Pharmaceutical Cocrystals of Diflunisal with Nicotinamide or

Article pubs.acs.org/OPRD

Pharmaceutical Cocrystals of Diflunisal with Nicotinamide or Isonicotinamide Lianyan Wang, Bo Tan, Hailu Zhang,* and Zongwu Deng* Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Suzhou 215123, P.R. China ABSTRACT: In order to improve the solubility of diflunisal (DIF), and hence the oral bioavailability, two 2:1 diflunisal cocrystals were prepared by solution crystallization from ethanol with nicotinamide (NIC) or isonicotinamide (ISO) as coformer. The cocrystals were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), as well as liquid- and solid-state nuclear magnetic resonance (LNMR and SSNMR). PXRD and NMR measurements indicate that the pure 2:1 cocrystals can be obtained even the DIF and coformer started from different ratios (2:1, 1:1 and 1:2). FTIR and 13C SSNMR measurements provide clues about the formation of amide−carboxylic acid heterosynthon and pyridine−carboxylic acid heterosynthon between DIF and coformer. The melting points of DIF-NIC and DIF-ISO cocrystals are 195 and 182 °C respectively, indicating their favorable thermal stability. Meanwhile, the two cocrystals exhibit faster dissolution rates and higher aqueous solubilities than the pure drug compound.

1. INTRODUCTION A cocrystal is defined as a multiple component crystal that consists of two or more solid components (at ambient conditions) in a definite stoichiometric ratio held together via noncovalent interactions.1 It has received increasing attention in the pharmaceutical industry because of the potential to adjust the physicochemical and biological properties of original active pharmaceutical ingredients (APIs),2−4 such as melting point, solubility, bioavailability and chemical stability, etc. Intermolecular interactions between different components provide opportunities for cocrystal synthesis by design through the use of supramolecular synthons,5 such as the pairs of carboxylic acid···carboxylic acid, carboxylic acid···aromatic nitrogen, carboxylic acid···amide, amide···amide, and amide··· aromatic nitrogen, etc. Recently, many efficient and versatile methods of cocrystal synthesis have been developed by skillfully using the supramolecular synthon rule, and the amount of pharmaceutical cocrystals keeps increasing. For some APIs, even dozens of cocrystals have been developed and identified.6 Diflunisal (DIF, Scheme 1a), a difluorphenyl derivative of salicylic acid, is often used as a nonsteroidal anti-inflammatory drug. According to the Biopharmaceutics Classification System (BCS), DIF belongs to class II drugs with low solubility and high permeability.7,8 Thus, there is a practical demand for improving the solubility and therefore the oral bioavailability of DIF. Four polymorphic structures of DIF with different intermolecular hydrogen-bonding interactions have been reported. The carboxylic acid and hydroxyl groups in DIF are considered as the main factors in forming intermolecular hydrogen bonds.9 Since the hydrogen-bonding interactions could be affected by the solvents and cocrystal formers,10 it could be likely to form hydrogen bonds between these active groups with coformers. To our knowledge, only one reference involving the cocrystal of DIF has been reported until now, in which the 1:1 pyrazinamide−diflunisal cocrystal was obtained by thermal activation of the equimolar mortar-ground mixture © XXXX American Chemical Society

Scheme 1. Molecular structures of DIF (a), NIC (b), and ISO (c)

at 80 °C.8 Novel DIF cocrystals with enhanced solubility are still highly interesting and more efforts are demanded. Nicotinamide (NIC, Scheme 1b) and isonicotinamide (ISO, Scheme 1c) are widely used as hydrophilic coformers in the context of cocrystals. For the coformers, the nitrogen atom at the pyridine group can form heterosynthons with APIs through carboxylic acid···pyridine, amide···pyridine, or other interactions, and the amide can also form homosynthons or heterosynthons with the involvement of amide···amide or carboxylic acid···amide moieties.11,12 A number of pharmaceutical cocrystals with NIC or ISO as the cocrystal coformer have been reported in recent literatures, which can be found in 1:1 theophylline−NIC cocrystal,13 1:1 furosemide−NIC cocrystal,14 1:1 carbamazepine−NIC cocrystal,3,5 1:1 benzoic acid− ISO cocrystal and 1:1 niclosamide−ISO cocrystal,15,16 etc. As the existence of the carboxylic acid group in DIF, DIF−NIC Received: July 8, 2013

