分子间作用力构筑的具有柔性结构的醋氯芬酸多聚物：晶体结构，热稳定性，溶解度和DFT计算

孙盼盼　刘翔宇　孙　琳　张　盛　魏　青尹　琰　杨　奇　陈三平（西北大学化学与材料科学学院，合成与天然功能分子化学教育部重点实验室，西安70069；宁夏大学化学化工学院，银川7500）

分子间作用力构筑的具有柔性结构的醋氯芬酸多聚物：晶体结构，热稳定性，溶解度和DFT计算

孙盼盼1，#刘翔宇1，2，#孙琳2张盛1魏青1，*尹琰1杨奇1陈三平1，*
（1西北大学化学与材料科学学院，合成与天然功能分子化学教育部重点实验室，西安710069；2宁夏大学化学化工学院，银川750021）

非甾体类抗炎药物醋氯芬酸（ACF）的水溶性差，导致其生物利用度较低.本文制备了三种多聚物，分别是醋氯芬酸与4，4Ȣ-联吡啶（BIPY）共晶（1），与3-氨基苯甲酸（3-ABA）盐（2）和与二甲基亚砜（DMSO）的溶剂化物（3），利用红外光谱、粉末X射线衍射和单晶X射线衍射对它们的结构进行了表征.结果表明，化合物1-3的超分子结构是通过氢键、C―H…π和π…π堆积作用构筑而成，三个多聚物具有良好的热稳定性.从热力学角度分析和密度泛函理论（DFT）计算说明ACF在化合物3中的构象比其在化合物1和2中更稳定.此外，ACF形成共晶、盐和溶剂化物后有效提高了其溶解度.

醋氯芬酸；多聚物；热稳定性；密度泛函理论；溶解度

www.whxb.pku.edu.cn

1　lntroduction

The solubility and bioavailability of drugs are the critical factors for the development of pharmaceutical industry.1-3In many cases，some active pharmaceutical ingredients（APIs）cannot be used as drug candidates due to their poor solubility and，consequently，inefficient bioavailability.4Thus，it is a great challenge to enhance the solubility without compromising the stability and other performance characteristics in the product development of drugs.5-11A number of crystallized solid-state forms improve physicochemical properties of drug substances，including polymorphs，12amorphous，13hydrates，14solvates，15and salts16.For example，salts are the most preferred formulation for improving the solubility of APIs，17which can only be formed for acidic or basic APIs.18Compared with the method above，cocrystals have been recently performed as a pharmaceutical development for neutral drug19and have gotten extensive attention in pharmaceutical science.20Pharmaceutical cocrystals are defined as structurally homogeneous crystalline materials comprising API and pharmaceutically acceptable cocrystal formers which are solids at room temperature.21The components of cocrystal are connected by noncovalent intermolecular interactions，such as hydrogen bonding，22，23halogen bonding，24π…π stacking，25，26and other noncovalent interactions.27-29Moreover，cocrystals have also been documented to be effective for improving the physicochemical properties of API，such as melting point，30photosensitivity，31dissolution behavior，and bioavailability.32

Aceclofenac（ACF，Scheme 1）performs diverse conformations in multiple component compounds，33which is the nonsteroidal anti-inflammatory drug（NSAID）derived from N-phenylanthranilic acid.It has remarkable anti-inflammatory，analgesic，antipyretic properties and a reduced level of gastrointestinal damage compared to some other anti-inflammatory drugs.34，35However，ACF is a biopharmaceutics classification system（BCS）class II drug with poor water solubility of 0.058 μg·mL-1.36Therefore，it is very necessary to improve the solubility and bioavailability of ACF through the method of multi-component forms in the development of new dosage forms.In 2008，Mutalik et al.37reported the chitosan-based solvent change approach to enhance the dissolution rate and bioavailability of aceclofenac.In 2011，Maulvi et al.38reported the solid dispersion technique to improve the dissolution rate ofACF.In 2013，Nangia et al.33reported four salts of ACF with piperazine，cytosine，L-lysine，and γ-aminobutyric acid，a salt hydrate with piperazine and a cocrystal hydrate with 4，4'-bipyridine.The same year，Saxena and Kuchekar39published three aceclofenac sodium saccharin PVPK-30 cocrystals.The research results show that ACF molecule integrating with appropriate coformers forming multi-components would effectively improve the solubility and bioavailability of the drug target. Pharmaceutically，dimethyl sulfoxide（DMSO）has anti-inflammatory analgesic effect and strong permeability，4，4'-bipyridine （BIPY）and 3-aminobenzoic acid（3-ABA）are acceptable coformers31，33（Scheme 1）.

