X-ray and NMR Crystallography Studies of Novel

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X-Ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding José A. Fernandes, Mariana Sardo, Luis Mafra, Duane Choquesillo-Lazarte, and Norberto Masciocchi Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b00279 • Publication Date (Web): 01 Jun 2015 Downloaded from http://pubs.acs.org on June 8, 2015

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Crystal Growth & Design

X-Ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding José A. Fernandes,a* Mariana Sardo,a Luís Mafra,a* Duane Choquesillo-Lazarte,b Norberto Masciocchic a

CICECO - Aveiro Institute of Materials, Department of Chemistry, University of

Aveiro, 3810-193 Aveiro, Portugal b

Laboratorio de Estudios Cristalográficos, IACT, CSIC-Universidad de Granada, Av. de lasPalmeras 4, E-18100 Armilla, Granada, Spain

c

Dipartimento di Scienza e Alta Tecnologia, Università dell’Insubria, 22100 Como,

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

Abstract Two new cocrystals of theophylline were prepared by Liquid Assisted Grinding. While compound 1 (theophylline: 4-aminosalicylic acid 2:1) was characterized by single crystal X-Ray diffraction, the crystal structure of compound 2 (theophylline: 4aminobenzoic acid 1:1) was determined combining X-ray powder diffraction (XRPD), solid-state NMR and DFT calculations. The use of 1D/2D 1H high-resolution solid-state NMR techniques provided structural insight on local length scales revealing internuclear proximities and relative orientations between the building blocks of compound 2, thus providing information on the type of hydrogen bond synthons formed. DFT calculations were also employed to generate meaningful structures and calculate NMR 1H and

13

C chemical shifts to further validate the XRPD model.

Compound 2 shows an unusual structure, in which the amino groups do not participate in hydrogen bonds, while compound 1 exhibits an extended hydrogen-bonding network, in which planar subunits can be recognized.

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Introduction The search for new forms of Active Pharmaceutical Ingredients (APIs) manifesting enhanced, or specifically tailored, physical properties led researchers in the pharmaceutical field to prepare and characterize cocrystalline species with a variety of coformers.1-3 Theophylline is the most important metabolite of caffeine and it is found in tea, coffee, cocoa beans and chocolate.4 This substance is an API for the treatment of respiratory diseases such as asthma.5 Theophylline appears in at least three different anhydrous forms,6-9 of which only the most thermodynamically stable form is normally observed, as well as a monohydrate form.9,10 The reversible formation of the monohydrate is an undesired feature to take into account in the formulation procedure,5 and several efforts have been spent to circumvent this problem. The most important way to avoid the formation of the hydrate is the preparation of cocrystals, which has involved so far a high number of coformers. Presently, the coformers forming cocrystals with theophylline can be divided in distinct classes, such as: other APIs,5,11-22 benzoic acid or phenol derivatives,23-30 carboxylic acids,31-36 other organic molecules19,20,30,36-38 and neutral coordination compounds.39-43 Other preparations not involving cocrystals include the formation of theophylline solvates,44 salts45 or even ionic coordination compounds.46,47 In cocrystal preparation, namely theophylline cocrystals, slow evaporation of solvent continues to be the most used technique.1,18-21,23-27,33-35,38 Other methods such as neat grinding,28, 48 mixing in a slurry17,29 and freeze-drying15 are also possible. Over the past few years Liquid Assisted Grinding (LAG)6-8 has gained some importance in the synthesis of cocrystals, including cocrystals of theophylline.16,22,30,31,32,36 This procedure is more advantageous than performing reactions within a solvent due to the considerably lower emission to the environment of toxic residues; it is also superior to the neat grinding method, as the addition of a small amounts of solvent (a few µL) increases the yield of the reaction, often up to completion. The structures of theophylline cocrystals are mainly governed by the formation of several types of synthons, which are thoroughly described in the work of Sarma & Sakia.30