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dx.doi.org/10.1021/op400182k | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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DE). Approximately 4 mg of sample was hermetically sealed in an aluminum pan and heated from 25 to 250 °C at a scan rate of 10.0 °C/min under nitrogen atmosphere (50 mL/min). 2.3. Dissolution Studies and Saturation Solubility. The dissolution studies were carried out by using a paddle apparatus (RC-6; Tianguang Optical Instruments Co., Ltd., Tianjin, China). Under the water-bath temperature of 37 ± 0.1 °C and the paddle speed of 100 rpm, each sample corresponding to 20 mg of DIF was added to a dissolution vessel containing 900 mL of ultrapure water. At appropriate time intervals, 5 mL of each sample was collected, and an equivalent amount of water was added. After filtration through 0.22 μm polycarbonate filters, the concentration of DIF was assayed by using the Waters HPLC system (Waters 2695, Milford, MA) equipped with a photodiode array detector at 250 nm. The C18 HPLC column (GraceSmart RP C18, 4.6 mm × 250 mm, 5 μm) was used as the stationary phase, acetonitrile and 0.1% trifluoroacetic acid in water were used as the mobile phase A and B, respectively, with a flow rate of 1 mL/min at 30 °C. The gradient elution started with an isocratic elution of 20% mobile phase A for 2 min, followed by a linear gradient increased to 90% mobile phase A in 6 min, an isocratic elution maintained for 5 min, and a final 8 min for equilibration. Each dissolution test was performed in triplicate. Saturation solubility studies of DIF and its cocrystals were carried out in water. Each sample equivalent to 50 mg of DIF was added to the screw-capped test tubes with 10 mL of ultrapure water. The oversaturated suspension was treated at 37 ± 0.5 °C in an incubator shaker rotating at 100 rpm. After 72 h, 2 mL of sample was taken from the solution and filtered through 0.22 μm polycarbonate filter. The concentration of DIF in each filtrate was detected by HPLC with the method mentioned above. Each test was performed in triplicate.

and DIF−ISO cocrystals may be obtained with high possibility via carboxylic acid···pyridine and/or carboxylic acid···amide heterodimers.17 However, whether the cocrystals can be really formed alone with the intermolecular interactions and modified physicochemical properties should be revealed by experimental evidence.

2. EXPERIMENTAL SECTION 2.1. Materials. The DIF of Form I (99.7%) was purchased from Juhua Group Co. Pharmaceutical Factory (Quzhou, China); NIC (≥98.5%) and ethanol (≥99.5%) were purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). ISO of chromatographic grade was purchased from Sigma-Aldrich (Shanghai, China). Ultrapure water was used throughout the experiments. Other chemicals used were of analytical grade and used as received without any further purification. DIF (1 mmol) was dissolved into 4 mL of ethanol in a 15mL glass sample bottle. At room temperature, 2 mL of ethanol solution containing 1 mmol coformer (NIC or ISO) was added into the DIF solution dropwise under magnetic stirring at a speed of 100 rpm. A precipitation occurred after 20−30 min stirring. After 4 h, stirring was stopped. The precipitation was filtrated and then kept in an oven (40 °C) for 10 h under vacuum to remove any residual solvent. Typically, about 150 mg of DIF−NIC and 75 mg of DIF−ISO can be obtained. Similarly, white precipitations were also obtained by starting with 2:1 and 1:2 stoichimetric mixtures of DIF and coformers. 2.2. Characterization. 2.2.1. Powder X-ray Diffraction (PXRD). PXRD measurements were conducted on a PANalytical X’Pert Pro X-ray powder diffractometer (PANalytical B.V., Almelo, Netherlands) equipped with an X’Celerator Real Time Multi-Strip detector. A Cu Kα radiation was used at 45 kV and 40 mA. Samples were scanned in the reflection mode from 3 to 40° 2θ using a scanning step size of 0.0167°. 2.2.2. Solid-State Nuclear Magnetic Resonance (SSNMR). 13 C SSNMR experiments were performed with a 4 mm doubleresonance MAS probe on a Bruker AVANCE III-500 spectrometer (Bruker BioSpin, Karlsruhe, Germany) operating at a magnetic field strength of 11.7 T. A total sideband suppression (TOSS) frame was embedded into the conventional Cross-Polarization (CP) pulse sequence, which was used to acquire the 13C CP/MAS spectra. The Harmann−Hahn conditions of the CP/MAS TOSS experiment were optimized by using adamantane. 13C CP/MAS TOSS NMR spectra were obtained at 8 kHz MAS spinning speed with a 2 ms contact time. Recycle delays for DIF, NIC, ISO, DIF−NIC and DIF− ISO were set as 120, 200, 1200, 60, and 60 s, respectively. The chemical shifts were externally referenced to tetramethylsilane (TMS, 0 ppm). 2.2.3. Liquid Nuclear Magnetic Resonance (LNMR). 1H NMR spectra were acquired on a Varian 400 MHz spectrometer (Varian Inc. Palo Alto, CA) using dimethyl sulfoxide-d6 as solvent with TMS (0 ppm) as internal standard. 2.2.4. Fourier Transform Infrared Spectroscopy (FTIR). FTIR spectra were obtained by using a Thermo-Nicolet 6700 IR spectrometer (Thermo Fisher Scientific, Waltham, MA). All the samples were compressed into disks with KBr and analyzed over the wavenumber range of 400−4000 cm−1 with 100 scans at a resolution of 4 cm−1. 2.2.5. Differential Scanning Calorimetry (DSC). DSC measurements were performed by using a TA Q2000 differential scanning calorimeter (TA Instruments, New Castle,