With this in mind，we report the preparation of three multicomponent forms，cocrystal of ACF with BIPY（1），salt of ACF with 3-ABA（2），and solvate ofACF with DMSO（3）.The structures of the three compounds are investigated by single-crystal X-ray diffraction（XRD）and density functional theory（DFT）calculation.The different conformations of ACF are also proved by DFT calculation.Additionally，the dissolutions of compounds 1-3 and ACF are investigated and compared as well.

Scheme 1　Structural formulae of aceclofenac and cocrystal formers

2　Experimental

2.1Chemicals

All solvents and chemicals were obtained from commercial sources and used without further purification unless otherwise stated.Aceclofenac（99.9%）was purchased from Xi'an Haixin Pharmaceutical Co.，Ltd.4，4'-Bipyridine（99.2%）and 3-aminobenzoic acid（99%）were purchased from Sigma-Aldrich.Dimethyl sulfoxide（99.5%），absolute ethanol（99.7%），methanol （99.5%），and acetonitrile（99.9%）were purchased from Xi'an Chemblossom Pharmaceutical Technology Co.，Ltd.

2.2Preparation of compounds 1-3

2.2.1ACF-0.5BIPY cocrystal（1）

Amixture ofACF（35.4 mg，0.1 mmol）and BIPY（15.6 mg，0.1 mmol）was dissolved in 7 mL of absolute ethanol and allowed to stir for 1 h at room temperature，and then the resulting solution was left to evaporate at room temperature.After 7 days，blockshaped yellow crystals of 1 were obtained in 70%yield.Anal.（%）Calcd.for C21H17Cl2N2O4（432.27）：C，58.35；H，3.96；N，6.48. Found：C，58.37；H，3.99；N，6.51.

2.2.2ACF-3-ABAsalt（2）

ACF（35.4 mg，0.1 mmol）and 3-ABA（13.7 mg，0.1 mmol）were dissolved in 7 mL of a 1：1 mixture of methanol and acetonitrile and left to slowly evaporate at room temperature.15 days later，colorless crystals of 2 were harvested in 85%yield.Anal.（%）Calcd.for C23H20Cl2N2O6（491.31）：C，56.23；H，4.10；N，5.70. Found：C，56.25；H，4.13；N，5.73.

2.2.3ACF-DMSO solvate（3）

ACF（35.4 mg，0.1 mmol）was dissolved in 5 mL of a 3：1 mixture of DMSO and water and left to slowly evaporate at room temperature.7 days later，plate-shaped colorless crystals of 3 were harvested in 90%yield.Anal.（%）Calcd.for C18H19Cl2NO5S （432.30）：C，50.01；H，4.43；N，3.24.Found：C，50.04；H，4，46；N，3.27.

2.3Single crystal X-ray diffraction

The single-crystal X-ray diffraction data of the crystals were collected on a Bruker Smart Apex charge-coupled-device（CCD）diffractometer equipped with graphite monochromatized Mo Kαradiation（λ=0.071073 nm）using ω and φ scan modes.The structures were solved by the direct methods using the SHELXS-9740and refined by means of full-matrix least-squares procedures on F2with SHELXL-97 program41.All non-hydrogen atoms were refined with anisotropic displacement parameters，and hydrogen atoms were placed in calculated positions and constrained to ride on their parent atoms.Selected crystallographic data and structural refinement details of 1-3 are summarized in Table 1.The hydrogen bonding distances and angles are listed in Table S1（in Supporting Information）.Oak ridge thermal ellipsoid plot（ORTEP）diagrams at 50%probability level for the compounds 1-3 are displayed in Fig.S1（in Supporting Information）.

2.4Dissolution study

The solubility studies forACF and compounds 1-3 in 25%（φ）ethanol-water medium were carried out with a Shimadzu UV-2450 spectrophotometer，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.Then，excess amounts（50 mg）of the samples were dipped into 5 mLof 25%ethanol-water medium in a 10 mLvial at 37°C，and the slurries were stirred continuously with magnetic stirrer （RCT，Germany IKA company）at a rate of 600 r·min-1.At each time interval an aliquot of the slurry was withdrawn from the vial and filtered through a 0.2 μm nylon filter.And appropriate dilutions were made to maintain absorbance readings within the standard curve.The resulting solution was measured with a UV/ V is spectrophotometer.After the dissolution experiment，the remaining solids were collected by filtration，dried and analyzed by powder X-ray diffraction（PXRD）.

