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Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 69| Part 3| March 2013| Pages o378-o379

Fluconazole–malonic acid (1/1)

aKrka d.d., Šmarješka cesta 6, 8501 Novo mesto, Slovenia, bUniversity of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia, and cUniversity of Ljubljana, Faculty of Chemistry and Chemical Technology, Aškerčeva 5, 1000 Ljubljana, Slovenia
*Correspondence e-mail: nina.lah@fkkt.uni-lj.si

(Received 24 January 2013; accepted 5 February 2013; online 13 February 2013)

Co-crystallizaton of the anti­fungal drug fluconazole [2-(2,4-difluoro­phen­yl)-1,3-bis­(1H-1,2,4-triazol-1-yl)propan-2-ol] with malonic acid in acetonitrile solution resulted in the formation of the title 1:1 co-crystal, C13H12F2N6O·C3H4O4. The geometry around the central fluconazole atom is distorted tetrahedral. The dihedral angles between the triazole rings and the fluorinated phenyl ring are 30.64 (7) and 61.91 (5)°. In the crystal, the basic packing motif may be envisioned as a cyclic aggregate formed of two fluconazole mol­ecules linked by two malonic acid mol­ecules through O—H⋯N and O—H⋯O hydrogen bonds. Such aggregates are further connected into (001) layers by further O—H⋯N hydrogen bonds. The structure also features weak non-classical C—H⋯O and C—H⋯N inter­actions.

Related literature

For general aspects of pharmaceutical co-crystals, see, for example: Brittain et al. (2012a[Brittain, H. G. (2012a). Cryst. Growth Des. 12, 1046-1054.],b[Brittain, H. G. (2012b). Cryst. Growth Des. 12, 5823-5832.]). For known fluconazole co-crystals, see: Kastelic et al. (2010[Kastelic, J., Hodnik, Ž., Šket, P., Plavec, J., Lah, N., Leban, I., Pajk, M., Planinšek, O. & Kikelj, D. (2010). Cryst. Growth Des. 10, 4943-4953.], 2011[Kastelic, J., Lah, N., Kikelj, D. & Leban, I. (2011). Acta Cryst. C67, o370-o372.]). For regulatory classification of pharmaceutical co-crystals, see: US Food and Drug Administration (2011[US Food and Drug Administration (2011). Guidance for Industry; Regulatory Classification of Pharmaceutical Co-crystals. Silver Spring, MD.]).

[Scheme 1]

Experimental

Crystal data
  • C13H12F2N6O·C3H4O4

  • Mr = 410.35

  • Orthorhombic, P b c n

  • a = 14.7196 (2) Å

  • b = 8.4891 (1) Å

  • c = 28.1096 (4) Å

  • V = 3512.47 (8) Å3

  • Z = 8

  • Mo Kα radiation

  • μ = 0.13 mm−1

  • T = 150 K

  • 0.18 × 0.18 × 0.12 mm

Data collection
  • Nonius Kappa CCD diffractometer

  • 7522 measured reflections

  • 4012 independent reflections

  • 3069 reflections with I > 2σ(I)

  • Rint = 0.024

Refinement
  • R[F2 > 2σ(F2)] = 0.038

  • wR(F2) = 0.100

  • S = 1.03

  • 4012 reflections

  • 274 parameters

  • H atoms treated by a mixture of independent and constrained refinement

  • Δρmax = 0.32 e Å−3

  • Δρmin = −0.29 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O1—H1⋯O11M 0.89 (2) 1.94 (2) 2.8057 (14) 166.2 (18)
O12M—H11⋯N14i 0.88 (2) 1.86 (2) 2.6830 (17) 156 (2)
O21M—H12⋯N24ii 0.88 (3) 1.89 (3) 2.7606 (17) 171 (2)
C6—H6⋯N14i 0.93 2.61 3.484 (2) 156
C12M—H12B⋯O11Miii 0.97 2.44 3.3880 (18) 165
C13—H13⋯O12Miv 0.93 2.54 3.3144 (19) 141
C25—H25⋯O11M 0.93 2.40 3.2018 (18) 144
C25—H25⋯O22Miii 0.93 2.37 3.0032 (19) 125
Symmetry codes: (i) [-x+1, y, -z+{\script{3\over 2}}]; (ii) [-x+{\script{1\over 2}}, y-{\script{1\over 2}}, z]; (iii) [-x+{\script{1\over 2}}, y+{\script{1\over 2}}, z]; (iv) [x+{\script{1\over 2}}, y-{\script{1\over 2}}, -z+{\script{3\over 2}}].

