Pyrazinamide-Diflunisal - American Chemical Society

ARTICLE pubs.acs.org/crystal

Pyrazinamide-Diflunisal: A New Dual-Drug Co-Crystal vora,† Ricardo A. E. Castro,‡ Teresa M. R. Maria,† Mario T. S. Rosado,† M. Ramos Silva,# Antonio O. L. E # A. Matos Beja, Jo~ao Canotilho,*,‡ and M. Ermelinda S. Eusebio*,† †

Department of Chemistry, ‡Faculty of Pharmacy, and #CEMDRX, Department of Physics, University of Coimbra, Portugal

bS Supporting Information ABSTRACT: A 1:1 co-crystal involving pyrazinamide, one of the first-line drugs recommended by the World Health Organization for tuberculosis treatment, and diflunisal, a nonsteroidal anti-inflammatory substance, has been synthesized for the first time. From a combination drug perspective, this is an interesting pharmaceutical co-crystal because of the known side effects of pyrazinamide therapy. Preliminary studies by computational methods on the relative stability of homodimers versus the two probable heterodimers indicated differences that could easily be overcome by the network of intermolecular interactions in a possible co-crystal structure. The co-crystal synthesis was first attempted by manually grinding equimolar mixtures. This procedure yields a physical mixture of the components, whose differential scanning calorimetry (DSC) curve indicates possible conditions for generating the co-crystal. The pyrazinamide-diflunisal co-crystal can be obtained from an equimolar mortar ground mixture by thermal activation at T = 80 C. The co-crystal synthesis was also successfully achieved from equimolar mixtures by two other methods: ethanol-assisted ball mill grinding and room temperature annealing of a low crystalline mixture obtained by neat ball mill grinding. The new species was characterized by DSC (Tfus = (147.4 ( 0.2) C, which lies between those of the pure components), polarized light thermal microscopy, X-ray powder diffraction, and Fourier transform infrared spectroscopy. The infrared spectra show evidence of pyridine-acid association.

’ INTRODUCTION Pharmaceutical co-crystals — crystalline adducts comprising an active pharmaceutical ingredient (API) and a co-crystal former — have recently emerged as an innovative strategy to improve the performance of medicines by modifying their physical properties without changing any covalent bonds in either of the species.14 The co-crystal former may be another API or, if not, it should ideally be a generally recognized as safe (GRAS) substance.5 As co-crystals represent unique solid forms of the parent APIs with different physical and chemical properties, multi-API co-crystals are also potential solid forms for the delivery of combination drugs that can be tested to overcome problems associated with traditional combination drugs.6 Another obvious benefit of a multi-API co-crystal is the improvement of patient’s long-term medication compliance in long-term drug therapy, since fewer pills need to be taken.7,8 The work presented here involves investigation of co-crystal formation between pyrazinamide (PZA), Figure 1a, an antituberculosis drug, and diflunisal (DFL), Figure 1b, a nonsteroidal anti-inflammatory compound (NSAID), which belongs to class II of the Biopharmaceutical Classification System (low aqueous solubility, high membrane permeability, as most NSAIDs).9 Tuberculosis is a global pandemic with a huge number of new cases every year,10,11 and pyrazinamide is one of the first-line drugs recommended by the World Health Organization for treatment of the disease.12 However, it is reported that in up to r 2011 American Chemical Society

Figure 1. (a) Pyrazinamide and (b) diflunisal molecular structures.

40% of the patients, nongouty polyarthralgia is observed as a sideeffect, with aspirin or an NSAID being the prophylaxis adopted.10,12 The synthesis of a pyrazinamide-diflunisal co-crystal therefore represents an attractive alternative, which has the potential for development of combination drug therapy formulations. In this work, a first insight on the feasibility of co-crystal formation between diflunisal and pyrazinamide is addressed by computational quantum chemistry methods applied to homodimers found in the API crystalline structures and to hypothetical heterodimers. Different experimental approaches have been attempted for Received: March 7, 2011 Revised: September 16, 2011 Published: September 20, 2011 4780

dx.doi.org/10.1021/cg200288b | Cryst. Growth Des. 2011, 11, 4780–4788

Crystal Growth & Design

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Scheme 1. Isodesmic Reactions for the Calculation of the Relative Stability of the Heterodimers vs Homodimers. (a) Acid-Amide Heterosynthon; (b) Acid-Pyridine Heterosynthon.