3. RESULTS AND DISCUSSION 3.1. Formation of the DIF cocrystals. The acid dissociation constant (pKa) is one of the featured physicochemical parameters of small molecules, and the ΔpKa (ΔpKa = pKa (base) − pKa(acid)) between API and coformer is usually used as a criterion to predict the possibility of salt or cocrystal formation although there are some exceptions. When ΔpKa > 3, salt is likely to be formed. By contrast, when in the range 0 < ΔpKa < 3, cocrystals may be formed.14,18 The pKa values of DIF, NIC, and ISO are 2.94, 3.43, and 3.67 respectively,18,19 and the ΔpKa between DIF and NIC (or ISO) is 0.49 (or 0.73), correspondingly. Therefore, DIF has a high potential to form cocrystals with the two coformers. Normally, mechanochemical cocrystallization and solution cocrystallization are the two most commonly used methods in cocrystal preparation.19 Mechanochemical cocrystallization is a very simple and highly efficient technique in cocrystal screening. Jones and co-workers have recently given a systematic overview of advances in understanding the mechanism of this method.20 Meanwhile, solution cocrystallization often offers better sample crystallization degree, and is the most common way to get single crystal sample. In order to check the possibility of cocrystal formation, we first tried the mechanochemical method. One mmol of DIF was ground with 1 mmol NIC (or ISO) in a pestle and mortar for 10 min followed by addition of one drop of alcohol, then the resulting mixture was further ground for 30 min. By such ethanolassisted grinding, the products give obviously different PXRD patterns from the physical mixtures, indicating new phases B



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formed. Then the solution cocrystallization method was used to prepare the cocrystals with better degree of crystallization, and the results are given and discussed in the following text. Figure 1a presents the PXRD patterns of the DIF, NIC, and the DIF−NIC product prepared by solution cocrystallization

Figure 2. 13C CP/MAS TOSS NMR spectra of DIF−NIC (a), DIF− ISO (b) and the raw components.