Data collection: COLLECT (Nonius, 1998[Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.]); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); data reduction: DENZO and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]).

Supporting information


Comment top

There has been an intense interest in the preparation and characterization of pharmaceutical cocrystals which is evident from the increasing number of research publications on this topic in the past decade (Brittain, 2012a,b and references therein). Pharmaceutical cocrystals present a sub-set of multicomponent crystal solid forms of the active pharmaceutical ingredient (API) with the ability to modulate API's physicochemical properties and to provide intellectual property implications. Until now no cocrystal drug substances have received regulatory approval yet. The relevance of cocrystals in drug formulation research and development has been confirmed with the publication of new U.S. Food and Drug Administration's (FDA) draft guidance for the regulatory classification of pharmaceutical cocrystals in December 2011 (US Food and Drug Administration, 2011).

Fluconazole is a wide spectrum triazole antifungal agent which is only slightly soluble in water. It is a weak base (pKa value of 1.76 for its conjugated acid). Therefore, the formation of a salt as a mean to improve solubility properties, could only be expected with very strong acids. On the other hand, cocrystallization offers possibilities to influence the solubility with numerous coformers. Along these lines, we have focused our research on the preparation of new fluconazole cocrystals. The results of our systematic cocrystallization screening are the cocrystals of fluconazole with three dicarboxylic acids, namely maleic, glutaric and fumaric (Kastelic et al., 2010) and a cocrystal with salicylic acid (Kastelic et al., 2011). As a continuation of our work we present here the crystal structure of a 1:1 cocrystal of fluconazole with malonic acid.

The asymmetric unit consists of one fluconazole and one malonic acid molecule, both in their neutral forms (Fig. 1). Both crystal formers can act as donors and/or acceptors in hydrogen bonding. As expected, the packing arrangement of the two molecules in the crystal is governed by hydrogen-bond interactions. A basic packing motif may be envisioned as a ring in which two fluconazole molecules (related by a two fold axis; symmetry code: +1-x, y, +1.5-z) are bridged by two malonic acid molecules by hydrogen bond interactions including fluconazole OH group as a donor to carboxylic O atom of malonic acid (for hydrgen bond geometry see Table 1). Additionally, the same carboxylic group acts as a donor to one of the triazole N atoms of the fluconazole moiety (Fig. 2). Such rings are further connected into two-dimensional layers through the interaction of the second carboxylic group of malonic acid with another fluconazole triazole nitrogen atom (N24) of the adjacent building unit . The layers are oriented perpendicular to the z axis (Fig. 3). Additionally, the structure is stabilized by non-classical H-bond interactions (for details see Table 1).

The packing in the title compound does not resemble the structures of other known fluconazole cocrystals with carboxylic acids where the formation of zigzag coloumns or sheets were observed. The generation of a flat-layered structure provides the possibilities for the improved mechanical properties relevant to the tablet formulation. Their investigations are underway.

Related literature top

For general aspects of pharmaceutical co-crystals, see, for example: Brittain et al. (2012a,b). For known fluconazole co-crystals, see: Kastelic et al. (2010, 2011). For regulatory classification of pharmaceutical co-crystals, see: US Food and Drug Administration (2011).

Experimental top

Fluconazole was obtained from Krka d.d., Novo mesto, malonic acid was obtained from Merck and both were used without further purification. Equimolar amounts of fluconazole (100 mg, 0.33 mmol) and malonic acid (34.3 mg, 0.33 mmol) were dissolved in 3 ml of acetonitrile by heating at 50°C. The clear solution was slowly cooled to ambient temperature and solvent was then allowed to evaporate to form a transparent film from which crystals grew in 72 h. Crystals suitable for single-crystal X-ray diffraction analysis were prepared by dissolving fluconazole (100.0 mg, 0.33 mmol) and malonic acid (34.3 mg, 0.33 mmol) in 3 ml of acetonitrile by heating at 50°C. Seeds from screening experiment described above were added to clear solution. The mixture was slowly cooled to ambient temperature and allowed to evaporate slowly until the crystals of suitable size and quality appeared.