Table 1　Crystal data and structure refinement for compounds 1-3

2.5Physical measurements

PXRD data were collected on a Bruker D8 ADVANCE diffractometer（Germany）.Experimental conditions：Cu-Kαradiation （λ=0.15406 nm），40 kV，40 mA，scanning interval 5°-50°（2θ）at a scan rate of 1（°）·min-1.Fourier transform infrared（FTIR）spectroscopy was performed on a Bruker Vector-33 Fourier transform infrared spectrometer（Bruker Spectrospin，Karlsruhe，Germany）with spectrum range of 4000-500 cm-1.IR spectra were recorded on samples dispersed in KBr pellets.Differential scanning calorimetry（DSC）and thermogravimetric analysis （TGA）were performed on a Netzsch STA 449C instrument （Germany）and a CDR-4P thermal analyzer of Shanghai Balance Instrument factory，respectively.The temperature range for the heating curve was 30-600°C，and the sample was heated at a rate of 10°C·min-1under a dry oxygen-free nitrogen atmosphere. Elemental analyses were performed on a Vario EL III fully automated trace element analyzer（USA）.

2.6DFT calculation

DFT calculation was carried out using X-ray crystallographic parameters of compounds 1-3.A Gaussian 03W package42was run on a personal computer.The geometric optimization and the frequency analyses were carried out using B3LYP43functional analyses with the 6-31+G（d）44basis set without any restraints.All of the optimized structures were characterized to be true local energy minima on the potential energy surface without imaginary frequencies.

3　Results and discussion

3.1Structure description

3.1.1ACF-0.5BIPY cocrystal（1）

The crystal structure of compound 1 crystallizes in the triclinic space group P1 with one molecule ofACF and a half molecule of BIPY in the asymmetric unit（Fig.1（a））.The ACF and BIPY molecules are linked together by O4―H4…N2（DO4…N2=0.25963 （25）nm）hydrogen bond to form a three component adduct observed in knownACF-BIPY-hydrate as reported in Ref.33，whichis further stabilized through numerous π…π（distance of 0.39236 （9）nm）interactions to form an infinite one-dimensional（1D）chain（Fig.1（b））.The adjacent chains are further connected by the interchain C―H…π（distance of 0.38939（8）nm）interactions from pyridine C―H and chlorophenyl ring，generating a two-dimensional（2D）layer（Fig.1（c））.Finally，the three-dimensional（3D）supramolecular structure of 1 is stacked by several 2D layers （Fig.1（d））.While in ACF-BIPY-hydrate，Cl…O hydrogen bonds exist inACF molecules and water molecules，acting as bridges to connectACF molecules between adjacent layers.

3.1.2ACF-3-ABAsalt（2）

The compound crystallizes in the triclinic space group P1，the asymmetric unit contains one ACF molecule and one 3-ABA molecule（Fig.2（a））.As shown in Fig.2（a），the proton transfer occurs in the compound from carboxyl group ofACF to the N―H base of 3-ABA，and eachACF molecule interacts with five 3-ABA cations via four types of hydrogen bonds of N1―H1B…O6#1（DN1…O6=0.2921（6）nm），N1―H1B…O6#2（DN1…O6=0.2822 （6）nm），N1―H1C…O5（DN1…O5=0.2924（7）nm），O2―H2A…O5 （DO2…O5=0.2647（6）nm）（Fig.2（b））.The combination of two 3-ABA cations produces one dimer through N1―H1A…O1（DN1…O1= 0.2924（7）nm）hydrogen bonds in the R22（14）ring motif（Fig.2（c））. Adjacent dimers are bridged by ACF molecules with the intermolecular hydrogen bonds of O2―H2A…O5 and N1―H1B…O6 to generate the 2D layer（Fig.2（d））.Adjacent layers are further linked through interchain hydrogen bonds N1―H1C…O5 to form the 3D supramolecular network of 2（Fig.2（e））.

3.1.3ACF-DMSO solvate（3）

The asymmetric unit of compound 3 contains oneACF molecule and one DMSO molecule.As shown in Fig.3（a），the hydrogen bonds of O4―H4…O5（DO4…O5=0.2608（5）nm）and O4―H4…S1（DO4…S1=0.3616（4）nm）connect ACF molecule and DMSO molecule.The molecular units connect to each other by means of C―H…πinteractions（distance of 0.34913（1）nm），presenting an infinite one-dimensional（1D）chain（Fig.3（b））.The interchain C―H…πinteractions（distance of 0.35561（7）nm）integrate the 1D chains to yield 2D layer-like structure（Fig.3（c））.Finally，the 3D supramolecular network of 3 is formed by the combination of countless 2D layers（Fig.3（d））.