Table 1. B3LYP/aug-cc-pVDZ Energies of Diflunisal and Pyrazinamide Homodimers and Heterodimersa symmetry

a

E0/ (kJ mol1)

H298 K/ (kJ mol1)

G298 K/ (kJ mol1)

1850.370

4857172

4857091

4857343

865.664

2272252

2272208

2272373

C1(2)

1358.019

3564717

3564654

3564863

C1(2)

1358.008

3564691

3564627

3564842

(degeneracy)

Eelec/Eh

DFL homodimer

Ci(1)

PZA homodimer

Ci(1)

DFL-PZA acid-amide DFL-PZA acid-pyridine

Eelec: electronic energy; E0: Eelec + zero point vibrational energy; H298 K: enthalpy at 298 K; G298 K: Gibbs energy at 298 K.

the co-crystal synthesis and their results interpreted using a combination of differential scanning calorimetry (DSC), polarized light thermal microscopy (PLTM), X-ray powder diffraction (XRPD), and infrared spectroscopy (FTIR).

’ EXPERIMENTAL PROCEDURES Materials. Diflunisal was acquired from Sigma-Aldrich and pyrazinamide from Fluka, with specified purity greater than 99% (N). Both compounds were used as received. Analytical grade solvents were employed in the crystallization from solution experiments. Computational Methods. All DFT calculations were carried out at the B3LYP/aug-cc-pVDZ level.1317 Starting geometries of PZA and DFL homodimers were extracted from their crystalline X-ray diffraction structures. Starting geometries were constructed from the molecular species found in the same crystals for two hypothetical heterodimers containing DFL and PZA, considering both acid-amide and acidpyridine synthons, as these are the supramolecular units expected in the new structures.3 The full geometry optimization for all supramolecular species was followed by calculation of vibrational frequencies at the same level of theory to elucidate the nature of the stationary points and to allow the calculation of Gibbs energies at room temperature. The calculations were performed using the GAMESS 12 JAN2009 (R3) software18 running in a Linux-based cluster of six commodity PCs. Co-Crystal Synthesis. Co-crystallization was attempted from equimolar amounts of diflunisal and pyrazinamide, both by grinding and by crystallization from solutions. Grinding experiments were carried out manually in an agate mortar using 0.05 mmol of each compound and no solvent. Mortar-ground solid

mixtures were also annealed at different temperatures, for various periods of time. A Retsch MM400 mill was also used: 0.25 mmol of each substance was ground in a 10 mL stainless steel jar for 30 min at 15 Hz frequency, with two stainless steel 7 mm diameter grinding balls. The experiments were carried out under two different conditions: without added solvent or with the addition of 10 μL of ethanol. In the solution crystallization experiments, ethyl acetate, tetrahydrofuran, ethanol, methanol, ethyl acetate-ethanol (1:1 v/v), isopropanol were used as solvents. The original materials (0.05 mmol of each API) were dissolved in 6 mL of the solvent, at room temperature, the solutions were filtered to a Petri dish, and the solvent was evaporated at room temperature (ca. 20 C). Additional experiments were performed with the same solution composition, by slow evaporation at ca. 20 C (until a solid phase was obtained) from ethanol and ethyl acetate, the solvents that produced the least contaminated co-crystal in the previous experiments. X-ray Powder Diffraction (XRPD). A glass capillary was filled with the powder obtained by grinding the solids. The samples were mounted on an ENRAF-NONIUS powder diffractometer (equipped with a CPS120 detector by INEL) and data were collected for 5 h using DebyeScherrer geometry. Cu Kα1 radiation was used (λ = 1.540598 Å). Silicon was chosen as an external calibrant. Infrared Spectroscopy (FTIR). The infrared spectra of the solids in KBr pellets were recorded at room temperature using a FTIR spectrometer, ThermoNicolet IR300, at 1 cm1 resolution. Polarized Light Thermal Microscopy (PLTM). The solids obtained were characterized by PLTM using a hot stage Linkam system, model DSC600, with a Leica DMRB microscope and a Sony CCD-IRIS/ RGB video camera. Real Time Video Measurement System software by 4781

dx.doi.org/10.1021/cg200288b |Cryst. Growth Des. 2011, 11, 4780–4788


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Figure 2. Infrared spectra: (1) Mortar ground equimolar diflunisal-I + pyrazinamide-α mixture; (2) diflunisal, polymorph I; (3) pyrazinamide, polymorph α.

