A 1:1 cocrystal of fluconazole with salicylic acid

The interaction of the antifungal pharmaceutical agent fluconazole with salicylic acid in acetonitrile solution yields the 1:1 cocrystal 2-(2,4-difluoro­phenyl)-1,3-bis­(1H-1,2,4-tri­az­ol-1-yl)propan-2-ol-2-hy­droxy­benzoic acid (1/1), C₁₃H₁₂F₂N₆O·C₇H₆O₃. The asymmetric unit consists of one molecule of fluconazole and one molecule of salicylic acid, both in their neutral forms. Both crystal agents form head-to-tail hydrogen-bonded dimers, which are further connected into hydrogen-bonded extended zigzag tapes propagating along the ac diagonal.

S1. Comment

An important goal of the solid-state formulation development of drugs with multicomponent crystalline phases is a search for new pharmaceutical cocrystal forms. A pharmaceutical cocrystal can be defined as a multicomponent crystal system of the active pharmaceutical ingredient (API) with another pharmaceutically acceptable molecule, both existing as solids under ambient conditions. The presence of a cocrystal former in a solid form can have an impact on the chemical and physical properties of APIs, which can lead to improved and optimized drug formulations. Thus, cocrystals have become a complementary tool in addition to polymorphs, pseudopolymorphs (solvates) and salts in the development of pharmaceuticals in solid form (Schultheiss & Newman, 2009; Chen et al., 2011, and references therein).

Fluconazole is a wide-spectrum triazole antifungal agent used in the treatment of localized candidiasis and systematic therapy of candidial infections, dermatophytic fungal infections and cryptococcal meningitis. It is commonly used as an accompanying therapy for immunodeficient patients with AIDS or cancer and patients taking immunodepresive agents (Sweetman et al., 2007). It is only slightly soluble in water. Thus, its cocrystallization with pharmaceutically acceptable cocrystal formers presents an attractive option to increase its solubility. Along these lines, we have focused our research on the preparation of new fluconazole cocrystals and have recently reported the crystal structures of three fluconazole cocrystals with three dicarboxylic acids, namely maleic, glutaric and fumaric acids (Kastelic et al., 2010). We have extended our research to the preparation and investigation of further fluconazole cocrystals, not only with aliphatic dicarboxylic acids which proved to be appropriate cocrystal formers, but also with aromatic and/or monocarboxylic acids. We present here the crystal structure of a 1:1 cocrystal of fluconazole and salicylic acid, (I).

The asymmetric unit of (I) consists of one fluconazole and one salicylic acid molecule (Fig. 1), both in their neutral forms. An intramolecular hydrogen bond of type S(6) (Bernstein et al., 1995) is observed in the salicylic acid group, with the OH group at the ortho position as donor and the carbonyl O atom of the carboxylic acid group as the acceptor. The hydrogen-bonding details are given in Table 1. The fluconazole and salicylic acid molecules each form homomeric centrosymmetric dimers via hydrogen bonds. The two fluconazole molecules, related by an inversion centre, are linked through an O—H···N hydrogen bond, forming an R₂²(14) motif. The fluconazole OH group serves as the hydrogen-bond donor to triazole atom N24 at position 4 of an adjacent fluconazole molecule. The salicylic acid molecules form centrosymmetric head-to-tail dimers through O—H···O interactions between neighbouring molecules, involving the ortho-OH group as the hydrogen-bond donor to the carbonyl O atom of an adjacent salicylic acid molecule, forming an R₂²(4) motif. Such a pattern differs from the hydrogen-bonding motif observed in the crystal structure of pure salicylic acid, where the typical head-to-tail interaction through the carboxylic acid groups is observed (Munshi et al., 2006). Thus, the carboxylic acid OH group remains available for further hydrogen-bond formation in (I). Indeed, the fluconazole and salicylic acid dimers in (I) are linked through an intermolecular O—H···N hydrogen bond, involving the carboxylic acid OH group and triazole atom N14 of an adjacent fluconazole moiety (Fig. 2). In this way, an infinite zig-zag tape of alternating fluconazole and salicylic acid dimers is formed, which runs along the ac diagonal. Additionally, two short C—H···X intermolecular contacts were observed (Table 1). The C15—H15···O21S(-x-1, -y+1, -z) contact connects the fluconazole and salicylic acid moieties within the tape and thus stabilizes its formation. F atoms (F4) protrude from the tape on both sides. The C25—H25···F4(x, y+1, z) interaction brings the adjacent parallel tapes closer and increases the dimensionality to a three-dimensional supramolecular structure.

Related literature

For related literature, see: Bernstein et al. (1995); Chen et al. (2011); Kastelic et al. (2010); Munshi & Guru Row (2006); Schultheiss & Newman (2009); Sweetman et al. (2007).

S2. Experimental

Equimolar amounts of fluconazole (100 mg, 0.33 mmol) and salicylic acid (45.1 mg, 0.33 mmol) were dissolved in acetonitrile (3.0 ml) by mixing at 323 K. After cooling to ambient temperature, the solvent was allowed to evaporate slowly. Colourless crystals of (I) appeared after 72 h.