formation of new phases. At the same time, no extra peaks related to ethanol were detected, which indicates the product is not solvated. The salt formation is also excluded by the inconspicuous values of ΔpKa and the small changes in the chemical shift for the carbonyl peak,15 alone with the existence of featured −COOH vibrations in FTIR spectra (vide infra). Although it is difficult to assign all of the 13C chemical shifts of the cocrystals without the help of 2D correlation spectra, the 13 C signals of carboxylic acid and amide group can be easily identified.21 For the DIF−NIC cocrystal (Figure 2a), 13C chemical shift of the amide group (C1′) is moved form 169.3 to 162.7 ppm. At the same time, the carboxylic acid group carbon (C13) at 175.1 ppm in pure DIF splits into two peaks at 176.9 and 174.1 ppm in the cocrystal. For DIF−ISO cocrystal (Figure 2b), similar results were obtained. The amide group (C1′) of ISO shifts upfield from 169.9 ppm in its pure form to 163.5 ppm in its cocrystal form; the single peak of the carboxylic acid group carbon (C13) in DIF at 175.1 ppm splits into two peaks at 177.6 and 172.3 ppm in its cocrystal form. Both the signal upfield movement of the amide group (C1′) for coformer and the signal splitting of carboxylic acid group (C13) for DIF were observed in two cocrystals as well. The spectral evidence reflects that there are two different kinds of chemical environments around C13, while one around C1′ in each cocrystal unit cell. Furthermore, the intensity of each C13 peak is similar to that of C1′ in the cocrystals. Therefore, we initially suspected that the molar ratio of DIF to coformer in the cocrystals should be 2:1, which was further confirmed by other analytical methods as discussed below. 3.2. Cocrystal Stoichiometry. To confirm the cocrystal stoichiometry, 1H LNMR experiments were performed for

Figure 1. PXRD patterns of DIF-NIC (a), DIF-ISO (b), and the raw components.

with a starting DIF/coformer ratio of 1:1. DIF (top of Figure 1a) shows its characteristic PXRD peaks at 4.1°, 13.3°, 14.4°, 14.7°, 16.6°, and 17.1° 2θ, which is consistent with the reported data for Form I (the most stable form of DIF polymorphs).9 The patterns of NIC (bottom of Figure 1a) is characterized by peaks at 14.8°, 22.2°, 23.4°, 25.4°, 25.8°, and 27.4° 2θ. The DIF−NIC product (middle of Figure 1a) presents the characteristic peaks at 3.2°, 13.2°, 14.1°, 14.8°, 16.4°, 17.2°, 20.9°, 22.5°, and 26.0° 2θ. It clearly shows that the PXRD pattern of DIF−NIC product is distinguishable from the simple overlap of those input components, which indicates the formation of a new solid phase. Starting with different DIF/ NIC ratios (2:1, 1:1 and 1:2), the products show exactly the same PXRD diffractogram. The DIF−ISO product behaves similarly to the DIF−NIC product, where the product is characterized by major peaks at 3.3°, 13.3°, 13.8°, 14.2°, 15.2°, 17.8°, 20.4°, 24.8°, and 25.8° 2θ (Figure 1b), and these peaks are also distinguishable from DIF and ISO. Again, the same PXRD diffractogram could be obtained even if the DIF and ISO started with different ratios of 2:1, 1:1, and 1:2. The 13C CP/MAS TOSS NMR spectra of DIF−NIC and DIF−ISO product together with individual components are presented in Figure 2. The obvious differences between product and input materials in the chemical shifts further indicate the C



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DIF−NIC and DIF−ISO cocrystals. The 1H NMR shows that the spectrum of the cocrystal is the simple overlap of its two components’ spectra, as the polar solvent of DMSO-d6 could destroy the weak intermolecular interactions such as the hydrogen bonds between the two components that exist in solid state. The 1H NMR chemical shift assignments of DIF− NIC and DIF−ISO cocrystals are as follows: DIF−NIC cocrystal: NIC δ 9.03 (dd, C3′-H), 8.70 (dd, C2′-H), 8.21 (ddd, C4′-H), 8.13 (s, C1′-H), 7.50 (ddd, C6′-H); DIF δ .92 (dd, C6-H), δ 7.68 (ddd, C4-H), 7.58 (td, C9-H), 7.35 (ddd, C12-H), 7.18 (m, C11-H), 7.07 (d, C3-H). DIF−ISO cocrystal: ISO 8.72 (dd, C4′-H and C5′-H), 8.19 (s, C1′-H), 7.77 (dd, C3′-H and C6′-H); DIF δ7.92 (dd, C6-H), δ 7.68 (ddd, C4-H), 7.58 (td, C9-H), 7.35 (ddd, C12-H), 7.18 (m, C11-H), 7.07 (d, C3-H). The integrals of the 1H signals marked in Figure 3 clearly indicate the molar ratio of DIF/

our DIF−NIC or DIF−ISO cocrystal, the two types of hydrogen-bonding interactions are expected to coexist in these systems. 3.3. Intermolecular Interactions. The FTIR spectra of DIF, coformers, and cocrystals are presented in Figure 4. The

Figure 4. FTIR spectra of DIF−NIC (a), DIF−ISO (b) and the raw components.

