Fluconazole-malonic acid (1/1).

Co-crystallizaton of the anti-fungal drug fluconazole [2-(2,4-difluoro-phen-yl)-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 mol-ecules linked by two malonic acid mol-ecules 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 inter-actions.

Related literature

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

Crystal data

C13H12F2N6O·C3H4O4

M = 410.35

Orthorhombic,

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)

R int = 0.024

Refinement

R[F 2 > 2σ(F 2)] = 0.038

wR(F 2) = 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

Data collection: COLLECT (Nonius, 1998 ▶); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO and SCALEPACK; 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 and PLATON (Spek, 2009 ▶).

Click here for additional data file.

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536813003656/gk2552sup1.cif

Click here for additional data file.

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813003656/gk2552Isup2.hkl

Click here for additional data file.

Supplementary material file. DOI: 10.1107/S1600536813003656/gk2552Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

C13H12F2N6O·C3H4O4	Dx = 1.552 Mg m−3
Mr = 410.35	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pbcn	Cell parameters from 4524 reflections
a = 14.7196 (2) Å	θ = 1.0–27.5°
b = 8.4891 (1) Å	µ = 0.13 mm−1
c = 28.1096 (4) Å	T = 150 K
V = 3512.47 (8) Å3	Hexagonal plates, colourless
Z = 8	0.18 × 0.18 × 0.12 mm
F(000) = 1696

Nonius Kappa CCD diffractometer	3069 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.024
Graphite monochromator	θmax = 27.5°, θmin = 2.0°
ω–scans at κ=55°	h = −19→19
7522 measured reflections	k = −11→11
4012 independent reflections	l = −36→36

Refinement on F2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.038	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.100	H 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 parameters	Δρmax = 0.32 e Å−3
0 restraints	Δρmin = −0.29 e Å−3

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.

	x	y	z	Uiso*/Ueq
C1	0.54177 (9)	0.13534 (17)	0.64550 (5)	0.0206 (3)
C2	0.58200 (10)	−0.00574 (18)	0.63211 (5)	0.0244 (3)
C3	0.55741 (11)	−0.15059 (19)	0.64974 (6)	0.0293 (3)
H3	0.5863	−0.2425	0.6400	0.035*
C4	0.48774 (11)	−0.15328 (19)	0.68268 (6)	0.0288 (3)
C5	0.44513 (11)	−0.01972 (19)	0.69784 (6)	0.0286 (3)
H5	0.3987	−0.0248	0.7202	0.034*
C6	0.47258 (10)	0.12392 (18)	0.67916 (5)	0.0241 (3)
H6	0.4439	0.2154	0.6894	0.029*
F2	0.65063 (6)	−0.00225 (11)	0.59954 (3)	0.0341 (2)
F4	0.46114 (7)	−0.29475 (11)	0.70033 (4)	0.0425 (3)
C10	0.57056 (9)	0.29636 (17)	0.62593 (5)	0.0200 (3)
O1	0.51652 (7)	0.41828 (12)	0.64549 (3)	0.0222 (2)
C21	0.56338 (10)	0.29942 (17)	0.57093 (5)	0.0230 (3)
H21A	0.6091	0.2302	0.5575	0.028*
H21B	0.5042	0.2604	0.5614	0.028*
N21	0.57605 (8)	0.45798 (15)	0.55235 (4)	0.0225 (3)
N22	0.65894 (9)	0.51379 (18)	0.53827 (5)	0.0319 (3)
C23	0.64032 (11)	0.6622 (2)	0.52823 (6)	0.0322 (4)
H23	0.6843	0.7322	0.5174	0.039*
N24	0.55240 (8)	0.70550 (15)	0.53487 (4)	0.0262 (3)
C25	0.51475 (10)	0.57304 (18)	0.55025 (5)	0.0233 (3)
H25	0.4539	0.5620	0.5585	0.028*
C11	0.66769 (9)	0.33814 (19)	0.64058 (5)	0.0224 (3)
H11A	0.7095	0.2650	0.6256	0.027*
H11B	0.6820	0.4431	0.6292	0.027*
N11	0.68076 (8)	0.33275 (14)	0.69205 (4)	0.0206 (3)
C15	0.64684 (10)	0.42420 (18)	0.72607 (5)	0.0231 (3)
H15	0.6054	0.5053	0.7212	0.028*
N14	0.68090 (9)	0.38273 (15)	0.76801 (4)	0.0260 (3)
C13	0.73709 (11)	0.26218 (19)	0.75655 (5)	0.0292 (3)
H13	0.7714	0.2088	0.7792	0.035*
N12	0.73963 (9)	0.22619 (15)	0.71109 (4)	0.0288 (3)
O11M	0.34684 (6)	0.39993 (12)	0.60035 (4)	0.0233 (2)
O12M	0.25373 (8)	0.51564 (13)	0.65244 (4)	0.0285 (2)
C11M	0.27804 (9)	0.47413 (16)	0.60930 (5)	0.0195 (3)
C12M	0.21064 (9)	0.52498 (17)	0.57209 (5)	0.0209 (3)
H12A	0.2418	0.5411	0.5421	0.025*
H12B	0.1833	0.6242	0.5815	0.025*
C13M	0.13749 (10)	0.40240 (17)	0.56589 (5)	0.0219 (3)
O21M	0.06834 (7)	0.45375 (13)	0.54002 (4)	0.0286 (3)
O22M	0.14215 (8)	0.27195 (13)	0.58274 (5)	0.0389 (3)
H1	0.4594 (14)	0.409 (2)	0.6360 (7)	0.039 (5)*
H11	0.2895 (15)	0.474 (3)	0.6739 (8)	0.050 (6)*
H12	0.0268 (17)	0.380 (3)	0.5357 (9)	0.068 (8)*

