ARTICLE pubs.acs.org/crystal
Naproxen Cocrystals with Pyridinecarboxamide Isomers Ricardo A. E. Castro,*,‡ Jo~ao D. B. Ribeiro,† Teresa M. R. Maria,† M. Ramos Silva,§ Consuelo Yuste-Vivas,§ Jo~ao Canotilho,‡ and M. Ermelinda S. Eusebio*,† †
CQC, Department of Chemistry, ‡CEF, Faculty of Pharmacy, and §CEMDRX, Department of Physics, University of Coimbra, Portugal 3000-578
bS Supporting Information ABSTRACT: A screening of naproxen cocrystals with coformers picolinamide, nicotinamide, isonicotinamide, and pyrazinamide is performed by the Kofler contact method and mechanochemistry. The solids obtained by mechanochemistry are characterized by differential scanning calorimetry, DSC, polarized light thermomicroscopy, PLTM, infrared spectroscopy, FTIR, and X-ray powder diffraction, XRPD. No cocrystal could be prepared under the experimental conditions investigated between naproxen and pyrazinamide, which bears two aromatic nitrogen atoms, ortho and meta to the amide group. For the o-, m-, and p-pyridinecarboxamide isomers, regardless of the aromatic nitrogen position, the coformer interacts with naproxen to give rise to new cocrystals: naproxen:picolinamide, naproxen2:nicotinamide, and naproxen:isonicotinamide. A supramolecular acid:aromatic nitrogen heterosynthon is found in all these cocrystals. The structure of the new naproxen:isonicotinamide compound was solved by single-crystal X-ray diffraction, SXD. As nicotinamide has FDA/GRAS status the naproxen:nicotinamide (2:1) cocrystal is of special relevance.
’ INTRODUCTION Essential to the development of a pharmaceutical solid form is the study of polymorphism, salt, and solvates formation. Cocrystal screening has recently become another standard tool.1 Pharmaceutical cocrystals are an innovative approach to improving the solubility and therefore the oral bioavailability of an active pharmaceutical ingredient (API) using suitable molecules as cocrystal formers.2 (S)-Naproxen, NPX, Scheme 1a, is a member of the 2-arylpropionic acid (Profen) family of nonsteroidal anti-inflammatory drugs (NSAIDs) and belongs to Class II (high permeability, low solubility) of the Biopharmaceutics Classification System (BCS).3 A single-crystalline structure is known: two records in the Cambridge Crystallographic Data Centre (CCDC) refer to the same form, COYRUD.4 Recently, three other polymorphs have been claimed, obtained under extreme crystallization conditions.5 With respect to naproxen cocrystals, a (2:1) cocrystal was obtained with trans-1,2-bis(4-pyridyl)ethylene,6 and two naproxen cocrystal patents are also found in literature: one with duloxetine (3:2)7 and another with tramadol (2:1),8 revealing the importance of this compound to the pharmaceutical industry. Analysis of cocrystals in the Cambridge Structural Database (CSD) indicates that the supramolecular heterosynthons presented in Scheme 1b, acid 3 3 3 amide and acid 3 3 3 aromatic nitrogen, are strongly favored9 over their respective acid 3 3 3 acid supramolecular homosynthons, present in naproxen.4,9 In the absence of competing H-bonding groups, the percentage occurrence of acid 3 3 3 aromatic nitrogen heterosynthon increases from r 2011 American Chemical Society
77% to a remarkable 98%.6 On the basis of this information, small structurally related compounds, containing one or both functional groups, were used as coformers, Scheme 1c: picolinamide, PA, nicotinamide, NA, isonicotinamide, INA, and pyrazinamide, PZA. The pyridinecarboxamides are widely used as coformers10 13 and involved in the regulation of sirtuin activity.14,15 Use of nicotinamide should be highlighted because the FDA regards it as GRAS (Generally Recognized as Safe).16 Pyrazinamide is used in medical practice for treatment of tuberculosis, and its cocrystals with naproxen are likely to be of interest due to their dual and complementary pharmaceutical activity.17,18 The ability of coformers to exhibit polymorphism has been related to synthon flexibility and is mentioned as an important contribution to enhance the ability to form cocrystals.19 All coformers chosen exhibit polymorphism. Picolinamide exists under two polymorphic forms.20 Nicotinamide has four polymorphic forms.21 Form I (NICOAM01)22 is the most stable, while the others have been observed by DSC studies using aluminum pans.21 Recently, form II has been isolated and studied by SXD while attempting to cocrystallize nicotinamide with the API isoxyl. 11 Isonicotinamide has two polymorphs, form I (EHOWIH01)19 and form II (EHOWIH02). 19 Recently, a new polymorph, form III, was obtained while searching for a cocrystal with isoxyl.11 The tuberculostatic pyrazinamide has five Received: August 1, 2011 Revised: September 23, 2011 Published: October 07, 2011 5396