Figure 3. Experimental X-ray powder diffraction spectra: (1) Mortar ground equimolar diflunisal-I + pyrazinamide-α mixture; (2) diflunisal, polymorph I;21 (3) pyrazinamide, polymorph α.20

Figure 4. DSC heating runs; scanning rate 10 C/min: (1) mortar ground equimolar diflunisal-I+pyrazinamide-α mixture, m = 1.57 mg; (2) diflunisal-I, m = 1.69 mg; (3) pyrazinamide-α, m = 2.13 mg; inset a: expansion of curve 1.

Linkam was used for image analysis. The images were obtained by combined use of polarized light and wave compensators, using a 200 magnification.

Differential Scanning Calorimetry (DSC). The studies were performed in a Pyris1 power compensation calorimeter from Perkin Elmer, with an intracooler cooling unit at 10 C - ethylenglycol-water, 1:1 (v/v), 4782



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Figure 5. Thermomicroscopy images obtained in a heating run performed at 10 C/min on a mortar ground equimolar diflunisal-I+pyrazinamide-α mixture, scanning rate 10 C min1; amplification 200. cooling mixture. The samples were hermetically sealed in aluminum pans and an empty pan was used as reference. A 20 mL/min nitrogen purge was employed. Temperature and enthalpy calibration were performed as described in previous work.19

’ RESULTS AND DISCUSSION Identification of Polymorphic Forms of Starting Materials. The pyrazinamide sample used in this work was previously characterized in our group as the α-polymorph19,20 (Figure S1a, Supporting Information). In the crystalline structure of α-pyrazinamide, monoclinic, P21/a, Z = 4, two molecules are linked together forming amideamide dimers (dNH 3 3 3 O = 2.905 Å; — NH 3 3 3 O = 179), with each dimer connected to two other molecules by NH 3 3 3 Nring hydrogen bonds (dNH 3 3 3 N = 3.138 Å; — NH 3 3 3 N = 136). From XRPD experiments, Figure S1b, Supporting Information, diflunisal was identified as form I, which was first structurally characterized by Cross et al.21 In diflunisal I, triclinic, P1, Z = 2, acidacid dimers are present (dOH 3 3 3 O= = 2.699 Å; — OH 3 3 3 O= = 170) and vanishing weak intermolecular OH 3 3 3 OH bonds connect the dimers. The same kind of acidacid homodimers are present in all known diflunisal crystalline structures,2124 and partial molecular disorder is reported with the ortho fluorine atom equally distributed over two sites. Computational Results. The formation of co-crystals is dependent on the ability of the constituent molecules to associate in a new mixed supramolecular species, due to the establishment of favorable noncovalent intermolecular interactions. The simplest entity that can simulate this association in the co-crystal synthon, retaining the main intermolecular interactions involved, is a heterodimer comprising one molecular unit of each starting substance. However, the existence of the heterodimer as a stable species is not sufficient to ascertain the possibility of co-crystal formation. It is a necessary condition that the heterodimers have greater stability than the corresponding homodimers, since the molecular units of the substances will associate in the thermodynamically most stable form. Since there are other molecular interactions present, the use of dimers as model species cannot be a complete representation of the crystalline chemical environment and structures. However, it seems to represent the most important aggregate to simulate the crystals because of the different scale of interactions present, as indicated by the intermolecular

Figure 6. DSC heating curves of mortar ground equimolar mixtures of diflunisal/pyrazinamide annealed for different periods of time, t, at T = 80 C; scanning rate 10 C/min: (1) t = 0, m = 1.30 mg; (2) t = 1 day, m = 1.90 mg; (3) t = 2 days, m = 1.30 mg; (4) t = 3 days, m = 1.50 mg; (5) t = 4 days, m = 1.52 mg; (6) t = 5 days, m = 1.24 mg. Inset a: expansion of curves 1 and 6.