Refinement top

All H atoms were initially found in a Fourier-difference map, but they were repositioned to their calculated positions and were refined using a riding model. Aromatic H atoms were permitted to ride with C—H = 0.93 Å and Ueq(H) = 1.2Uiso(C). H atoms of the CH2 group were constrained with C—H = 0.97 Å and Ueq(H)=1.2Uiso(C). H atoms of hydroxyl groups involved in the formation of hydrogen bonds were freely refined.

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. The asymmetric unit of the title compound, showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level.
[Figure 2] Fig. 2. Part of the crystal structure showing the formation of a cyclic hydrogen bonded heterotetramer built from two fluconazole and two malonic acid molecules (projection down the b axis). Symmetry code for generation of the tetramer: -x+1, y, -z+1.5.
[Figure 3] Fig. 3. Two-dimensional (001) layers viewed down the b axis. The tetrameric buliding units are alternately coloured red and blue to emphasize their linkage. Hydrogen bonds are indicated as dashed lines.
(I) top
Crystal data top
C13H12F2N6O·C3H4O4Dx = 1.552 Mg m3
Mr = 410.35Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, PbcnCell parameters from 4524 reflections
a = 14.7196 (2) Åθ = 1.0–27.5°
b = 8.4891 (1) ŵ = 0.13 mm1
c = 28.1096 (4) ÅT = 150 K
V = 3512.47 (8) Å3Hexagonal plates, colourless
Z = 80.18 × 0.18 × 0.12 mm
F(000) = 1696
Data collection top
Nonius Kappa CCD
diffractometer
3069 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.024
Graphite monochromatorθmax = 27.5°, θmin = 2.0°
ω–scans at κ=55°h = 1919
7522 measured reflectionsk = 1111
4012 independent reflectionsl = 3636
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.038Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.100H atoms treated by a mixture of independent and constrained refinement
S = 1.03 w = 1/[σ2(Fo2) + (0.0504P)2 + 1.0478P]
where P = (Fo2 + 2Fc2)/3
4012 reflections(Δ/σ)max = 0.001
274 parametersΔρmax = 0.32 e Å3
0 restraintsΔρmin = 0.29 e Å3
Crystal data top
C13H12F2N6O·C3H4O4V = 3512.47 (8) Å3
Mr = 410.35Z = 8
Orthorhombic, PbcnMo Kα radiation
a = 14.7196 (2) ŵ = 0.13 mm1
b = 8.4891 (1) ÅT = 150 K
c = 28.1096 (4) Å0.18 × 0.18 × 0.12 mm
Data collection top
Nonius Kappa CCD
diffractometer
3069 reflections with I > 2σ(I)
7522 measured reflectionsRint = 0.024
4012 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0380 restraints
wR(F2) = 0.100H atoms treated by a mixture of independent and constrained refinement
S = 1.03Δρmax = 0.32 e Å3
4012 reflectionsΔρmin = 0.29 e Å3
274 parameters
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.54177 (9)0.13534 (17)0.64550 (5)0.0206 (3)
C20.58200 (10)0.00574 (18)0.63211 (5)0.0244 (3)
C30.55741 (11)0.15059 (19)0.64974 (6)0.0293 (3)
H30.58630.24250.64000.035*
C40.48774 (11)0.15328 (19)0.68268 (6)0.0288 (3)
C50.44513 (11)0.01972 (19)0.69784 (6)0.0286 (3)
H50.39870.02480.72020.034*
C60.47258 (10)0.12392 (18)0.67916 (5)0.0241 (3)
H60.44390.21540.68940.029*
F20.65063 (6)0.00225 (11)0.59954 (3)0.0341 (2)