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Crystal Growth & Design Scheme 1. (a) Naproxen, API. (b) Supramolecular Heterosynthons. (c) Aromatic Acid Amide Cocrystal Formers
polymorphic forms whose relative stability has been studied in depth.23,24 Another important factor to take into account in the selection of cocrystal formers is the pKa difference, ΔpKa = pKa (base) pKa (acid), which predicts the occurrence of proton transfer.6 According to Johnson and Rumon,25 an acid 3 3 3 aromatic nitrogen hydrogen bond may be formed if ΔpKa is less than 3.75. All coformers selected in the current work fulfill this hydrogen-bond formation criterion (pKa values for these compounds are NPX = 4.2,26 PA = 2.22,27 NA = 3.35,28 INA = 3.67,29 and PZA = 0.530). The screening methodology described in this paper proposes the Kofler contact method as a first approach.31,32 This can give a rapid indication about cocrystal formation.33 37 In a second step, liquid-assisted milling was used to prepare possible cocrystals that were studied by DSC, FTIR, and XRPD. The data collected inform us if a new cocrystal has been prepared. The new cocrystals were studied in depth by these techniques. Crystallization was also attempted by solution methods using cooling and evaporative techniques to obtain crystals suitable for singlecrystal X-ray diffraction to elucidate their crystalline structure.
’ EXPERIMENTAL PROCEDURES Materials. (S)-Naproxen, Fluka 98%, was identified by XRPD as the solid form described by Ravikumar et al.4 Commercial isonicotinamide was acquired from Aldrich 99%, and its crystalline structure was identified by XRPD as polymorph II.19 Nicotinamide from Aldrich 99% corresponds to polymorph I22 and original picolinamide, Aldrich 98%, to the structure described by Takano et al. (PICAMID)20 hereafter called polymorph II. With pyrazinamide, Fluka 99%, the alpha
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polymorph is identified.38 High-purity solvents were used in the solution crystallization experiments. Grinding. Retsch MM400 with a 10 mL stainless steel grinding jar and two 7 mm diameter stainless steel balls per jar were used for grinding NPX with the coformers. A total mass of about 50 mg with 5 μL of ethanol was ground for 30 min at a frequency of 15 Hz. The ground products were analyzed by XRPD. Equimolar mixtures of both substances were prepared, and depending on the results, other NPX + coformer molar proportions were also mixed. Polarized Light Thermal Microscopy (PLTM). The solids obtained were characterized by PLTM using a Linkam hot stage system, model DSC600, with a Leica DMRB microscope and a Sony CCD-IRIS/ RGB video camera. Real Time Video Measurement System software by Linkam was used for image analysis. The images were obtained by combined use of polarized light and wave compensators, using a 200 magnification. The Kofler contact experiments were carried out as described by Berry et al.36 The microscope slide was placed over the Linkam DSC 600 furnace, and heating runs were carried out at 1 °C/min to observe the mixed zone behavior. Differential Scanning Calorimetry (DSC). The studies were performed on a PerkinElmer Pyris1 power compensation calorimeter with an intracooler cooling unit at 25 °C (ethylene glycol water, 1:1 (v/v), cooling mixture). The samples, mass ∼2 mg, were hermetically sealed in 30 μL aluminum pans, and an empty pan was used as reference. A 20 mL/min nitrogen purge was employed. Temperature calibration39,40 was performed with the high-grade standards biphenyl (CRM LGC 