3.1.4Summaries of structures

According to reported previously，the carboxylate anion in salt displays two close D（C―O）values（ΔD（C―O）≤0.003 nm），while the neutral carboxyl group in cocrystal exhibits two different D（C―O）values（ΔD（C―O）＞0.008 nm）.41，45-47The ΔD（C―O）values are 0.0126 nm for 1 and 0.0125 nm for 3，conforming that 1 is cocrystal and 3 is solvate（Table S2，in Supporting Information）.A relatively small ΔD（C―O）value of 0.0043 nm suggests that compound 2 is salt.As shown in Figs.1-3，the ACF molecules in the three compounds display intramolecular hydrogen bonds of N―H…O（C=O of ester group）or N―H…O（C―O of ester group）for compounds 1-3，the distances of O…N are 0.2935，0.3063，and 0.2946 nm，and the angles of N―H…O are 150°，140°，and 130°，respectively.ACF molecules connect with BIPY and DMSO through O―H…N and O―H…S hydrogen bonds in compounds 1 and 3，respectively，while connect with 3-ABA through O―H…O and N―H…O hydrogen bonds in compound 2.In addition，the weak C―H…πinteraction exists in compounds 1 and 3.

Fig.1　（a）Asymmetric unit of compound 1 showing the part of atom-numbering scheme and intermolecular hydrogen bonds （shown as dashed lines）；（b）1D chain of 1；（c）2D layer of 1；（d）3D structure of 1

Fig.2　（a）Asymmetric unit of compound 2 showing the part of atom-numbering scheme and intermolecular hydrogen bonds（shown as dashed lines）；（b）the hydrogen bond modes ofACF；（c）dimer R22（14）ring motif between two 3-ABAcations；（d）2D layer of 2；（e）3D structure of 2

Fig.3　（a）Asymmetric unit of compound 3 showing the part of atom-numbering scheme and intermolecular hydrogen bonds （shown as dashed lines）；（b）1D chain of 3；（c）2D structure of 3；（d）3D structure of 3

3.2Optimized structure with DFT

The isolated molecules of the compounds are selected as the initial structure，the DFT-B3LYP/6-31+G（d）method is used to optimize the structure of the compounds and compute their frequencies.Vibration analysis indicates that the optimized structures are in accordance with the minimum points on the potential en-ergy planes，which means no virtual frequencies，confirming that the optimized structures are stable，as shown in Fig.4.Obviously，the optimized structures have a good agreement with the measured one.Besides，the calculated distances of intramolecular hydrogen bond O…N are 0.2956，0.2971，and 0.2958 nm，and the angles of N―H…O are 146.77°，146.60°，and 142.23°for 1-3，respectively，which match with the measured value.This indicates that the method of DFT-B3LYP/6-31+G（d）is appropriate to carry out relevant study.The energies of compounds 1-3 are calculated as-2388.601080，-2369.372531，and-2446.491928 hartree，respectively.Thermodynamically，it is obvious that compound 3 is more stable than the other two compounds，as shown in Fig.5.

Fig.4　Optimized structures of compounds（a）1，（b）2，and（c）3 using DFT calculation

Fig.5　Energies of compounds 1-3

3.3Conformational analysis with DFT for ACF

According to the structural analysis above，it is demonstrated that ACF consists of N-2，6-dichlorophenyl and N-phenylacetyloxyacetic acid groups，and is conformationally flexible molecule stems from the rotation at C―N and CH2―COO moieties（Fig.6 （a）round box）.The flexible conformation in ACF is determined by the following four torsion angles（atoms numbering corresponds to Fig.6（b）），（i）C（3）N（1）C（7）C（8），the angle characterizes the flip of the N-2，6-dichlorophenyl ring along the axis of the N（1）―C（7）bond；（ii）C（4）C（13）C（14）O（4），the angle characterizes the rotation of the CO2CH2COOH fragment along the C（13）―C（14）bond；（iii）C（15）O（3）C（14）O（4），the angle characterizes the twist of the OCH2COOH fragment along the O（3）―C（14）bond；（iv）O（3）C（15）C（16）O（1），the angle characterizes the twist of the carboxyl group along the C（15）―C（16）bond.The selected torsion angles for compounds 1-3 are listed in Table S3（in Supporting Information）.First，the aryl rings are twisted at certain angle to relieve steric hindrance of ortho-substituted phenyls at the secondary amine，the dihedral angles between the two ring planes are 74.18°，73.18°，and 58.86°separately for compounds 1-3，as indicated in Fig.6（a）.Noteworthily，the CO2CH2COOH fragment of ACF in compound 2 rotates a larger angle along the C（13）―C（14）bond than the angles in other two compounds，thereby，ACF molecules with various conformations show two types of intramolecular hydrogen bonds of N―H…O in the three compounds.