	U11	U22	U33	U12	U13	U23
C1	0.0193 (7)	0.0243 (7)	0.0182 (6)	0.0026 (6)	−0.0046 (5)	−0.0010 (6)
C2	0.0215 (7)	0.0309 (8)	0.0208 (7)	0.0057 (6)	−0.0003 (6)	−0.0017 (6)
C3	0.0352 (8)	0.0239 (8)	0.0288 (8)	0.0076 (7)	−0.0042 (7)	−0.0020 (6)
C4	0.0347 (8)	0.0235 (8)	0.0281 (8)	−0.0023 (7)	−0.0050 (7)	0.0044 (6)
C5	0.0267 (8)	0.0319 (9)	0.0273 (8)	−0.0005 (7)	0.0019 (6)	0.0018 (6)
C6	0.0231 (7)	0.0241 (8)	0.0250 (7)	0.0042 (6)	−0.0001 (6)	−0.0018 (6)
F2	0.0322 (5)	0.0348 (5)	0.0351 (5)	0.0114 (4)	0.0111 (4)	0.0001 (4)
F4	0.0563 (6)	0.0244 (5)	0.0468 (6)	−0.0023 (5)	0.0060 (5)	0.0071 (4)
C10	0.0182 (6)	0.0231 (7)	0.0188 (7)	0.0048 (6)	−0.0018 (5)	−0.0028 (6)
O1	0.0202 (5)	0.0232 (5)	0.0233 (5)	0.0050 (4)	−0.0017 (4)	−0.0039 (4)
C21	0.0264 (7)	0.0240 (8)	0.0185 (7)	0.0038 (6)	−0.0034 (6)	−0.0002 (6)
N21	0.0206 (6)	0.0281 (7)	0.0188 (6)	0.0021 (5)	−0.0007 (5)	0.0014 (5)
N22	0.0226 (6)	0.0449 (9)	0.0282 (7)	0.0032 (6)	0.0054 (5)	0.0101 (6)
C23	0.0271 (8)	0.0390 (10)	0.0306 (8)	−0.0031 (7)	0.0039 (7)	0.0110 (7)
N24	0.0267 (6)	0.0296 (7)	0.0223 (6)	0.0001 (6)	0.0016 (5)	0.0028 (5)
C25	0.0215 (7)	0.0269 (8)	0.0215 (7)	0.0018 (6)	−0.0006 (6)	0.0007 (6)
C11	0.0202 (7)	0.0291 (8)	0.0180 (7)	0.0003 (6)	0.0002 (5)	0.0014 (6)
N11	0.0186 (5)	0.0232 (6)	0.0201 (6)	−0.0005 (5)	−0.0033 (5)	0.0020 (5)
C15	0.0226 (7)	0.0237 (8)	0.0230 (7)	−0.0001 (6)	−0.0024 (6)	0.0001 (6)
N14	0.0293 (7)	0.0272 (7)	0.0214 (6)	−0.0056 (5)	−0.0025 (5)	0.0015 (5)
C13	0.0334 (8)	0.0286 (8)	0.0255 (8)	0.0013 (7)	−0.0073 (6)	0.0054 (6)
N12	0.0309 (7)	0.0297 (7)	0.0260 (6)	0.0079 (6)	−0.0067 (5)	0.0028 (5)
O11M	0.0208 (5)	0.0226 (5)	0.0265 (5)	0.0019 (4)	−0.0007 (4)	−0.0007 (4)
O12M	0.0301 (5)	0.0361 (6)	0.0193 (5)	0.0079 (5)	−0.0008 (5)	−0.0002 (5)
C11M	0.0203 (7)	0.0157 (7)	0.0227 (7)	−0.0030 (6)	0.0015 (5)	0.0008 (5)
C12M	0.0217 (7)	0.0199 (7)	0.0211 (7)	0.0010 (6)	−0.0001 (5)	0.0018 (5)
C13M	0.0214 (7)	0.0213 (8)	0.0229 (7)	0.0025 (6)	−0.0023 (6)	−0.0019 (6)
O21M	0.0254 (6)	0.0267 (6)	0.0338 (6)	−0.0024 (5)	−0.0108 (5)	0.0061 (5)
O22M	0.0306 (6)	0.0216 (6)	0.0646 (8)	−0.0022 (5)	−0.0169 (6)	0.0094 (6)