distances in the crystalline structures of pure APIs. This method gives a first insight into the practical feasibility of a co-crystal. To minimize potential errors the relative stability of the heterodimers vs homodimers can be evaluated from the calculated reaction free energies in the isodesmic reactions (a) and (b), Scheme 1. Results obtained for the dimeric structures are presented in Table 1. Geometry optimization of homodimers did not lead to significant differences in the structure. The analysis of the relative stabilities of heterodimers and homodimers provides an indication of the feasibility of formation of pyrazinamide-diflunisal adducts at least in acid-amide synthons (ΔGo298 K = 5 kJ mol1) corresponding to the isodesmic reaction (a) in Scheme 1). The calculations indicate that the acid-pyridine association is 16 kJ mol1 less stable than the homodimers of initial substances (ΔGo298 K of the isodesmic reaction (b) in Scheme 1). These relatively small stability differences obtained for the dimers point to a delicate 4783



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Figure 7. PLTM images obtained in the heating process of a mortar ground equimolar diflunisal/pyrazinamide mixture, after annealing at T = 80 C, for 5 days; scanning rate 10 C/min, amplification 200.

Figure 8. X-ray powder diffraction patterns: (1) Experimental for an equimolar diflunisal/pyrazinamide mixture annealed at 80 C for 5 days. (2) Simulated for (a) diflunisal, polymorph I;21 (b) diflunisal, polymorph III;21 (c) diflunisal, polymorph V.22

balance of equilibria among the homodimers and any of the possible heterosynthons, and that this can eventually be tipped toward one or another, depending on the physicochemical environment of the API and coformer mixture. Co-Crystal Synthesis and Characterization. The co-crystal synthesis was initially attempted by manual grinding of equimolar amounts of pyrazinamide, polymorph α, and diflunisal, form I, in an agate mortar. X-ray diffraction, infrared spectroscopy, and differential scanning calorimetry were used to characterize the resulting mixture and identify possible co-crystal formation.

The infrared spectra and the XRPD patterns of the initial compounds and of the ground mixture are shown in Figures 2 and 3, respectively. The infrared spectra and the X-ray powder diffractograms clearly show that no co-crystal formation took place, since the results for the ground mixture correspond to the sum of the individual characteristics of the separate compounds. However, interesting results were obtained by differential scanning calorimetry/ thermomicroscopy as shown in Figures 4 and 5. In Figure 4 the DSC traces obtained for the pure compounds and for the mixture 4784



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Figure 9. X-ray powder diffraction patterns: (1) Experimental for an equimolar diflunisal/pyrazinamide mixture annealed at 80 C for 5 days. (2) Simulated for (a) pyrazinamide, polymorph α;20 (b) pyrazinamide, polymorph α0 ;26 (c) pyrazinamide, polymorph β;27 (d) pyrazinamide, polymorph γ;19,25 (e) pyrazinamide, polymorph δ.28

are compared; heating runs were made from room temperature up to the diflunisal melting temperature. For this compound, a single thermal event is observed, corresponding to the melting process, Tfus = (211.8 ( 0.3) C, ΔfusH = (36 ( 1.6) kJ/mol, number of replicates, n = 6. For pyrazinamide, the endothermic transition from solid form α to polymorph γ is observed at Ttrs = (146.9 ( 0.5) C (at a 10 C/min heating rate) and is followed

by melting of form γ at Tfus = (188.3 ( 0.1) C, ΔfusH = (28.1 ( 0.3) kJ/mol.19 For the ground mixtures, an exothermic event is observed at T ∼ 110 C and is followed by an irregular endothermic peak. Thermomicroscopy images, shown in Figure 5 for a heating run at the same scanning rate, confirm the growth of a new phase in the exothermic process (see images from 113 to 146 C) with the last event being the melting process. The results 4785



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Figure 10. Infrared spectra: (1) 1:1 diflunisal/pyrazinamide co-crystal; (2) equimolar diflunisal-I/α-pyrazinamide physical mixture.

indicate that a new species is being formed in the exothermic event observed in the DSC curve. Following from these observations, the synthesis of this new species was attempted by annealing manually ground equimolar mixtures in closed containers in an oven. As the DSC experiments were carried out in the scanning mode, it is anticipated that the exothermic event will occur at a lower temperature when isothermal conditions are employed. The first annealing experiments were therefore carried out at T = 65 C, well below the onset recorded in the DSC experiments. However, even after two days only residual sample evolution was observed. The oven temperature was subsequently raised to 80 C and the solids produced after different periods of time were analyzed by DSC. After a 5 day period, the DSC curve shows a sharp single peak, Figure 6 (Tfus = (147.4 ( 0.2) C, ΔfusH = (55.5 ( 0.9) kJ mol1; n = 4), which is assigned to co-crystal melting. Thermomicroscopy experiments confirm the single phase transition observed as a melting process (see Figure 7). The XRPD spectrum of the 1:1 mixture of pyrazinamidediflunisal annealed at 80 C was obtained and compared with the simulated spectra of the polymorphs of both APIs. Three polymorphs of diflunisal have been previously characterized by single-crystal X-ray diffraction. From Figure 8 it is seen that none of them is present in the mixture. The crystalline structure of pyrazinamide has been the object of research for a long time.19,2529