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The large amount of structural information has been routinely obtained by conventional single-crystal X-ray diffraction analysis; more recently X-ray powder diffraction (XRPD) methods for structure determination of small molecules have been shown to provide a viable structural tool when monocrystalline specimen are not available.31 Although structural XRPD studies are not trivial and significantly more challenging than single-crystal analyses, their power in the pharmaceutical field has been exploited in a number of cases (see Refs. 51-53 and references therein for very recent examples,). In addition, also NMR crystallography provides complementary structural information since it combines the high sensitivity of solid-state (ss) NMR to probe the short-range local structure, with the accuracy of XRPD in detecting long-range ordering. DFT calculations can be employed for geometry optimization of hydrogen atom positions and to obtain theoretical NMR chemical shifts that can be then compared with experimental data for structural validation of XRPD models. This increases the success rate and confidence level in the obtained final structure.54,55 Accordingly, structural constraints were recently obtained from NMR13C-13C dipolar couplings combined with DFT calculations of NMR parameters and crystal structure prediction approaches of solid theophyline.56 Such NMR crystallography approach is becoming popular in the structure validation of cocrystals.57-59 In the present paper, we report the isolation and full characterization of cocrystals theophylline 4-aminosalicylic acid (2:1) – compound 1, and theophylline 4aminobenzoic acid (1:1) – compound 2, selectively, and quantitatively, prepared by the LAG method discussed above, involving the solid reactants depicted in Figure 1.

Figure 1. Chemical structure of the API (left) and coformers (middle and right) used in the present work.



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Experimental Part

General Methods Details of the methods and of the results from Fourier Transformed Infrared (FT-IR), Fourier Transformed Raman (FT-Raman) spectroscopies and Thermogravimetric Analysis (TGA) are supplied in ESI.

Preparation of cocrystals by Liquid Assisted Grinding Theophylline (ca. 1 mmol) and the stoichiometric amount of coformer were ground during two periods of 30 minutes each within a mechanical mill operating at 25 Hz, with manual mixing with a spatula in between the two runs and addition of 100 µL of acetone in each period. Two different mills were used for the preparations, with no perceivable differences in the results: a Retsch MM 200 mill with two 10 mL vessels of stainless steel and a Fritsch Pulverisette 23 with a 5 mL grinding bowl. Three spheres of stainless steel of about 5 mm of width were added in the reactors on all the preparations. As first approach, the reagents were mixed in equimolar proportions. However, we soon realized that the stoichiometry of compound 1 was not equimolar, because the obtained cocrystal product was the actual 2:1 proportion mixed with an excess of 4aminosalicylic acid. Any attempts to prepare the theophylline···4-aminosalicylic acid (1:1) or theophylline···4-aminobenzoic acid (2:1) cocrystals, resulted in physical mixtures of compounds 1 and 2 with the respective reagent in excess (See figures S2 and S3 for details) 1: Theophylline 4-aminosalicylic acid (2:1): 179.9 mg of theophylline (0.999 mmol) and 76.3 mg of 4-aminosalicylic acid (0.498 mmol). 2: Theophylline 4-aminobenzoic acid (1:1): 181.6 mg of theophylline (1.008 mmol) and 137.7 mg mmol of 4-aminosalicylic acid (1.004 mmol).

Synthesis of cocrystals by solution chemistry 1: Theophylline 4-aminosalicylic acid (2:1): A solution of 4-aminosalicylic acid (78.9 mg; 0.515 mmol) in ethanol (4.0 mL) at 40 ºC was added to a slurry of theophylline (184.0 mg; 1.021 mmol) in chloroform (15 mL) at 40 ºC giving a clear solution. Then,


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some seeds of the suitable powder prepared by LAG were added. The slow evaporation of the solvent resulted in the formation of a mixture of crystals, from which a suitable crystal for single crystal X-ray diffraction was harvested. The bulk of the solid crystals is mainly composed of pure theophylline, as determined by XRPD.

Single-Crystal X-ray Diffraction Studies Single crystals of 1 were manually harvested from the crystallization vials and immediately immersed in highly viscous FOMBLIN Y perfluoropolyether vacuum oil (LVAC 140/13, Sigma-Aldrich) to avoid degradation caused by the evaporation of the solvent, then mounted on Mitegen Micromounts. Data were collected on a Bruker D8 Venture diffractometer (Cu Kα multilayer-monochromated radiation, λ = 1.54178 Å) controlled by the APEX2 software package.60,61 Images were processed using the software package SAINT+,62 and data were corrected for absorption by the multiscan semi-empirical method implemented in SADABS.63 The structure was solved using the direct methods algorithm implemented in SHELXS-97,64,65 which allowed the immediate location of most of non-hydrogen atoms. The remaining non-hydrogen atoms were located from difference Fourier maps calculated from successive full-matrix leastsquares refinement cycles on F2 using SHELXL-97,65,66 and refined using anisotropic displacement parameters. The hydrogen atoms bound to carbon were placed at their idealized positions using appropriate HFIX instructions in SHELXL: 137 for the –CH3 groups and 43 for the CH groups of the aromatic rings. These atoms were included in subsequent refinement cycles in riding motion approximation with isotropic thermal displacements parameters (Uiso) fixed at 1.2×Ueq or 1.5×Ueq of the parent carbon atoms. In opposition, H atoms bonded to nitrogen and oxygen were located by Fourier differences and the distance N–H and O–H fixed at 0.88 and 0.84 Å, respectively, with isotropic thermal displacements parameters (Uiso) fixed at 1.5×Ueq of the parent atoms. The last difference Fourier map synthesis of 1 showed the highest peak (0.307 eÅ-3) located at 0.62 Å from C15, and the deepest hole (-0.172 eÅ-3) at 1.90 Å from H17. Information concerning crystallographic data collection and structure refinement details is summarized in Table 1.



