)H(2)O(5) to form a dimer (Figure 1), with the N(1)O(4) and N(2)O(5) distances of 2.672(2) and 2.650(2) , respectively (Table S1). Two (mebendazole-trifluroacetate) dimers further connect through two N(3)H(3)O(3)a hydrogen bonds to form a tetramer (Figure 1), with the N(3)O(3)a distance of 2.918(3) (Table S1, a x+2, y+1, z+2). There is an intramolecular hydrogen bond of N(3)H(3)O(2) in each mebendazole cation, with the N(3)O(2) distance
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of 2.693(3) . The tetramers interact with each other by interactions to form a one dimensional (1D) column (Figure S1a), with the shortest inter-tetramer distance of 3.35 . All the 1D columns pack along a axis to generate the three dimensional (3D) structure of 1 (Figure S1b).

Chen & Lu

Figure 1

The structure of a tetramer in 1.

The strucutre of 2 is different from that of 1, in which one asymmetric unit contains three independent mebendazole cations, three formate anions, and six formic acid molecules, and the three independent mebendazole cations originate from the different orientation of phenyl groups of mebendazole. Similar to 1, a proton is transferred from one formic acid to the imidazole group in mebendazole to form a mebendazole cation and a formate anion, and the mebendazole cation connects the formate anion through two NHO hydrogen bonds to form a dimer (Figure 2), with the NO distances of 2.657(4)2.793(4) (Table S1). The adjacent dimers further connect with the second formic acids through one OHO and one NHO hydrogen bonds to form a 1D chain (Figure 2), with the NO and OO distance of 2.779(4)2.791(4) and 2.574(4)2.609(4) , respectively (Table S1). The third formic acids link to the chain through a OHO hydrogen bond (Figure 2), with the OO distances of 2.597(5)2.613(5) (Table S1). There is also a NHO intramolecular hydrogen bond in each mebendazole cation, with the NO distances of 2.725(5)2.752(5) . It is interesting to note that there are three independent chains in 2 (Figure S2), and each chain contains one mebendazole cation, one formate anion, and two formic acid molecules, respectively. The three independent chains pack

in an (ABC)(CBA) fashion along a axis to form the 3D structure of 2 (Figure S2). The structures of 37 are similar, and they are also similar to the structure of 1, thus only the structure of 3 was discussed herein, and the structures of 47 are shown in Figures S4S7, respectively. As shown in Figure 3, each mebendazole moleclue connects the carboxyl group through two N(1)H(1)O(4) and O(5) H(5)N(2) hydrogen bonds (Scheme 1, synthon II) to form a dimer, with the NO distances of 2.752(2) and 2.689(2) , respectively (Table S1), and two dimers further connect through two N(3) H(3) O(3)c hydrogen bonds to form a tetramer (cx2, y1, z), with the N(3)O(3)c distances of 2.952(2) (Table S1). There is also an intramolecular hydrogen bond of N(3)H(3)O(2) in each mebendazole molecule, with the N(3)O(2) distance of 2.729(2) . Similar to 1, the tetramers in 3 interact with interactions to form a 1D column, with the inter-tetramer distances of 3.57 (measured by the atomatom distance). All the 1D columns pack along a axis to generate the 3D structure of 3 (Figure S3). It is interesting to note that the lengths of the c axis in 37 increase along with the increase of alkyl chain length of carboxylic acids, from 13.7931(7) in 3 to 16.146(2) in 7 (Tables 1 and 2).

Figure 3

The structure of a tetramer in 3.

Mebendazole crystalline forms: neutral or ionic? pKa value is widely accepted as the key to predict whether a proton will transfer.[25,26] It is generally considered that, if pKa0, the resulting compound will be neutral, whereas it is typically ionic if pKa3. As pKa values [pKapKa(mebendazole)pKa(acid)] are 4.71, 1.27, 0.25, 0.23, 0.19, 0.19 and 0.13 for trifluroacetic acid, formic acid, acetic acid, propanoic acid, butanoic acid, valeric acid and hexanoic acid, respectively (Table S2), it is expected that trifluroacetic acid could protonate mebendazole whereas other carboxylic acids may form either ionic or neutral compounds with mebendazole. Further investigation into the CO distances of carboxyl groups from crystal structures was performed to identify the position of the proton. Based on two CO distances of a carboxyl group, a distinction between an ionic and a neutral carboxyl group can be made by the fact that a carboxylate anion possesses two close
Chin. J. Chem. 2013, 31, 635640

Figure 2
638

The structure of 1D chain in 2.