2610, Tfus= (68.93 ( 0.03)°C), benzoic acid (CRM LGC 2606, Tfus= (122.35 ( 0.02)°C), indium (Perkin-Elmer, x = 99.99%, Tfus= 156.60 °C), and caffeine (Mettler Toledo calibration substance, ME 18 872, Tfus = (235.6 ( 0.2)°C). Enthalpy calibration was performed with indium (ΔfusH = 3286 ( 13 J/mol).39 Infrared Spectroscopy (FTIR). Spectra of the solids were recorded at room temperature with the KBr pellet technique using a ThermoNicolet IR300 FTIR spectrometer, resolution 1 cm 1, and on a PerkinElmer Spectrum 400 FTIR/ATR, resolution 1 cm 1. Single-Crystal X-ray Diffraction (SXD). A small crystal of NPX: INA was analyzed on a Bruker-Nonius Kappa Apex II CCD diffractometer using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). The structures were solved by direct methods (SHELXS-97).41 The structure was refined by full matrix least-squares on F2 (SHELXL-97).41 All non-H atoms were refined anisotropically. The H atoms’ positions could all be located in a difference Fourier map, but they were refined riding on the attached parent atoms using SHELXL-9741 defaults with isotropic thermal factors proportional to those of their parent atoms. Because of the absence of strong anomalous scatterers at Mo Kα wavelength, the Friedel pairs were merged in the last cycles of the refinement, and the absolute configuration was assumed from that specified for the starting material. The crystallographic details are given in Table 2. X-ray Powder Diffraction (XRPD). Glass capillaries (0.5 mm diameter) were filled with the powdered specimens. The samples were mounted on an ENRAF-NONIUS powder diffractometer (equipped with a CPS120 detector by INEL), and data were collected for 15 min to 1 h using Debye Scherrer geometry. Monochromatized Cu Kα1 radiation was used (λ = 1.5406 Å). Silicon was chosen as an external calibrant.
’ RESULTS AND DISCUSSION Cocrystal Screening by the Kofler Contact Method. The Kofler contact method, although sometimes difficult to interpret, is always a good, fast first screening approach.36,37 In Figure 1 images obtained for the system NPX + PA, NPX + NA, and NPX + INA are presented. This method could not be applied to the NPX + PZA system due to the high sublimation rate of PZA. 5397
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Figure 1. Kofler contact method images of the NPX + PA, NPX + NA, and NPX + INA systems.
Figure 2. DSC heating curves of: (a) NPX, NPX : PA, PA, (b) NPX, NPX + NA, NPX2 : NA, NA, (c) NPX, NPX : INA, INA, and (d) NPX, NPX + PZA, PZA. β = 10 °C min 1.
The images of the NPX + INA system are very instructive, and we can say that a new cocrystal is identified.36,37 In fact, in the mixture zone two molten eutectic mixtures and one solid NPX:INA cocrystal compound are observed. A short explanatory movie is available as Supporting Information. The results for the other two systems are not conclusive: the observations may result, for instance, from a single eutectic fusion or from very close eutectic and cocrystal fusion temperatures.
Samples Prepared by Liquid-Assisted Mechanochemistry. Cocrystal synthesis was also carried out by liquid-assisted solidstate grinding.42 Pure (S)-naproxen and pure coformers were both submitted to the same experimental treatment to ascertain if any polymorphic modifications occurred due the liquid-assisted ball-milling process. No changes were observed in any of the materials, except isonicotinamide. For this pyridinecarboxamide isomer the ball-mill grinding process leads to polymorph I, EHOWIH01.19 5398
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Table 1. Thermodynamic Parameters of Phase Transitions Observed by DSC for NPX, Coformers, And Mixtures API Tonset/°C
ΔfusH/kJ mol 33.0 ( 0.5
1
Tonset/°C
mixture
ΔfusH/kJ mol
1
Tonset/°C
ΔfusH/kJ mol
106.1 ( 0.3
19.7 ( 0.5
91.0 ( 0.3
NPX + NA (2:1)
128.2 ( 0.2
23.2 ( 0.4
125.6 ( 0.4
75 ( 1
NPX + INA (1:1)
155.4 ( 0.6
24.5 ( 0.8
125.4 ( 0.5
49.2 ( 0.9
NPX + PZA (1:1)
188.3 ( 0.1
28.1 ( 0.3
125.1 ( 0.3
NPX + PA (1:1)
155.6 ( 0.2
coformer
1
33.1 ( 0.9
Figure 3. Experimental FTIR spectra of (a) NPX, NPX:PA, PA, (b) NPX, NPX2:NA, NA, (c) NPX, NPX:INA, INA, and (d) NPX, NPX + PZA, PZA.