Fig.6　（a）Overlaid conformations ofACF molecule in the compounds 1-3 and（b）numbering scheme used for the analysis of torsion angles

In order to analyze the conformations of ACF definitely，DFT method has been used to optimize the conformations of ACF and calculate the frequencies.Vibrational analysis indicates that the optimized conformations are in accordance with the minimum points on the potential energy planes，proving that the three conformations of ACF are reliable.Thermodynamically，the energies of the three conformations of ACF in 1-3 are calculated to be-1893.365358，-1893.365644，and-1893.366412 hartree，respectively.It indicates that the third conformation ofACF is themost stable form，corresponding to the compound 3 with the most stable structures.

3.4Powder X-ray diffraction analyses

Powder X-ray diffraction is introduced to demonstrate the formation of new phases and the purity of the bulk phase.As a result，the patterns of the products are different from the starting materials and match with the PXRD patterns simulated from the crystal structure data，indicating the formation of new phases and qualified purity of the bulk phase（Fig.7）.

3.5FTlR analysis

Vibrational spectroscopy is a reliable technique to characterize hydrogen bonding and crystal packing in the solid state.48IR spectra of compounds 1-3 show clear differences compared to the pure component，as shown in Fig.S2（in Supporting Information）. The IR spectrum of ACF exhibits peaks at 1768 cm-1for the carboxylic carbonyl stretching vibration，at 1715 cm-1for the ester function，and at 3324 cm-1for vibrations of the amine functional. The stretches of C―O bond and bend of O―H bond appear at 1259 and 1431 cm-1，respectively.33In compounds 1 and 3，the N―H stretching frequencies red shift to 3302 and 3293 cm-1，respectively.Due to the hydrogen bonding between BIPY molecule and the acid group in ACF，the C=N stretching in BIPY shifts from 1409 to 1416 cm-1in compound 1.Similarly，the S=O stretching in DMSO shifts from 1663 to 1715 cm-1in compound 3.In compound 2，two strong peaks at 3368 and 3218 cm-1correspond to amine group and a broad peak around 2900 cm-1belongs to hydroxyl group.Comparing with the 3-ABA monomer，a red shift emerges in the curve of compound 2 resulting from the formations of hydrogen bonds between 3-ABA and ACF.Additionally，the carboxylate anions in compound 2 show two symmetric stretching vibrations at 1452 and 1267 cm-1.

Fig.7　PXRD patterns ofACF，BIPY，as-synthesized，and simulated from the single-crystal data for（a）1，（b）2，and（c）3

3.6Thermal analysis

The first information about the existence of new solid phases is obtained from the change of the melting points between compounds and the start materials.As shown in Fig.8，the first endothermic peaks in the DSC curves of compounds 1-3 correspond to the processes of melt，the melting points of 1-3 and the starting materials are listed in Table 2.The specific melting or decomposition tendencies are shown as endothermic or exothermic peaks in the DSC curves.We do not notice any relationship between the melting points of the coformers and corresponding multi-component forms，similar to previous cocrystal systems.33，49

The TGA measurements indicate that the ACF decomposes at the temperature of 155°C（Fig.8（a））.The weight losses for compounds 1 and 2 initiate at approximately 171 and 159°C （Fig.8（b，c）），respectively，while compound 3 starts from about 134°C due to the release of DMSO molecule and the carboxylate group inACF molecule（Fig.8（d））.