The exhaustive work performed on this API led to four different polymorphs being identified, α, β, γ, and δ-pyrazinamide, as well as a possible fifth polymorph, α0 , which is similar to α. The experimental XRPD spectrum of the 1:1 pyrazinamide-diflunisal mixture annealed for 5 days is compared in Figure 9 to those of the different pyrazinamide polymorphs. The results are conclusive: the presence of any of the pyrazinamide polymorphs is also excluded. Since there are no traces of any known polymorphs of the original APIs in the ground mixture annealed at 80 C, a new species must have been formed. The combined DSC, thermomicroscopy, and XRPD results support the formation, in the annealing process, of a 1:1 co-crystal involving pyrazinamide and diflunisal. The infrared spectra of the co-crystal and of the 1:1 physical mixture of diflunisal and pyrazinamide are presented together in Figure 10. There are differences observed in the pyrazinamide NH stretching bands: νass (NH2) = 3414 cm1 (physical mixture, p.m.) and νass (NH2) = 3409 cm1 (co-crystal, c.c.); νs (NH2) = 3364 cm1 (p.m.) and νs (NH2) = 3370 cm1 (c.c.); in the amide II and ring vibration modes found between 1650 and 1550 cm1; in the amide III vibration around 1370 cm1 and also in the bands tentatively assigned to ring modes in ref 19, found in the spectrum of physical mixtures at 1054 and 432 cm1, and at 1062 and 444 cm1, respectively, in the co-crystal. With diflunisal, 4786


Crystal Growth & Design the OH stretching vibration mode in the 31002400 cm1 region is modified considerably in the new crystalline environment. The same occurs with the CdO and the COH stretching modes: νs (CdO) = 1689 cm1 (p.m.), νs (CdO) = 1672 cm1 (c.c.) and νs (COH) = 1200 cm1 (p.m.), νs (COH) = 1233 cm1 (c.c.). It is well established that adducts containing carboxylic acid OH 3 3 3 N hydrogen bonds exhibit typical broad infrared band profiles with characteristic maxima centered at approximately 2500 and 1910 cm1.3034 This feature is usually assigned to Fermi resonance of OH stretching and overtones of bending modes in OH 3 3 3 N complexes.31 These bands are identified in the pyrazinamide-diflunisal co-crystal spectrum and are absent in the physical mixture. This observation provides clear evidence of the establishment of this hydrogen bonding type, giving rise to the acid-pyridine heterosynthon, which is only possible between the two different APIs, thus confirming their association in a new structure. Co-Crystal Synthesis by Crystallization from Solutions and by Ball Mill Grinding. The crystallization from solution experiments performed so far, from 1:1 solutions of the components, gave rise to mixtures of the co-crystal and pure APIs in variable proportions. These observations are consistent with different solubilities of diflunisal and pyrazinamide, giving rise to noncongruently saturating systems.3537 Despite all experimental effort, no crystals could be obtained of appropriate size and quality for structure determination. Co-crystallization was also attempted by either ethanol assisted or neat grinding of equimolar amounts of both compounds in a ball mill. Ethanol (10 μL) assisted grinding for 30 min at 15 Hz results in complete conversion to the co-crystal structure. The neat process gives rise to a low crystalline material, and the cocrystal is obtained from this material in about 60 min, at room temperature.