The two-component solid mixtures obtained were studied by DSC, FTIR, and XRPD. The thermal behavior of these systems is presented in Figure 2, and the respective relevant peak thermodynamic values are shown in Table 1. The DSC curves presented in Figure 2 for equimolar mixtures of NPX with PA and INA show a single melting process, also observed for the NPX mixture with NA in a (2:1) molar proportion. The DSC curve of the equimolar NPX + NA mixture, Figure 2b, can be interpreted as the melting of a eutectic mixture followed by fusion of a substance in excess. This is also observed for the NPX + PZA, Figure 2d, system, although a smaller excess component is observed. The DSC results are consistent with NPX:PA, NPX2:NA, and NPX:INA cocrystal formation. The comparison of infrared spectra of the pure components and those of the systems under study, Figure 3, will be used to
support this conclusion by giving information about the establishment of a new hydrogen-bond network. We expect to observe red shifts or blue shifts and intensity differences of the bands involved in the new hydrogen bonds. Figure 3a shows the modifications observed in the infrared spectrum of NPX:PA relative to the original compounds, NPX and PA, and provides evidence that a new hydrogen-bond network was established. The band attributed to νas(NH2) at 3418 cm 1 in the infrared spectrum of PA is blue shifted to 3438 cm 1 in the NPX:PA spectrum. The ν(CdO) stretching band at 1728 cm 1 in NPX and 1664 cm 1 in the PA spectra appear in the NPX:PA spectrum at 1698 cm 1. We also point out the presence of two new bands at 2458 and 1941 cm 1 (indicated by two arrows in the spectrum) that result from the O Hcarboxylic acid 3 3 3 Naromatic hydrogen bond.43 45 This provides 5399
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Figure 4. Experimental (gray and black lines) and simulated (red and blue lines) XRPD spectrum of (a) NPX (COYRUD11),51 NPX + PA (1:2), NPX: PA cocrystal, NPX + PA (2:1), PA II (PICAMD),20 (b) NPX, NPX + NA (1:2), NPX + NA (1:1), NPX2:NA cocrystal, NA I (NICOAM01),22 (c) NPX, NPX + INA (1:2), NPX:INA cocrystal, NPX + INA (2:1), INA I(EHOWIH01),19 and (d) NPX, NPX + PZA, PZA α (PYRZIN).38
clear proof that the hydroxyl group of NPX interacts with the aromatic nitrogen of PA. With respect to the NPX2:NA mixture, the νas(NH2) band shows a blue shift from 3363 cm 1 in NA to 3376 cm 1. The ν(CdO) stretching band is red shifted from 1728 cm 1 in NPX to 1703 cm 1 in NPX2:NA. The two bands attributed to the O Hcarboxylic acid 3 3 3 Naromatic hydrogen bond are also present at 2541 and 1978 cm 1. We verified by XRPD that commercial INA is present as form II and transformed into form I after milling. To follow the hydrogen-bond network we must compare the infrared spectra of the NPX:INA mixture with that of INA I. To the best of our knowledge, this is the first time that this infrared spectrum has been assigned to the polymorphic form.46 50 It can be seen in Figure 3c that the νas(NH2) band at 3366 cm 1 in INA I is blue shifted to 3415 cm 1 in NPX:INA cocrystal. The ν(CdO) stretching band in NPX red shifts from 1728 to 1704 cm 1, and once again, two bands at 2447 and 1942 cm 1 are observed indicating the presence of a O Hcarboxylic acid 3 3 3 Naromatic hydrogen bond. In Figure 3d the NPX + PZA α spectrum neither shows any shifts of the infrared bands relative to the infrared spectra of the pure compounds nor are any new bands observed. This spectrum
reveals that no new hydrogen bonds were established, no cocrystal is formed: the sample consists of a physical mixture of the original compounds. The final confirmation that we have new cocrystals is provided by XRPD: (1:1) naproxen:picolinamide, (2:1) naproxen:nicotinamide, and (1:1) naproxen:isonicotinamide cocrystals were synthesized for the first time. These three mixtures give rise to diffractograms different from those resulting from the simple sum of the pure component spectra, in contrast to what is obtained for the physical mixture NPX + PZA, Figure 4d. The XRPD study was also carried out on mixtures of molar proportions other than those of the cocrystals in order to emphasize the correct cocrystal stoichiometry. The excess present in diffractograms with nonstoichiometric proportion also allows identification of the polymorphic form of the coformer present. In Figure 4a the presence of PA II in excess (blue dotted line at 28.4°) is clearly seen in the NPX + PA (1:2) diffractogram. In the NPX + PA (2:1) diffractogram, an excess of NPX is observed (red dotted line at 19.1°). The NPX2:NA cocrystal diffractogram is presented in Figure 4b. In the other two diffractograms the NA I excess (blue dotted line at 14.9°) and the absence of free NPX (red dotted line at 6.6°) are evident. 5400
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Figure 5. PLTM images of crystals resulting from the evaporative technique of equimolar solutions of NPX and INA. The solvents used, crystallization temperature, and melting interval are indicated under the pictures. β = 10 °C/min.