S3. Refinement

All H atoms were initially found in a difference Fourier map, but they were repositioned in their calculated positions and refined using a riding model. Aromatic H atoms were permitted to ride with C—H = 0.93 Å and U_iso(H) = 1.2U_eq(C), H atoms bonded to O with O—H = 0.82 Å and U_iso(H) = 1.5U_eq(O), and H atoms of the CH₂ group with C—H = 0.97 Å and U_iso(H) = 1.2U_eq(C).

Computing details

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, 1997); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures

	Fig. 1. The asymmetric unit of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. Dashed lines indicate the intramolecular hydrogen bond in the salicylic acid molecule and the hydrogen bond between the fluconazole and salicylic acid molecules.
	Fig. 2. The one-dimensional hydrogen-bonded structure of (I), with alternating fluconazole and salicylic acid molecules.

2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol– 2-hydroxybenzoic acid (1/1)

Crystal data

C13H12F2N6O·C7H6O3	Z = 2
Mr = 444.40	F(000) = 460
Triclinic, P1	Dx = 1.446 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 6.8522 (2) Å	Cell parameters from 4060 reflections
b = 10.5580 (4) Å	θ = 1–27.5°
c = 14.3009 (6) Å	µ = 0.12 mm^−1
α = 82.862 (3)°	T = 150 K
β = 84.892 (2)°	Prismatic, colourless
γ = 86.091 (3)°	0.18 × 0.16 × 0.15 mm
V = 1020.80 (6) Å^3

Data collection

Nonius KappaCCD area-detector diffractometer	3385 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.028
Graphite monochromator	θmax = 27.4°, θmin = 3.4°
ω scans at κ = 55°	h = −8→8
8238 measured reflections	k = −13→13
4579 independent reflections	l = −18→18

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.044	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.114	H-atom parameters constrained
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0516P)^2 + 0.286P] where P = (Fo^2 + 2Fc^2)/3
4579 reflections	(Δ/σ)max < 0.001
292 parameters	Δρmax = 0.23 e Å^−3
0 restraints	Δρmin = −0.23 e Å^−3

Special details

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 > 2σ(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 (Ų)