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Table 1. Experimental details for single crystal X-ray diffraction of Theophylline 4-aminosalicylic acid (2:1) Crystal data Chemical formula

2(C7H8N4O2)·(C7H7NO3)

Mr

513.48

Crystal system, space group

Monoclinic, P21/n

Temperature (K)

100

a, b, c (Å)

10.4505 (5), 12.4248 (5), 17.9950 (8)

β (°)

99.758 (3) 3

V (Å )

2302.76 (18)

Z

4 -3

Dx (Mg m )

1.481

Radiation type

Cu Kα

No. of reflections for cell measurement 3206

θ range (°) for cell measurement -1

4.3–71.6

µ (mm )

0.97

Crystal shape and colour

Colourless Plate

Crystal size (mm)

0.10 × 0.10 × 0.04

Data collection

Tmin, Tmax

0.909, 0.962

No. of measured, independent and observed [I > 2σ(I)] reflections

17152, 4341, 3368

Rint

0.037 -1

(sinθ/λ)max (Å )

0.615

Range of h, k, l

h = -12→6, k = -13→15, l = -18→22

Refinement

R[F2> 2σ(F2)], wR(F2), S

0.046,0.124,1.03

No. of reflections

4341

No. of parameters

356

No. of restraints

6

Weighting scheme, Where P = (Fo2 + 2Fc2)/3

w = 1/[σ2(Fo2) + (0.0618P)2 + 0.7781P]

Largest difference peak and hole

0.31, -0.17 e Å-3


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X-ray Powder Diffraction Characterization Analytical Studies: Routine X-ray powder diffraction data were collected using Cu Kα radiation (λ = 1.5418 Å) on a PANalytical X’Pert PRO diffractometer equipped with a PIXcel detector operating at 45 kV and 40 mA. For the diffracted beam an automatic variable divergence slit, with an irradiated length of 10 mm, was used. 2θ range: 5º 80º; step size: 0.039º (2θ). In order to check the stability of the new cocrystal phases in time and under exposure to moisture, powders of 1 and 2 were sealed in chambers with controlled relative humidity (75%) and temperature (21 ºC). XRPD measurements were performed ex situ at the beginning and 7, 15, 21, 35 and 42 days later. (See ESI for details) Thermal stability was estimated by performing variable temperature XRPD experiments using a custom made sample heater (supplied by Officina Elettrotecnica di Tenno, Ponte Arche, Italy), installed on a Bruker AXS D8 diffractometer. Data were collected in the interval 5-37° 2θ with temperatures between 30 and 210 °C, in 10 °C steps. Structural Studies of 2: for a complete XRPD structural determination, powders of 2 were gently ground in an agate mortar and deposited in the hollow of an aluminum holder equipped with a quartz monocrystal zero background plate. Diffraction data (Nifiltered Cu Kα radiation, λ= 1.5418 Å) were collected on a θ:θ vertical scan Bruker AXS D8 diffractometer, equipped with parallel (Soller) slits and a linear position sensitive Lynx eye detector. The generator was operated at 40 kV and 40 mA. Divergence slit used: 0.5°. Nominal resolution for the present setup is 0.08° 2θ (Cu Kα1) for the LaB6 peak at ca. 21.3° (2θ). Data were collected in the 5−105° 2θ range. Standard peak search methods and indexing of the first lines (2θ 10 ppm. The experimental 1H MAS NMR spectrum shows however that there are 1H resonances appearing at CSs at high frequency ranges (> 10 ppm), which are assigned to hydrogen