Figure 6. PLTM images of NPX:INA cocrystal during the heating process. β = 10 °C/min.
In Figure 4c the presence of INA polymorph I is confirmed, and NPX:INA is the correct cocrystal proportion. In fact, in the other two diffractograms we observe an excess of either INA I (blue dotted line at 31.2°) or NPX (red dotted line at 19.1°). The experimental diffractogram presented in Figure 4d for the NPX + PZA α (1:1) mixture is, as expected, the sum of the diffractograms of the pure components.
Crystallization from Solutions. As the next step, attempts were made to obtain crystals suitable for study by single-crystal X-ray diffraction. Although we knew that congruent crystallization from solvents may not happen due to solubility differences between the API and the coformer,52 a first screening was performed from solutions of the compounds in the molar proportions of the cocrystals. 5401
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Figure 7. ORTEP diagram of NPX:INA. Ellipsoids are drawn at the 50% probability level.
Table 2. Crystal Data and Structure Refinement Parameters for NPX:INA empirical formula
C20H20N2O4
fw
352.38
temperature/K
293(2)
wavelength/Å cryst syst
0.71073 monoclinic
space group
P21
a/Å
5.8146(4)
b/Å
6.2269(4)
c/Å
49.370(3)
β/deg
90.531(5)
volume/Å3
1787.5(2)
Z calcd density/g cm
4 1.309
abs coeff/mm
3
1
H3 3 3A
a
D3 3 3A
H-bond angle
O1 H1 3 3 3 N1(i) N2 H2A 3 3 3 O8(ii)
1.79
2.558(4)
156
2.05
2.903(5)
174
N2 H2B 3 3 3 O2(iii) N4 H4A 3 3 3 O4(iv)
2.14
2.958(5)
159
2.06
2.909(5)
172
2.15
2.977(4)
162
1.79
2.554(5)
158
N4 H4B 3 3 3 O6 O5 H5 3 3 3 N3
Symmetry transformations: (i) 1 + x, y, z. (ii) 1 + x, 1 + y, z. (iii) x, 1 + y, z. (iv) 1 + x,1 + y, z. (v) x, 1 + y, z. (vi) 1 + x, y, z.
0.092
F000
256
cryst form, color
needle, colorless
cryst size/mm
0.40 0.14 0.12
θ range for data collection/°
1.24
27.36
7 < h < 7,
index ranges
8 < k < 8,
63 < l < 63
reflns collected/unique completeness to θmax
51 454/4341 [R(int) = 0.1039] 98.7%
refinement method
full-matrix least-squares on F2
data/restraints/parameters
4341/1/474
goodness-of-fit on F2
0.999
final R indices [I > 2σ(I)]
R1 = 0.0507, wR2 = 0.1055
R indices (all data)
R1 = 0.1214, wR2 = 0.1305
largest diff peak and hole/e Å
Table 3. Hydrogen-Bond Geometric Parameters (Angstroms and degrees) for NPX:INAa
3
0.251/ 0.196
Until now, successful results could only be obtained for the NPX:INA system. For this system, crystals were obtained by solvent evaporation at room temperature and 2 °C. The solids obtained were observed by PLTM in heating runs performed until complete melting. The results are presented in Figure 5, where the melting temperature range of the solids is also indicated. The small melting temperature range, close to the NPX:INA cocrystal fusion temperature (125 °C), is attained for crystals obtained in ethanol at 2 °C. This means that with this solvent a less contaminated cocrystal is obtained.
Figure 8. Hydrogen-bonding network of NPX:INA. H bonds are drawn as dashed lines.
The solubility differences of naproxen and isonicotinamide in ethanol at 25 °C, xNPX/ethanol = 0.012426 and xINA/ethanol = 0.0333,53 suggest the use of nonequivalent reactant concentrations to achieve the cocrystal stability region in noncongruently saturating solvent.52 A solution was prepared by weighing 0.183 g of NPX and 0.270 g of INA in 5 mL of ethanol, that is, a nearly saturated solution of the coformer is prepared and then a convenient amount of NPX is added to also be near its saturation 5402
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Figure 9. Packing diagram of NPX:INA.
molecule 2 (atoms O5 to C40). The methoxy groups are almost coplanar with the ring they are attached to, the C1 C10 O3C14 torsion angle is 174.7(3)°, and the torsion angle C40 O7 C32 C33 is 178.4(4)°.