FTIR spectra of cocrystals show obvious differences in the wavenumbers and intensities for some major bands compared to their individual components. For the DIF−NIC cocrystal, the bands assigned to the asymmetric and symmetric stretching vibrations of the −NH2 group at 3367 and 3161 cm−1 in NIC are blue-shifted to 3407 and 3228 cm−1 in the cocrystal, respectively. The CO stretching vibration of carboxylic acid group at 1688 cm−1 in DIF is red-shifted to 1672 cm−1. In addition, the appearance of two new bands at 2525 and 2182 cm−1 is due to the hydrogen-bonding interaction between O− Hcarboxylic acid and Naromatic.27 Similarly for DIF−ISO cocrystal, the asymmetric and symmetric stretching vibrations of the −NH2 are hypsochromic shifted from 3370 and 3187 cm−1 in DIF to 3392 and 3211 cm−1 in the DIF−ISO cocrystal respectively; and a bathochromic shift from 1688 to 1680 cm−1 for CO stretching vibration. The two bands assigned to the hydrogen-bonding interaction between O−Hcarboxylic acid and Naromatic are also observed at 2518 and 2184 cm−1. The existence of carboxylic acid···pyridine synthon in DIF− NIC or DIF−ISO is clearly revealed by FTIR evidence. On the other hand, though the hypsochromic shifts for stretching vibrations of the −NH2 were observed, such variations can not indicate the existence of carboxylic acid···amide synthon, for wavenumber changes of −NH2 were also found in those carboxylic acid···pyridine interacted cocrystals.27 The new

Figure 3. 1H NMR spectra of DIF−NIC (a) and DIF−ISO (b) cocrystals. RI: relative integrals of the 1H signals; NH: the H numbers of each group in one DIF, NIC, or ISO molecule.

coformer should be 2:1 for either of the cocrystals, which is consistent with our initial suspicion from the 13C CP/MAS spectra. The molar ratio of DIF/coformer in each product remains the same as 2:1 regardless the starting ratio (2:1, 1:1, or 1:2). For APIs with carboxylic acid or salicylic acid groups, two types of hydrogen-bonding interactions could be mainly found in their cocrystal with NIC or ISO as mentioned above, that is carboxylic acid···aromatic nitrogen, and carboxylic acid···amide synthons. Mostly, carboxylic acid···pyridine interaction can be favorably formed.21−24 Cocrystals with carboxylic acid···amide synthon or with both of the synthons are relatively less reported.23,25,26 Since the 2:1 stoichiometry was determined for D



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bands at 3352 (Figure 4a) and 3332 cm−1 (Figure 4b) in the cocrystals can be assigned to the intermolecular hydrogenbonding interaction between Ocarboxylic acid and N−Hamide.28 Although such interaction can be also formed in those 1:1 cocrystals with carboxylic acid···pyridine synthon, it is more reasonable to form a carboxylic acid···amide hydrogen-bonding pair in our 2:1 cocrystals. Generally, the repacking of molecules in a different crystal cell often leads to a 13C chemical shift change less than 5 ppm. Thus, the larger 13C chemical shift changes of N bonded carbon atoms (Figure 2), such as C1′ (6.6 ppm), C2′ (6.8 ppm) and C3′ (6.9 ppm) in DIF−NIC, and C1′ (6.4 ppm) in DIF−ISO, should originate from both the changes of molecular arrangement as well as intermolecular interactions, which also show the clues for the existence of the two types of intermolecular hydrogen-bonding interactions in our cocrystals (Scheme 2). Such coexistence of two types of synthons can be also found in 2:1 naproxen−NIC and benzoic acid−ISO cocrystals.22,25 Scheme 2. Carboxylic acid···pyridine (I) and carboxylic acid···amide (II) synthons in DIF−NIC (a) and DIF−ISO (b) cocrystals

Figure 5. DSC thermograms of DIF−NIC (a), DIF−ISO (b) and the raw components.