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bonded OH and NH functional groups. The hydrogen-bonded groups will be discussed ahead. The correctness of the XRPD model becomes evident from the remaining ssNMR discussion. The CS values of the three shoulders observed in the 1H MAS spectrum are centred at 8.35, 7.26 and 6.03 ppm after appropriate peak deconvolution and are assigned to the proton environments shown in Figure9. We have deconvoluted this region of the NMR spectrum with three Gaussian peaks and associated the three curves to the closest theoretical 1H CS peaks to be able to plot Figure S17. As expected, the resonances arising due to CH3 protons are overlapped and all six methyl protons appear around 3 ppm. Complete 1H spectral assignment was once again assisted by GIPAW CS calculations and the final results are summarized in Table S1. As mentioned in the experimental section, the proposed structure geometry of 2 was reoptimized at the DFT level by relaxing the proton positions as well as all the remaining heavier atoms, until a maximum force magnitude of 0.021 eV/Å is reached with respect to atom positions. The 1H and13C chemical shieldings of 2 were then calculated using the GIPAW formalism and compared with the experimental CSs for final structure validation (Figure S17and Table S1), showing that they present a very good agreement, thus strongly indicating that the DFT optimized XRPD model is correct. The comparison of calculated and experimental CSs represents thus a robust and independent validation of the structure. To provide a deeper structural insight in hydrogen bond connectivities and crystal packing arrangement, 2D 1H-1H DQ MAS spectroscopy was performed. This technique combines 1H CS resolution and information on 1H···1H proximities.81 The observation of individual DQ signals (along the indirect dimension in Figure 10), implies the existence of dipole-dipole couplings, between pairs of close1 H nuclei. The absence of DQ 1H cross peak indicates a lack of dipolar couplings, which can either be due to longdistances between two 1H spins (typically > 3.5 Å)82,83 or, in the presence of fast local molecular dynamics on time scales < 100 µs.84 As cocrystal 2 forms a network of hydrogen bonds the intensity of cross-peaks observed in Figure 10is mainly influenced by 1H···1H distances and not by molecular dynamics. The 2D spectrum of Figure 10 (correlations presented in detail in Table 4) shows that the two strong hydrogen bonded N-H (H17) and O-H (H7) protons appearing at 13.7 and 11.6 ppm, respectively, show DQ correlations with CH3 protons at δDQ = 16.7 ppm (cross-peak C) and δDQ = 14.6 ppm (cross-peak B), expected due to the short 1H···1H


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distance (< 3.5 Å) involving the corresponding protons. In addition, there are also correlations between the N-H protons and the aromatic protons δDQ = 19.7 ppm (crosspeak E) and δDQ = 22.1 ppm (cross-peak F), also expected as the distance between C-H and N-H protons is between 2.4-3.8 Å. The presence of 1H···1H proximities between chemically equivalent protons are expected to appear along the diagonal. Therefore, the absence of chemically equivalent hydrogen bonded N-H protons along the diagonal (expected at around δDQ = 27.4 ppm) indicates that equivalent N-H protons are not sufficiently close in space to generate DQ coherences and thus not visible. In the other hand, this spectrum shows that equivalent O-H protons are close enough (3.2 Å; Figure 14b, cross-peak G) to contribute with a faint DQ cross-peak at 23.2 ppm. This observation is in perfect agreement with the proposed DFT optimized XRPD model where OH groups are closer to other OH groups from adjacent molecules than NH groups are to each other. The remaining correlations observed arise from the dipolar couplings among CH3 groups (diagonal cross-peak at δDQ = 6.0 ppm), intramolecular connections between OH and CH aromatic protons (H7···H2, δDQ = 17.6 ppm) and between the O-H and N-H groups (δDQ = 25.3 ppm). Cross-peaks D and F correspond to intramolecular contacts, indicating the correlation between H7 and H2 [(or H3 or H1Y-H5): 4-aminobenzoic acid] and H17 and H14 (theophylline), respectively. All the remaining observed correlations are intermolecular contacts between 4-aminobenzoic acid and theophylline moieties. In the case of correlations C-E, one of the cross-peaks (on the right of the diagonal) is not observed in Figure 10. As expected, by lowering the contour level in the spectrum (and therefore increasing the noise level), these correlations appear weaker than the remaining peaks (Figure not shown).