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New Crystalline Forms of Mebendazole with n-Alkyl Carboxylic Acids

d(CO) values [d(CO)0.03 ], whereas a neutral carboxyl group possesses two distinctively different d(CO) values [d(CO)0.08 ].[26,27] The d(C O) values are 0.008 for trifluroacetate anion in 1 and 0.0010.007 for formate anions in 2 (Table 3), respectively, while the d(CO) values are 0.080.11 for carboxylic acids in 37 (Table 3), demonstrating 1 and 2 are salts, while 37 are solvates. In addition, the d(CO) values are 0.0850.126 for another six formic acids in 2 (Table 3), indicating they are neutral acids rather than anions.
Table 3 1 1.237(3) 1.245(6) 2a 1.223(6) 1.166(6) 3 1.216(3) 4b 1.207 5 1.206(3) 6 1.211(3) 7 1.210(3)
a

have begun to escape from crystal lattice before TGA test. For 3, the TGA mass loss occurring in the temperature range of 69176 was estimated as 15.1%, in agreement with the calculated value of 16.9% expected for a 11 stoichiometric composition. Analogous thermal behaviors were observed for the crystalline forms 4 6, which all demonstrate a 1 1 stoichiometric composition. Relative stability Thermogravimetric analysis was also employed to gauge the relative thermal stabilities of 1 6. For desolvation events, the difference between the desolvation onset temperature and the boiling point of the pure solvent (TToTb) has been suggested as one simple measure of solvate thermal stability.[28] The Tb values for trifluroacetic, acetic, propanoic, butanoic and valeric acids are 72, 118, 141, 163.5 and 186 respectively, and the T values for the corresponding mebendazole solid forms are 23, 49, 67, 76 and 93 (Table S2), yielding the thermal stability order 1>>3456. And 2 is the most unstable one, since formic acid molecules begin to escape from crystal lattice under ambient condition as mentioned above.

Carbon-oxygen bond distances for 17 d(CO)/ OCO/(o) 0.008 0.001 0.085 0.126 0.08 0.10 0.09 0.10 0.11 129.1(2) 126.3(4) 124.9(4) 125.6(5) 123.86(19) 122.86 123.69(19) 123.3(2) 123.8(2) 1.245(3) 1.246(6) 1.308(5) 1.292(7) 1.295(3) 1.307 1.300(3) 1.312(3) 1.321(3)

d(CO)/ d(CO)/

Selected value from one of the three independent sets. b Value from Ref [24].

Conclusions
The cocrystallization of mebendazole with a series of potential pharmaceutically acceptable carboxylic acids has been carried out, yielding two salts of 12 and five solvates of 37. In all of the products, mebendazole and coformers are connected through carboxylic acid (carboxylate)/carbamyl benzimidazole synthon, demonstrating synthon II (Scheme 1) is an efficient hydrogen bonding synthon for the constructions of new crystalline forms of mebendazole. Compounds 1 7 provide new solid forms of mebendazole for improvement of its physical and chemical properties.

PXRD analysis This technique enabled rapid preliminary identification of new crystalline phases produced in the new crystalline form screening experiments. The PXRD patterns of the recrystallization products are different from that of mebendazole (Figure S8), indicating the formation of new crystalline phases. In addition, all the peaks displayed in the measured patterns for 1 6 closely match those in the simulated patterns generated from single-crystal diffraction data (Figure S8), confirming the formation of corresponding salts and solvates. Stoichiometry determination The stoichiometric composition for crystalline forms 16 was determined by thermogravimetric analyses, which presented distinct mass losses due to the release of the respective coformers on heating (Figure S9). In all cases, there is an apparent one-step coformer mass loss, and the percentages are listed in Table S2. The coformer mass loss registered in TGA for 1 was 27.5% in the temperature range of 95197 , corresponding to the degradation of trifluroacetic acid for a 1 1 stoichiometric ratio (calcd value: 27.9%). The TGA weight loss of 2 started at room temperature because of the weak hydrogen bonding interaction of neutral formic acid molecules in the structure. And the total formic acid weight loss is 19.3% in the 38156 temperature range, corresponding to a mebendazole/formic acid composition of 11.5 stoichiometric ratio (calcd value: 18.9%), this is attributed to the fact that 2 is unstable under ambient condition and formic acid molecules
Chin. J. Chem. 2013, 31, 635640

Acknowledgement
This work was supported by 973 Program of China (No. 2012CB821705), and the NSFC (Nos. 20831005, 91127002, 21101173 and 21121061).

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