Figure 10. Newman projections of the two independent naproxen molecules in NPX:INA.
solubility. The sealed solution was heated to 40 °C under magnetic stirring and remained there until complete dissolution. The hot plate was disconnected to achieve a slow cooling to room temperature. Then the solution was kept at 7 °C in a refrigerated chamber. Using this approach pure and good-quality crystals of NPX:INA suitable for single-crystal X-ray study were obtained, Figure 6. Crystalline Structure of the (S)-Naproxen:Isonicotinamide Cocrystal. A new crystal structure has been solved (Figure 7 and Table 2), and the structural data have been deposited at the Cambridge Crystallographic Data Centre (CCDC 815241). NPX:INA crystallizes in the P21 chiral space group with Z = 2. The asymmetric unit contains 2 independent isonicotinamide molecules and 2 neutral and independent naproxen ((+)-6methoxy-α-methyl-2-naphtalene acetic acid) molecules. The two independent isonicotinamide molecules have the carboxamide groups face to face, and their atoms share approximately the same plane. Only O4 and O8 deviate 0.18 Å (above and below) from such a least-squares plane. The two isonicotinamide molecules are linked by two hydrogen bonds (Table 3). The same dimeric head-to-head motif is seen in the polymorphic form I of pure isonicotinamide. The naproxen molecules are bonded sideways to the isonicotinamide dimers, an H atom is shared between the naproxen carboxylic group and the isonicotinamide aromatic N atom. The same carboxylic group is an acceptor of the H atom of a neighboring amide group (Figure 8). The dimers are therefore joined in infinite ribbons that pile on top of each other along b; thus, the crystal is composed of alternating naproxen/isonicotinamide slabs (Figure 9). The two independent naproxen molecules have different conformations involving different orientations of the carboxyl group to the naphthalene plane, as can be seen from a Newman projection along the C11 C12 and C37 C38 bonds (Figure 10). The two benzene rings of the naphthalene moiety make an angle of 3.5(2)° in molecule 1 (atoms O1 to C14) and 2.9(2)° in
’ CONCLUSIONS The screening process based on the Kofler contact method, DSC, FTIR and XRPD, has led to the discovery of three new cocrystals of the low solubility, BCS Class II, anti-inflammatory drug naproxen:naproxen:picolinamide (1:1), naproxen:nicotinamide (2:1), and naproxen:isonicotinamide (1:1). The Kofler contact method gives the first clear evidence of the NPX:INA cocrystal, but for the other two systems a correct interpretation was only achieved after combination with further data. The thermal behavior provides evidence that all new cocrystals have lower melting temperatures than NPX, which is a good indicator that the new cocrystals may improve the solubility of NPX.54,55 The ν(CdO) stretching band of NPX is red shifted in the three cocrystals, indicating that the new hydrogen bonds involving this group are stronger than that of NPX. Infrared spectra also provide evidence of the presence of the acid 3 3 3 aromatic nitrogen heterosynthon in all new cocrystals, as the characteristic two bands resulting from the O Hcarboxylic acid 3 3 3 Naromatic hydrogen bond are present in all spectra. The supramolecular acid 3 3 3 aromatic nitrogen heterosynthon is expected, regardless of the ortho, meta, and para position of the aromatic nitrogen. The infrared spectrum of isonicotinamide form I is ascribed for the first time. Noncongruent solution crystallization gives rise to NPX:INA crystals suitable for single-crystal X-ray diffraction study. In this cocrystal crystalline structure the isonicotinamide I amide 3 3 3 amide supramolecular homosynthon remains unchanged and, as anticipated from the above results, the supramolecular heterosynthon acid 3 3 3 aromatic nitrogen is present. ’ ASSOCIATED CONTENT Supporting Information. A movie file of the NPX + INA system observed by the Kofler contact method. This material is available free of charge via the Internet at http://pubs.acs.org.
bS
’ AUTHOR INFORMATION Corresponding Author
*E-mail: rcastro@ff.uc.pt;
[email protected].
’ ACKNOWLEDGMENT We are grateful to FEDER/POCI 2010 for financial support and also thankful to UCQfarma for the FTIR/ATR facility. 5403
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Crystal Growth & Design
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