C1—C2	1.388 (2)	C23—H23	0.9300
C1—C6	1.394 (2)	N24—C25	1.326 (2)
C1—C10	1.533 (2)	C25—H25	0.9300
C2—F2	1.3637 (17)	C11—N11	1.4601 (17)
C2—C3	1.374 (2)	C11—H11A	0.9700
C3—C4	1.382 (2)	C11—H11B	0.9700
C3—H3	0.9300	N11—C15	1.3292 (19)
C4—F4	1.3570 (18)	N11—N12	1.3623 (17)
C4—C5	1.364 (2)	C15—N14	1.3285 (18)
C5—C6	1.388 (2)	C15—H15	0.9300
C5—H5	0.9300	N14—C13	1.355 (2)
C6—H6	0.9300	C13—N12	1.314 (2)
C10—O1	1.4163 (16)	C13—H13	0.9300
C10—C11	1.5296 (19)	O11M—C11M	1.2190 (17)
C10—C21	1.5497 (18)	O12M—C11M	1.3126 (17)
O1—H1	0.89 (2)	O12M—H11	0.88 (2)
C21—N21	1.4558 (19)	C11M—C12M	1.505 (2)
C21—H21A	0.9700	C12M—C13M	1.507 (2)
C21—H21B	0.9700	C12M—H12A	0.9700
N21—C25	1.3311 (19)	C12M—H12B	0.9700
N21—N22	1.3674 (18)	C13M—O22M	1.2063 (18)
N22—C23	1.320 (2)	C13M—O21M	1.3247 (17)
C23—N24	1.358 (2)	O21M—H12	0.88 (3)
C2—C1—C6	115.84 (14)	N24—C23—H23	122.4
C2—C1—C10	123.64 (12)	C25—N24—C23	102.34 (13)
C6—C1—C10	120.51 (13)	N24—C25—N21	110.69 (13)
F2—C2—C3	117.17 (13)	N24—C25—H25	124.7
F2—C2—C1	118.65 (13)	N21—C25—H25	124.7
C3—C2—C1	124.18 (14)	N11—C11—C10	112.50 (11)
C2—C3—C4	116.86 (14)	N11—C11—H11A	109.1
C2—C3—H3	121.6	C10—C11—H11A	109.1
C4—C3—H3	121.6	N11—C11—H11B	109.1
F4—C4—C5	119.27 (14)	C10—C11—H11B	109.1
F4—C4—C3	118.27 (14)	H11A—C11—H11B	107.8
C5—C4—C3	122.46 (15)	C15—N11—N12	110.12 (12)
C4—C5—C6	118.58 (14)	C15—N11—C11	130.18 (12)
C4—C5—H5	120.7	N12—N11—C11	119.60 (11)
C6—C5—H5	120.7	N14—C15—N11	109.99 (13)
C5—C6—C1	122.06 (14)	N14—C15—H15	125.0
C5—C6—H6	119.0	N11—C15—H15	125.0
C1—C6—H6	119.0	C15—N14—C13	102.69 (12)
O1—C10—C11	104.54 (11)	N12—C13—N14	115.10 (13)
O1—C10—C1	110.91 (11)	N12—C13—H13	122.5
C11—C10—C1	111.62 (11)	N14—C13—H13	122.5
O1—C10—C21	109.67 (11)	C13—N12—N11	102.10 (12)
C11—C10—C21	109.17 (11)	C11M—O12M—H11	111.3 (14)
C1—C10—C21	110.74 (11)	O11M—C11M—O12M	123.77 (13)
C10—O1—H1	110.4 (13)	O11M—C11M—C12M	123.54 (13)
N21—C21—C10	111.39 (11)	O12M—C11M—C12M	112.67 (12)
N21—C21—H21A	109.3	C11M—C12M—C13M	110.69 (12)
C10—C21—H21A	109.3	C11M—C12M—H12A	109.5
N21—C21—H21B	109.3	C13M—C12M—H12A	109.5
C10—C21—H21B	109.3	C11M—C12M—H12B	109.5
H21A—C21—H21B	108.0	C13M—C12M—H12B	109.5
C25—N21—N22	109.74 (13)	H12A—C12M—H12B	108.1
C25—N21—C21	127.41 (13)	O22M—C13M—O21M	124.14 (14)
N22—N21—C21	122.58 (12)	O22M—C13M—C12M	123.20 (13)
C23—N22—N21	101.97 (12)	O21M—C13M—C12M	112.65 (12)
N22—C23—N24	115.26 (14)	C13M—O21M—H12	112.1 (16)
N22—C23—H23	122.4

D—H···A	D—H	H···A	D···A	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

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	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⋯O11M iii	0.97	2.44	3.3880 (18)	165
C13—H13⋯O12M iv	0.93	2.54	3.3144 (19)	141
C25—H25⋯O11M	0.93	2.40	3.2018 (18)	144
C25—H25⋯O22M iii	0.93	2.37	3.0032 (19)	125

Symmetry codes: (i) ; (ii) ; (iii) ; (iv) .