from the melting peak of the DIF−NIC cocrystal, a small endothermic transition at around 122 °C could be observed when a DIF/NIC starting molar ratio of 1:1 is used. No endothermic peak at this temperature was detected for cocrystal product obtained with a DIF/NIC starting ratio of 2:1, and a more intense peak was detected for the product obtained with a 1:2 starting ratio. Therefore, we believe this peak should be attributed to the endothermic event of a trace amount of NIC encapsulated by the agminated cocrystal product. The thermodynamic behavior of the DIF−ISO cocrystal is similar to that of DIF−NIC cocrystal, with a Tm at 182 °C. Such Tm’s (much higher than room temperature) may ensure the cocrystals have favorable thermal stability during processing and storage. Additionally, no low-temperature endothermic peaks were detected in the two cocrystals, excluding the formation of solvate or hydrate. The aqueous solubility of APIs can also be modified via cocrystal formation.31,32 Figure 6 shows the comparison of the drug dissolution rates of the cocrystals and DIF, as well as their solubilities. Both cocrystals exhibit faster dissolution rates than pure DIF, and their solubilities are respectively achieved at 66 and 128 μg/mL, which are ∼1.5 and 3.0 times of that of DIF, respectively. Pure DIF has a moderate solubility of 47 μg/mL, which may have solubility problems.33 Such possible problems can be fixed by the use of cocrystals, which have a solubility classified as high.33 The 1.5-/3-fold increases in solubility also offer potential choices to reduce the API dosage needed by the patient and, consequently, a high possibility to lower the cost of treatment.

3.4. Thermal and Dissolution Properties. Thermodynamic property of API may be readily modified by cocrystal formation.29 For example, the melting temperature (Tm) of cocrystal is often between the API and the coformer, or below both individual components.30 It is crucial to know and control the thermodynamic parameter of the drug substance since the undesired melting or phase transformation has a significant effect on the stability and processability. In our work, the DSC experiments were conducted to study the thermal behavior of the cocrystals. Figure 5 shows the DSC curves of DIF−NIC and DIF−ISO, and their individual components. An obvious endothermic event of DIF−NIC occurred at 195 °C between the Tm’s of DIF (213 °C) and NIC (129 °C). This thermodynamic property of DIF−NIC indicates that DIF and NIC should be in one substance as a cocrystal form instead of a mixture and the Tm of the cocrystal should be 195 °C. Apart E



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4. CONCLUSIONS In this study, two 2:1 DIF cocrystals were obtained with NIC or ISO by using a solution cocrystallization method. Carboxylic acid−amide and carboxylic acid−pyridine hydrogen bonds are the main intermolecular forces between DIF and the coformer. DIF−NIC and DIF−ISO have Tm’s at 195 and 182 °C, respectively, indicating their favorable thermal stability. In addition, both of the cocrystals show dissolution rates and solubilities more greatly enhanced than those of DIF. This study further confirms that supramolecular synthon approach affords a feasible way to develop new pharmaceutical cocrystals, and cocrystallization offers a valuable way to improve the physicochemical properties of the API. AUTHOR INFORMATION

Corresponding Authors

*Telephone: +86-512-62872713. Fax: +86-512-62603079. Email: [email protected]. *Telephone: +86-512-62872559. Fax: +86-512-62872559. Email: [email protected]. Notes

The authors declare no competing financial interest.