3.7Solubility and dissolution study

Dissolution rate and apparent solubility of solids are of crucial factor in pharmaceutical development and quality control，and shorter dissolution times and higher apparent solubility may lead to more absorption.The solubility of compounds 1-3 was performed in 25%ethanol-water medium because the concentration of ACF in pure water is very low，33the powder dissolution curves are shown in Fig.9.It can be found that the three compounds display an increase in the dissolution rates and solubility values compared to ACF.Compound 1 appears the maximum solubility after 90 min，while compound 2，3 and ACF reach the maximum solubility within 30 min，and then decrease over the time.This particular model of the solubility is a product derived from the “spring and parachute effect”which has been exhibited in a number of pharmaceutical cocrystals.15，50The maximum solubility values of compounds 1-3 are approximately 2.9，2.4，and 3.4 times as large as that of ACF，respectively，which is close to that of ACF-PIP-hydrate reported inNangiaʹsgroup work33，and it follws othe order of 3＞1＞2＞ACF，demonstrating that the solubility ofAPI can be increased through the multi-component forms.After the dissolution experiments，the undissolved solids are filtered，dried，and characterized by PXRD analysis.It is observed that compound 1 maintains the original component，while the residues of compounds 2 and 3 are determined as ACF due to the dissolution of 2 and 3（Fig.S3，in Supporting Information）.

Fig.8　DSC and TGAcurves of（a）ACF，（b）1，（c）2，（d）3

Fig.9　Powder dissolution profiles forACF and compounds 1-3

Table 2　Melting points for compounds 1-3 and the starting materials

4　Conclusions

The cocrystal，salt，and solvate of ACF are obtained，of which the supramolecular structures are constructed through a numerous of intermolecular interactions.Three types of conformations of ACF exist in 1-3，respectively，and the most stable conformation locates in 3 which possesses the most stable structure in the three compounds，which is verified by DFT calculation.The results of DSC-TGA indicate that the compounds 1-3 exhibit good thermolstabilities，and the melting points of 1-3 are different from those of starting materials.In addition，the solubility of ACF has been increased after the formation of compounds 1-3，indicating that the solubility and bioavailability ofACF can be improved via cocrystal，salt，and solvate.Obviously，the construction of multicomponent forms can be a viable strategy for improving the physicochemical properties ofAPI.

Supporting lnformation：Hydrogen bonding distances and angles（Table S1），ΔD（C―O）of the C―O bond lengths （Table S2），torsion angles（Table S3），ORTEP diagrams（Fig. S1），IR spectra（Fig.S2），PXRD patterns before and after dissolution experiments（Fig.S3），and X-ray crystallographic data for 1-3 in CIF format have been included.This information is available free of charge via the internet at http：//www.whxb. pku.edu.cn.CCDC numbers for 1-3 are 1000083，988514，and 988511，respectively.These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_request/cif.

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lntermolecular lnteraction lnduced Multi-Polymers of Aceclofenac with Flexible Conformation：Crystal Structure，Thermostability，Solubility and DFT Calculations

SUN Pan-Pan1，#LIU Xiang-Yu1，2，#SUN Lin2ZHANG Sheng1WEI Qing1，*
YIN Yan1YANG Qi1CHEN San-Ping1，*
（1Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education，College of Chemistry and Materials Science，Northwest University，Xiʹan710069，P.R.China；
2School of Chemistry and Chemical Engineering，Ningxia University，Yinchuan 750021，P.R.China）

The non-steroidal anti-inflammatory drug aceclofenac（ACF）has low bioavailability because of its poor water solubility.To enhance its water solubility we synthesized three compounds：a co-crystal of ACF-0.5BIPY（4，4'-bipyridine）（1），a salt of ACF-3-ABA（3-aminobenzoic acid）（2），and a solvate of ACF-DMSO （dimethyl sulfoxide）（3）.These compounds were characterized by infrared spectroscopy，powder and single crystal X-ray diffractions.The supramolecular structures of 1-3 are sustained by hydrogen bonding C―H…π and π…π stacking interactions and they have favorable thermal stabilities.Thermodynamically，DFT calculations revealed that the most stable conformation ofACF exists in compound 3 and this structure is more stable than 1 and 2.Furthermore，upon the formations of the co-crystal，the salt or the solvate the solubility ofACF improves significantly.

October 30，2014；Revised：December 22，2014；Published on Web：December 23，2014.

Aceclofenac；Multi-polymer；Thermostability；Density functional theory；Solubility

O641

10.3866/PKU.WHXB201412231

#These authors contributed equally to this work.

The project was supported by the National Natural Science Foundation of China（21373162，21463020，21073142，21173168）and Natural Science Foundation of Shaanxi Province，China（11JS110，2013JM2002，SJ08B09）.

国家自然科学基金（21373162，21463020，21073142，21173168）和陕西自然科学基金（11JS110，2013JM2002，SJ08B09）资助项目

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