F40.46114 (7)0.29475 (11)0.70033 (4)0.0425 (3)
C100.57056 (9)0.29636 (17)0.62593 (5)0.0200 (3)
O10.51652 (7)0.41828 (12)0.64549 (3)0.0222 (2)
C210.56338 (10)0.29942 (17)0.57093 (5)0.0230 (3)
H21A0.60910.23020.55750.028*
H21B0.50420.26040.56140.028*
N210.57605 (8)0.45798 (15)0.55235 (4)0.0225 (3)
N220.65894 (9)0.51379 (18)0.53827 (5)0.0319 (3)
C230.64032 (11)0.6622 (2)0.52823 (6)0.0322 (4)
H230.68430.73220.51740.039*
N240.55240 (8)0.70550 (15)0.53487 (4)0.0262 (3)
C250.51475 (10)0.57304 (18)0.55025 (5)0.0233 (3)
H250.45390.56200.55850.028*
C110.66769 (9)0.33814 (19)0.64058 (5)0.0224 (3)
H11A0.70950.26500.62560.027*
H11B0.68200.44310.62920.027*
N110.68076 (8)0.33275 (14)0.69205 (4)0.0206 (3)
C150.64684 (10)0.42420 (18)0.72607 (5)0.0231 (3)
H150.60540.50530.72120.028*
N140.68090 (9)0.38273 (15)0.76801 (4)0.0260 (3)
C130.73709 (11)0.26218 (19)0.75655 (5)0.0292 (3)
H130.77140.20880.77920.035*
N120.73963 (9)0.22619 (15)0.71109 (4)0.0288 (3)
O11M0.34684 (6)0.39993 (12)0.60035 (4)0.0233 (2)
O12M0.25373 (8)0.51564 (13)0.65244 (4)0.0285 (2)
C11M0.27804 (9)0.47413 (16)0.60930 (5)0.0195 (3)
C12M0.21064 (9)0.52498 (17)0.57209 (5)0.0209 (3)
H12A0.24180.54110.54210.025*
H12B0.18330.62420.58150.025*
C13M0.13749 (10)0.40240 (17)0.56589 (5)0.0219 (3)
O21M0.06834 (7)0.45375 (13)0.54002 (4)0.0286 (3)
O22M0.14215 (8)0.27195 (13)0.58274 (5)0.0389 (3)
H10.4594 (14)0.409 (2)0.6360 (7)0.039 (5)*
H110.2895 (15)0.474 (3)0.6739 (8)0.050 (6)*
H120.0268 (17)0.380 (3)0.5357 (9)0.068 (8)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0193 (7)0.0243 (7)0.0182 (6)0.0026 (6)0.0046 (5)0.0010 (6)
C20.0215 (7)0.0309 (8)0.0208 (7)0.0057 (6)0.0003 (6)0.0017 (6)
C30.0352 (8)0.0239 (8)0.0288 (8)0.0076 (7)0.0042 (7)0.0020 (6)
C40.0347 (8)0.0235 (8)0.0281 (8)0.0023 (7)0.0050 (7)0.0044 (6)
C50.0267 (8)0.0319 (9)0.0273 (8)0.0005 (7)0.0019 (6)0.0018 (6)
C60.0231 (7)0.0241 (8)0.0250 (7)0.0042 (6)0.0001 (6)0.0018 (6)
F20.0322 (5)0.0348 (5)0.0351 (5)0.0114 (4)0.0111 (4)0.0001 (4)
F40.0563 (6)0.0244 (5)0.0468 (6)0.0023 (5)0.0060 (5)0.0071 (4)
C100.0182 (6)0.0231 (7)0.0188 (7)0.0048 (6)0.0018 (5)0.0028 (6)
O10.0202 (5)0.0232 (5)0.0233 (5)0.0050 (4)0.0017 (4)0.0039 (4)
C210.0264 (7)0.0240 (8)0.0185 (7)0.0038 (6)0.0034 (6)0.0002 (6)
N210.0206 (6)0.0281 (7)0.0188 (6)0.0021 (5)0.0007 (5)0.0014 (5)
N220.0226 (6)0.0449 (9)0.0282 (7)0.0032 (6)0.0054 (5)0.0101 (6)
C230.0271 (8)0.0390 (10)0.0306 (8)0.0031 (7)0.0039 (7)0.0110 (7)
N240.0267 (6)0.0296 (7)0.0223 (6)0.0001 (6)0.0016 (5)0.0028 (5)
C250.0215 (7)0.0269 (8)0.0215 (7)0.0018 (6)0.0006 (6)0.0007 (6)
C110.0202 (7)0.0291 (8)0.0180 (7)0.0003 (6)0.0002 (5)0.0014 (6)
N110.0186 (5)0.0232 (6)0.0201 (6)0.0005 (5)0.0033 (5)0.0020 (5)
C150.0226 (7)0.0237 (8)0.0230 (7)0.0001 (6)0.0024 (6)0.0001 (6)
N140.0293 (7)0.0272 (7)0.0214 (6)0.0056 (5)0.0025 (5)0.0015 (5)
C130.0334 (8)0.0286 (8)0.0255 (8)0.0013 (7)0.0073 (6)0.0054 (6)
N120.0309 (7)0.0297 (7)0.0260 (6)0.0079 (6)0.0067 (5)0.0028 (5)
O11M0.0208 (5)0.0226 (5)0.0265 (5)0.0019 (4)0.0007 (4)0.0007 (4)
O12M0.0301 (5)0.0361 (6)0.0193 (5)0.0079 (5)0.0008 (5)0.0002 (5)