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REFERENCES

(1) ter Horst, J. H.; Deij, M. A.; Cains, P. W. Cryst. Growth Des. 2009, 9, 1531. (2) Rodriguez-Spong, B.; Price, C. P.; Jayasankar, A.; Matzger, A. J.; Rodriguez-Hornedo, N. Adv. Drug Delivery Rev. 2004, 56, 241. (3) Seefeldt, K.; Miller, J.; Alvarez-Nunez, F.; Rodriguez-Hornedo, N. J. Pharm. Sci. 2007, 96, 1147. (4) Kim, S.; Li, Z.; Tseng, Y. C.; Nar, H.; Spinelli, E.; Varsolona, R.; Reeves, J. T.; Lee, H.; Song, J. J.; Smoliga, J.; Yee, N.; Senanayake, C. Org. Process Res. Dev. 2013, 17, 540. (5) Chieng, N.; Hubert, M.; Saville, D.; Rades, T.; Aaltonen, J. Cryst. Growth Des. 2009, 9, 2377. (6) Jayasankar, A.; Reddy, L. S.; Bethune, S. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 889. (7) Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L. Mol. Pharmaceutics 2006, 3, 631. (8) Evora, A. O. L.; Castro, R. A. E.; Maria, T. M. R.; Rosado, M. T. S.; Silva, M. R.; Beja, A. M.; Canotilho, J.; Eusebio, M. E. S. Cryst. Growth Des. 2011, 11, 4780. (9) Martinezoharriz, M. C.; Martin, C.; Goni, M. M.; RodriguezEspinosa, C.; Deilarduya-Apaolaza, M. C. T.; Sanchez, M. J. Pharm. Sci. 1994, 83, 174. (10) Price, S. L. Adv. Drug Delivery Rev. 2004, 56, 301. (11) Hathwar, V. R.; Pal, R.; Row, T. N. G. Cryst. Growth Des. 2010, 10, 3306. (12) Desiraju, G. R. Crystal Engineering: The Design of Organic Solids; Elsevier: Amsterdam and New York, 1989. (13) Lu, J.; Rohani, S. Org. Process Res. Dev. 2009, 13, 1269. (14) Ueto, T.; Takata, N.; Muroyama, N.; Nedu, A.; Sasaki, A.; Tanida, S.; Terada, K. Cryst. Growth Des. 2012, 12, 485. (15) Sanphui, P.; Kumar, S. S.; Nangia, A. Cryst. Growth Des. 2012, 12, 4588. (16) Boyd, S.; Back, K.; Chadwick, K.; Davey, R. J.; Seaton, C. C. J. Pharm. Sci. 2010, 99, 3779. (17) Fabian, L.; Hamill, N.; Eccles, K. S.; Moynihan, H. A.; Maguire, A. R.; McCausland, L.; Lawrence, S. E. Cryst. Growth Des. 2011, 11, 3522. (18) Mohamed, S.; Tocher, D. A.; Vickers, M.; Karamertzanis, P. G.; Price, S. L. Cryst. Growth Des. 2009, 9, 2881. (19) Li, Z.; Yang, B. S.; Jiang, M.; Eriksson, M.; Spinelli, E.; Yee, N.; Senanayake, C. Org. Process Res. Dev. 2009, 13, 1307. (20) Friscic, T.; Jones, W. Cryst. Growth Des. 2009, 9, 1621. (21) Maruyoshi, K.; Iuga, D.; Antzutkin, O. N.; Alhalaweh, A.; Velagad, S. P.; Brown, S. P. Chem. Commun. 2012, 48, 10844. (22) Seaton, C. C.; Parkin, A.; Wilson, C. C.; Blagden, N. Cryst. Growth Des. 2009, 9, 47. (23) Lou, B.; Hu, S. J. Chem. Crystallogr. 2011, 41, 1663. (24) Soares, F. L. F.; Carneiro, R. L. Cryst. Growth Des. 2013, 13, 1510. (25) Ando, S.; Kikuchi, J.; Fujimura, Y.; Ida, Y.; Higashi, K.; Moribe, K.; Yamamoto, K. J. Pharm. Sci. 2012, 101, 3214. (26) Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2012, 14, 8193. (27) Castro, R. A. E.; Ribeiro, J. D. B.; Maria, T. M. R.; Silva, M. R.; Yuste-Vivas, C.; Canotilho, J.; Eusebio, M. E. S. Cryst. Growth Des. 2011, 11, 5396. (28) Chow, S. F.; Chen, M.; Shi, L.; Chow, A. H. L.; Sun, C. C. Pharm. Res. 2012, 29, 1854. (29) Friscic, T.; Jones, W. J. Pharm. Pharmacol. 2010, 62, 1547. (30) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950. (31) Good, D. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 2252. (32) Aakeroy, C. B.; Forbes, S.; Desper, J. J. Am. Chem. Soc. 2009, 9, 17049. (33) Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662.

Figure 6. Dissolution profiles (a) and saturation solubility (b) of DIF, DIF−NIC and DIF−ISO cocrystals in water at 37.0 °C.

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ACKNOWLEDGMENTS

This work was supported by the Natural Science Foundation of China (No. 21205129, 21073226) and Jiangsu Provincial Fund for Natural Sciences (No. BK2012191). The NMR system used in this study was funded through the key scientific equipment plan of the Chinese Academy of Sciences. F


Pharmaceutical Cocrystals of Diflunisal with Nicotinamide or

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