’ CONCLUSIONS Co-crystal formation involving the first-line antituberculosis drug, pyrazinamide, and diflunisal, a nonsteroidal anti-inflammatory drug has been investigated. A first insight into the feasibility of co-crystal formation involving the two APIs was obtained using computational quantum chemistry methods. The thermodynamic stabilities of the homodimers present in the APIs crystalline structures and those of hypothetical heterodimers were compared using suitable isodesmic reactions. The relatively small stability differences found indicate a delicate equilibrium among the possible intermolecular associations that can be tipped one way or another, depending on the physicochemical environment of the mixture. A 1:1 pyrazinamide-diflunisal co-crystal was successfully prepared by three different experimental methods: annealing a mortar ground mixture at 80 C, room temperature annealing of a low crystallinity mixture obtained by neat ball mill grinding, and ethanol assisted ball milling. The new species was characterized by differential scanning calorimetry, polarized light thermal microscopy, X-ray powder diffraction, and infrared spectroscopy. The pyrazinamide-diflunisal co-crystal is of considerable interest because of its potential application in a combination drug therapy, due to the side effects of pyrazinamide, and, in addition, it offers the potential to improve diflunisal aqueous solubility.

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’ ASSOCIATED CONTENT

bS

Supporting Information. Figure S1a: pyrazinamide X-ray powder diffraction spectra; Figure S1b: diflunisal X-ray powder diffraction spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]; [email protected].

’ ACKNOWLEDGMENT We are grateful to FEDER/POCI 2010 for financial support. ’ REFERENCES (1) Miroshnyk, I.; Mirza, S.; Sandlert, N. Expert Opin. Drug Delivery 2009, 6, 333–341. (2) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950–2967. (3) Meanwell, N. A. Annu. Rep. Med. Chem. 2008, 43, 373–404. (4) Shan, N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440–446. (5) U.S. Food and Drug Administration - Database of Select Committee on GRAS Substances (SCOGS) Reviews. http://www. accessdata.fda.gov/scripts/fcn/fcnNavigation.cfm?rpt=scogsListing (accessed 15/02/2011). (6) Frantz, S. Nat. Rev. Drug Discovery 2006, 5, 881–882. (7) Pan, F.; Chernew, M. E.; Fendrick, A. M. J. Gen. Intern. Med. 2008, 23, 611–614. (8) Vermeire, E.; Hearnshaw, H.; Van Royen, P.; Denekens, J. J. Clin. Pharm. Ther. 2001, 26, 331–342. (9) Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L. Mol. Pharmaceutics 2006, 3, 631–643. (10) Hall, R. G.; Leff, R. D.; Gumbo, T. Pharmacotherapy 2009, 29, 1468–1481. (11) Dye, C. Lancet 2006, 367, 938–940. (12) Cavalcante, S.; Chakaya, J. M.; Egwaga, S. M.; Gie, R.; Gondrie, P.; Harries, A. D.; Hopewell, P.; Kumar, B.; Weezenbeck, K. L.-v.; Mase, S.; Menzies, R.; Mukwaya, A. N.; Nasehi, M.; Nunn, A.; Pai, M.; Sch€unemann, H.; Udwadia, Z. F.; Vernon, A.; Vianzon, R. G.; Williams, V. Treatment of tuberculosis: Guidelines, 4th ed.; World Health Organization: Geneva, 2010. (13) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (14) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (15) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (16) Dunning, T. H. J. Chem. Phys. 1989, 90, 1007–1023. (17) Woon, D. E.; Dunning, T. H. J. Chem. Phys. 1993, 98, 1358–1371. (18) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A.; Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem. 1993, 14, 1347–1363. vora, A. O. L.; Feiteira, J. C.; (19) Castro, R. A. E.; Maria, T. M. R.; E Silva, M. R.; Beja, A. M.; Canotilho, J.; Eusebio, M. E. S. Cryst. Growth Des. 2010, 10, 274–282. (20) Takaki, Y.; Sasada, Y.; Watanabe, T. Acta Crystallogr. 1960, 13, 693–702. (21) Cross, W. I.; Blagden, N.; Davey, R. J.; Pritchard, R. G.; Neumann, M. A.; Roberts, R. J.; Rowe, R. C. Cryst. Growth Des. 2003, 3, 151–158. (22) Kim, Y. B.; Park, I. Y. J. Kor. Pharm. Sci. 1996, 26, 55–59. (23) Hansen, L. K.; Perlovich, G. L.; Bauer-Brandl, A. Acta Crystallogr., Sect. E: Struct. Rep. Online 2001, 57, o604–o606. (24) Hansen, L. K.; Perlovich, G. L.; Bauer-Brandl, A. Acta Crystallogr., Sect. E: Struct. Rep. Online 2001, 57, o477–o479. 4787



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Pyrazinamide-Diflunisal - American Chemical Society

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