C11M0.0203 (7)0.0157 (7)0.0227 (7)0.0030 (6)0.0015 (5)0.0008 (5)
C12M0.0217 (7)0.0199 (7)0.0211 (7)0.0010 (6)0.0001 (5)0.0018 (5)
C13M0.0214 (7)0.0213 (8)0.0229 (7)0.0025 (6)0.0023 (6)0.0019 (6)
O21M0.0254 (6)0.0267 (6)0.0338 (6)0.0024 (5)0.0108 (5)0.0061 (5)
O22M0.0306 (6)0.0216 (6)0.0646 (8)0.0022 (5)0.0169 (6)0.0094 (6)
Geometric parameters (Å, º) top
C1—C21.388 (2)C23—H230.9300
C1—C61.394 (2)N24—C251.326 (2)
C1—C101.533 (2)C25—H250.9300
C2—F21.3637 (17)C11—N111.4601 (17)
C2—C31.374 (2)C11—H11A0.9700
C3—C41.382 (2)C11—H11B0.9700
C3—H30.9300N11—C151.3292 (19)
C4—F41.3570 (18)N11—N121.3623 (17)
C4—C51.364 (2)C15—N141.3285 (18)
C5—C61.388 (2)C15—H150.9300
C5—H50.9300N14—C131.355 (2)
C6—H60.9300C13—N121.314 (2)
C10—O11.4163 (16)C13—H130.9300
C10—C111.5296 (19)O11M—C11M1.2190 (17)
C10—C211.5497 (18)O12M—C11M1.3126 (17)
O1—H10.89 (2)O12M—H110.88 (2)
C21—N211.4558 (19)C11M—C12M1.505 (2)
C21—H21A0.9700C12M—C13M1.507 (2)
C21—H21B0.9700C12M—H12A0.9700
N21—C251.3311 (19)C12M—H12B0.9700
N21—N221.3674 (18)C13M—O22M1.2063 (18)
N22—C231.320 (2)C13M—O21M1.3247 (17)
C23—N241.358 (2)O21M—H120.88 (3)
C2—C1—C6115.84 (14)N24—C23—H23122.4
C2—C1—C10123.64 (12)C25—N24—C23102.34 (13)
C6—C1—C10120.51 (13)N24—C25—N21110.69 (13)
F2—C2—C3117.17 (13)N24—C25—H25124.7
F2—C2—C1118.65 (13)N21—C25—H25124.7
C3—C2—C1124.18 (14)N11—C11—C10112.50 (11)
C2—C3—C4116.86 (14)N11—C11—H11A109.1
C2—C3—H3121.6C10—C11—H11A109.1
C4—C3—H3121.6N11—C11—H11B109.1
F4—C4—C5119.27 (14)C10—C11—H11B109.1
F4—C4—C3118.27 (14)H11A—C11—H11B107.8
C5—C4—C3122.46 (15)C15—N11—N12110.12 (12)
C4—C5—C6118.58 (14)C15—N11—C11130.18 (12)
C4—C5—H5120.7N12—N11—C11119.60 (11)
C6—C5—H5120.7N14—C15—N11109.99 (13)
C5—C6—C1122.06 (14)N14—C15—H15125.0
C5—C6—H6119.0N11—C15—H15125.0
C1—C6—H6119.0C15—N14—C13102.69 (12)
O1—C10—C11104.54 (11)N12—C13—N14115.10 (13)
O1—C10—C1110.91 (11)N12—C13—H13122.5
C11—C10—C1111.62 (11)N14—C13—H13122.5
O1—C10—C21109.67 (11)C13—N12—N11102.10 (12)
C11—C10—C21109.17 (11)C11M—O12M—H11111.3 (14)
C1—C10—C21110.74 (11)O11M—C11M—O12M123.77 (13)
C10—O1—H1110.4 (13)O11M—C11M—C12M123.54 (13)
N21—C21—C10111.39 (11)O12M—C11M—C12M112.67 (12)
N21—C21—H21A109.3C11M—C12M—C13M110.69 (12)
C10—C21—H21A109.3C11M—C12M—H12A109.5
N21—C21—H21B109.3C13M—C12M—H12A109.5
C10—C21—H21B109.3C11M—C12M—H12B109.5
H21A—C21—H21B108.0C13M—C12M—H12B109.5
C25—N21—N22109.74 (13)H12A—C12M—H12B108.1
C25—N21—C21127.41 (13)O22M—C13M—O21M124.14 (14)
N22—N21—C21122.58 (12)O22M—C13M—C12M123.20 (13)
C23—N22—N21101.97 (12)O21M—C13M—C12M112.65 (12)
N22—C23—N24115.26 (14)C13M—O21M—H12112.1 (16)
N22—C23—H23122.4
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···O11M0.89 (2)1.94 (2)2.8057 (14)166.2 (18)
O12M—H11···N14i0.88 (2)1.86 (2)2.6830 (17)156 (2)
O21M—H12···N24ii0.88 (3)1.89 (3)2.7606 (17)171 (2)
C6—H6···N14i0.932.613.484 (2)156
C12M—H12B···O11Miii0.972.443.3880 (18)165
C13—H13···O12Miv0.932.543.3144 (19)141
C25—H25···O11M0.932.403.2018 (18)144
C25—H25···O22Miii0.932.373.0032 (19)125
Symmetry codes: (i) x+1, y, z+3/2; (ii) x+1/2, y1/2, z; (iii) x+1/2, y+1/2, z; (iv) x+1/2, y1/2, z+3/2.