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Figure 10 (a) 2D 1H-1H DQ-SQ CRAMPS spectrum of 2 recorded at B0=16.4 T and MAS rate of 30 kHz. 224 t1 points with 16 scans each were acquired along the F1 dimension; the DQ excitation and reconversion time was set to 58 µs. (b) Crystal structure scheme illustrating the intra- and intermolecular contacts, with corresponding distances, of correlations highlighted in (a). Numbers indicated in the scheme correspond to the shortest distances in Å found in the structure for each pair of protons. The colors of the dashed lines observed in the 2D spectrum correspond to 1H···1H distances illustrated in the structure scheme (right) with the same color code.

Table 4. List of experimental 1H δSQ and δDQ observed in Figure 10. Proton label Cross Peak (functional groups in close proximity)

δSQ ;δSQ / ppm

δDQ / ppm

3.0 ; 3.0

6.0

11.6 ; 3.0

14.6

H17 ··· H11-H13

13.7 ; 3.0

16.7

H7 ··· H2

11.6 ; 6.0

17.6

13.7 ; 6.0

19.7

H11-H13 ··· H11-H13 A (CH3H3C) H7 ··· H11-H13 B (OHH3C) C (NHH3C) D (OHHC) H17 ··· H2 E (NHHC) F (NHHC)

H17··· H18

13.7 ; 8.4

22.1

G (OHHO)

H7 ··· H7

11.6 ; 11.6

23.2

H (NHHO)

H17 ··· H7

13.7 ; 11.6

25.3


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Thermal Stability: Thermodiffractometry studies performed on powder batches revealed the title compound is stable, at least, up to 180 ºC (Figure S10). Lattice parameters of the 30 and 180 °C patterns were determined by standard indexing procedures and refined by the le Bail method: At 30 °C,

a =7.023, b = 8.782, c = 13.117 Å, α=96.9, β = 90.8, γ=115.5º;

At 180 °C,

a =7.137, b = 8.890, c = 13.164 Å, α=96.6, β = 91.07, γ=116.2º.

Thermal expansion coefficients, in the form of ∂lnx/∂T (x = a, b, c and V) are 108, 82, 24 and 180 MK-1, respectively. However, the actual oblique crystal symmetry requires a deeper evaluation (than the simple linear expansion coefficients) of the thermal strain properties, as shown by the thermal strain tensor visualized in Figure S11 up. From this Figure, it can easily be seen that the direction of maximum thermal strain is approximately aligned with the [-110] direction. As in all non-cubic systems, this direction does not coincide with the normal to the (-110) plane, but is not too far from it. Consequently, as a first approximation, the stacking normal to the (-110) plane, depicted in Figure S11 bottom, can be assumed to be responsible for the “softer”, more easily perturbed, crystal direction. More precisely, the aromatic rings lie in the (-540) plane, which, to a good approximation, matches the “ideal” (-110) [or, equivalently, the (550)] one. We can further observe that, while the softer direction appears to be related to the π-π stacking occurring along the b-2a direction, the thermal strain is minimal along c, with no obvious, nor simple, structural interpretation.

Stability to Moisture Since APIs need to be distributed and marketed as materials stable in time for prolonged periods of time, and often under non-ideal conditions (presence of aerial moisture or occasional exposure to heat), we performed stability tests in order to verify resistance to moist environments. Unfortunately, we found that compound 1, if exposed to a 75% relative humidity at 21 ºC, starts to be considerably degraded already after 7 days, the product of decomposition remaining so far unidentified (See ESI for details). At variance, no



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changes have been observed in the XRPD traces of the theophylline 4-aminobenzoic acid (1:1) even after 35 days under the same T and relative humidity conditions. Figure S7 nicely confirms that compound 2 shows significant chemical stability toward high humidity environments and, as witnessed by with the results of thermodiffractometric measurements presented above, also a relevant thermal inertness.

4. Conclusions Two new cocrystals containing theophylline were prepared and their structures were determined either by single crystal or powder diffraction X-ray analyses. Compound 1 (bis-theophylline 4-aminosalicylic acid) exhibits infinite planar structures containing most of the hydrogen bonds present in the crystal. Compound 2 (theophylline 4aminobenzoic acid) has a peculiar structure, as rather unexpectedly, the amino groups do not participate in hydrogen bonding. Proof of absence of intermolecular interaction engaging the amino groups is also given by FT-IR and ssNMR spectroscopies. The latter technique showed to be particularly useful, since the experimental 1H and

13

C

NMR CSs are in good agreement with calculated CSs from the resulting DFT geometryoptimized XRPD structure model. Excluding the hydrogen atoms, the DFT structure was highly superimposable to the XRPD experimental model. Both compounds are thermally stable up to (at least) 130 ºC, while, in moist environments, only compound 2 survives. Acknowledgements The project “Factoría de Cristallización, CONSOLIDER INGENIO-2010” provided Xray structural facilities for this work. This work was also developed in the scope of the project CICECO-Aveiro Institute of Materials (Ref. FCT UID /CTM /50011/2013), financed by national funds through the FCT/MEC and when applicable co-financed by FEDER under the PT2020 Partnership Agreement. The Portuguese NMR Network (RNRMN) is also acknowledged. We thank FCT for the awarded development Grant (IF/01401/2013) to L.M., for the postdoc grant (SFRH/BPD/65978/2009) awarded to M.S. and the funded R&D project EXPL/QEQ-QFI/2078/2013. The authors heartily thanks the Master of Crystallography and Crystallization, Universidad Internacional Menéndez Pelayo, 2013 Edition, for giving them the opportunity of setting up this collaboration.


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Supporting Information Available

Graphical representation of synthons present in the crystal structures; additional preparation attempts to prepare the cocrystals with the corresponding X-ray powder diffractograms; thermogravimetric analyses; moisture and thermal stability tests; thermal strain tensor determination; FT-IR, FT-Raman and 13C CPMAS NMR spectra; DFT calculations of 13C chemical shifts. This information is available free of charge via the Internet at http://pubs.acs.org/. References 1. Childs, S. L.; Stahly, G. P.; Park, A., Mol. Pharm. 2007, 4, 323-338. 2. Good, D. J.; Rodríguez-Hornedo, N., Cryst. Growth Des. 2009, 9, 2252-2264. 3. Jayasankar, A.; Good, D. J.; Rodríguez-Hornedo, N., Mol. Pharm. 2007, 4, 360-372. 4. Jafari, M. T.; Rezaei, B.; Javaheri, M., Food Chem. 2011, 126, 1964-1970. 5. Trask, A. V.; Motherwell, W. D. S.; Jones, W., Int. J. Pharm. 2006, 320, 114-123. 6. Ebisuzaki, Y.; Boyle, P. D.; Smith, J. A., Acta Crystallogr. Sect. C 1997, 53, 777779. 7. Zhang, S.; Fischer, A., Acta Crystallogr. Sect. E 2011, 67, o3357. 8. Khamar, D.; Pritchard, R. G.; Bradshaw, I. J.; Hutcheon, G. A.; Seton, L., Acta

Crystallogr. Sect. C 2011, 67, o496-o499. 9. Fucke, K.; McIntyre, G. J.; Wilkinson, C.; Henry, M.; Howard, J. A. K.; Steed, J. W.,

Cryst. Growth Des. 2012, 12, 1395-1401. 10. Sun, C.; Zhou, D.; Grant, D. J. W.; Young, V. G., Jr, Acta Crystallogr. Sect. E 2002,

58, o368-o370. 11.Eddleston, M. D.; Lloyd, G. O.; Jones, W., Chem. Commun. 2012, 48, 8075-8077 12. Shefter, E.; Sackman, P., J. Pharm. Sci. 1971, 60, 282-286. 13. Nakao, S.; Fujii, S.; Sakaki, T.; Tomita, K.-I., Acta Crystallogr. Sect. B 1977, 33, 1373-1378.



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For Table of Contents Use Only X-Ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding José A. Fernandes,a* Mariana Sardo,a Luís Mafra,a* Duane Choquesillo-Lazarte,b Norberto Masciocchic

a

CICECO - Aveiro Institute of Materials, Department of Chemistry, University of

Aveiro, 3810-193 Aveiro, Portugal b

Laboratorio de Estudios Cristalográficos, IACT, CSIC-Universidad de Granada, Av. de las Palmeras 4, E-18100 Armilla, Granada, Spain

c

Dipartimento di Scienza e Alta Tecnologia, Università dell’Insubria, 22100 Como,

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

Two new cocrystal forms of theophylline were prepared by liquid assisted grinding. While compound 1 (theophylline: 4-aminosalicylic acid 2:1) was characterized by single crystal X-Ray diffraction, the crystal structure of compound 2 (theophylline: 4aminobenzoic acid 1:1) was determined combining X-ray powder diffraction, solid-state NMR and DFT calculations. 2 presents an unusual non-hydrogen-bridging -NH2 moiety.


X-ray and NMR Crystallography Studies of Novel

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