Experimental details

Crystal data
Chemical formulaC13H12F2N6O·C3H4O4
Mr410.35
Crystal system, space groupOrthorhombic, Pbcn
Temperature (K)150
a, b, c (Å)14.7196 (2), 8.4891 (1), 28.1096 (4)
V3)3512.47 (8)
Z8
Radiation typeMo Kα
µ (mm1)0.13
Crystal size (mm)0.18 × 0.18 × 0.12
Data collection
DiffractometerNonius Kappa CCD
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
7522, 4012, 3069
Rint0.024
(sin θ/λ)max1)0.649
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.038, 0.100, 1.03
No. of reflections4012
No. of parameters274
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.32, 0.29

Computer programs: COLLECT (Nonius, 1998), DENZO and SCALEPACK (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), ORTEP-3 for Windows (Farrugia, 2012), SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···O11M0.89 (2)1.94 (2)2.8057 (14)166.2 (18)
O12M—H11···N14i0.88 (2)1.86 (2)2.6830 (17)156 (2)
O21M—H12···N24ii0.88 (3)1.89 (3)2.7606 (17)171 (2)
C6—H6···N14i0.932.613.484 (2)156
C12M—H12B···O11Miii0.972.443.3880 (18)165
C13—H13···O12Miv0.932.543.3144 (19)141
C25—H25···O11M0.932.403.2018 (18)144
C25—H25···O22Miii0.932.373.0032 (19)125
Symmetry codes: (i) x+1, y, z+3/2; (ii) x+1/2, y1/2, z; (iii) x+1/2, y+1/2, z; (iv) x+1/2, y1/2, z+3/2.
 

Acknowledgements

The financial support of the Slovenian Ministry of Education, Science, Culture and Sport through grant P1–175–103 is gratefully acknowledged. JK thanks ARRS for funding through the Innovative Scheme supported financially by the European Social Fund.

References

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First citationUS Food and Drug Administration (2011). Guidance for Industry; Regulatory Classification of Pharmaceutical Co-crystals. Silver Spring, MD.

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Volume 69| Part 3| March 2013| Pages o378-o379
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