	x	y	z	Uiso*/Ueq
C10	0.2580 (2)	0.34959 (15)	0.29105 (11)	0.0214 (3)
O1	0.07917 (16)	0.42443 (11)	0.28560 (8)	0.0255 (3)
H1	0.0209	0.4221	0.3384	0.038*
F2	0.56548 (14)	0.15618 (10)	0.33173 (9)	0.0436 (3)
F4	0.13257 (18)	−0.16925 (10)	0.41991 (9)	0.0508 (3)
C1	0.2242 (2)	0.21160 (14)	0.33335 (11)	0.0209 (3)
C2	0.3774 (2)	0.12039 (16)	0.34912 (12)	0.0283 (4)
C3	0.3528 (3)	−0.00678 (17)	0.37904 (13)	0.0344 (4)
H3	0.4591	−0.0648	0.3897	0.041*
C4	0.1629 (3)	−0.04356 (16)	0.39231 (13)	0.0330 (4)
C5	0.0038 (3)	0.03938 (16)	0.37807 (13)	0.0313 (4)
H5	−0.1229	0.0112	0.3876	0.038*
C6	0.0366 (2)	0.16730 (16)	0.34885 (11)	0.0254 (3)
H6	−0.0706	0.2250	0.3394	0.030*
O1S	−0.41051 (17)	0.37408 (11)	−0.02620 (9)	0.0302 (3)
O2S	−0.29626 (16)	0.17181 (11)	−0.03183 (9)	0.0310 (3)
H2S	−0.2115	0.1947	−0.0016	0.047*
C11S	−0.4229 (2)	0.26734 (15)	−0.05132 (11)	0.0233 (3)
O21S	−0.73928 (17)	0.45112 (11)	−0.09975 (9)	0.0325 (3)
H21S	−0.6434	0.4572	−0.0705	0.049*
C1S	−0.5854 (2)	0.23845 (15)	−0.10572 (11)	0.0224 (3)
C2S	−0.7373 (2)	0.33159 (15)	−0.12520 (11)	0.0234 (3)
C3S	−0.8966 (2)	0.30116 (16)	−0.17059 (12)	0.0276 (4)
H3S	−0.9978	0.3624	−0.1832	0.033*
C4S	−0.9044 (2)	0.18029 (17)	−0.19687 (12)	0.0291 (4)
H4S	−1.0118	0.1606	−0.2267	0.035*
C5S	−0.7540 (3)	0.08771 (16)	−0.17939 (12)	0.0302 (4)
H5S	−0.7592	0.0069	−0.1983	0.036*
C6S	−0.5964 (2)	0.11684 (16)	−0.13363 (12)	0.0285 (4)
H6S	−0.4962	0.0547	−0.1212	0.034*
C21	0.4020 (2)	0.41730 (16)	0.34217 (11)	0.0260 (4)
H21A	0.5270	0.3683	0.3421	0.031*
H21B	0.4238	0.5010	0.3078	0.031*
N21	0.32956 (19)	0.43207 (13)	0.43930 (9)	0.0239 (3)
N22	0.3401 (2)	0.33195 (14)	0.50916 (10)	0.0311 (3)
C23	0.2546 (3)	0.38283 (17)	0.58286 (13)	0.0316 (4)
H23	0.2385	0.3364	0.6424	0.038*
N24	0.1915 (2)	0.50788 (14)	0.56605 (10)	0.0306 (3)
C25	0.2419 (2)	0.53436 (16)	0.47433 (12)	0.0266 (4)
H25	0.2191	0.6135	0.4393	0.032*
C11	0.3419 (2)	0.35202 (15)	0.18702 (11)	0.0241 (3)
H11A	0.3416	0.4397	0.1572	0.029*
H11B	0.4766	0.3170	0.1848	0.029*
N11	0.22649 (18)	0.27812 (12)	0.13536 (9)	0.0219 (3)
N12	0.28188 (19)	0.15352 (13)	0.12599 (10)	0.0255 (3)
C13	0.1353 (2)	0.11649 (16)	0.08485 (12)	0.0264 (4)
H13	0.1314	0.0341	0.0687	0.032*
N14	−0.01002 (19)	0.20836 (13)	0.06786 (10)	0.0258 (3)
C15	0.0523 (2)	0.30860 (15)	0.10112 (11)	0.0244 (3)
H15	−0.0150	0.3882	0.1007	0.029*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C10	0.0181 (7)	0.0233 (8)	0.0232 (8)	−0.0005 (6)	−0.0011 (6)	−0.0054 (6)
O1	0.0252 (6)	0.0263 (6)	0.0243 (6)	0.0052 (5)	−0.0021 (5)	−0.0037 (5)
F2	0.0182 (5)	0.0378 (6)	0.0738 (8)	0.0020 (4)	−0.0038 (5)	−0.0050 (5)
F4	0.0628 (8)	0.0223 (6)	0.0662 (8)	−0.0076 (5)	−0.0067 (6)	0.0031 (5)
C1	0.0211 (7)	0.0225 (8)	0.0200 (8)	0.0006 (6)	−0.0019 (6)	−0.0062 (6)
C2	0.0187 (8)	0.0310 (9)	0.0359 (10)	−0.0007 (6)	−0.0030 (7)	−0.0072 (7)
C3	0.0333 (9)	0.0266 (9)	0.0430 (11)	0.0063 (7)	−0.0077 (8)	−0.0048 (8)
C4	0.0434 (10)	0.0195 (8)	0.0361 (10)	−0.0041 (7)	−0.0048 (8)	−0.0015 (7)
C5	0.0278 (9)	0.0301 (9)	0.0365 (10)	−0.0073 (7)	−0.0023 (7)	−0.0031 (7)
C6	0.0222 (8)	0.0278 (9)	0.0263 (8)	−0.0006 (6)	−0.0016 (6)	−0.0046 (7)
O1S	0.0289 (6)	0.0236 (6)	0.0406 (7)	−0.0012 (5)	−0.0070 (5)	−0.0104 (5)
O2S	0.0248 (6)	0.0260 (6)	0.0454 (8)	0.0032 (5)	−0.0123 (5)	−0.0123 (5)
C11S	0.0207 (8)	0.0227 (8)	0.0260 (8)	−0.0004 (6)	0.0018 (6)	−0.0044 (6)
O21S	0.0328 (7)	0.0215 (6)	0.0452 (8)	0.0038 (5)	−0.0129 (6)	−0.0080 (5)
C1S	0.0215 (8)	0.0223 (8)	0.0233 (8)	−0.0016 (6)	0.0001 (6)	−0.0034 (6)
C2S	0.0271 (8)	0.0194 (8)	0.0232 (8)	−0.0015 (6)	0.0005 (6)	−0.0024 (6)
C3S	0.0259 (8)	0.0281 (9)	0.0284 (9)	0.0012 (6)	−0.0053 (7)	−0.0011 (7)
C4S	0.0283 (9)	0.0340 (9)	0.0261 (9)	−0.0057 (7)	−0.0057 (7)	−0.0038 (7)
C5S	0.0325 (9)	0.0269 (9)	0.0333 (9)	−0.0041 (7)	−0.0040 (7)	−0.0097 (7)
C6S	0.0256 (8)	0.0257 (9)	0.0345 (9)	0.0030 (6)	−0.0039 (7)	−0.0068 (7)
C21	0.0251 (8)	0.0272 (9)	0.0266 (9)	−0.0057 (6)	0.0009 (7)	−0.0071 (7)
N21	0.0240 (7)	0.0244 (7)	0.0242 (7)	−0.0032 (5)	−0.0019 (5)	−0.0056 (5)
N22	0.0364 (8)	0.0280 (8)	0.0285 (8)	−0.0047 (6)	−0.0015 (6)	−0.0013 (6)
C23	0.0311 (9)	0.0362 (10)	0.0282 (9)	−0.0076 (7)	−0.0005 (7)	−0.0053 (7)
N24	0.0234 (7)	0.0388 (9)	0.0319 (8)	−0.0029 (6)	−0.0029 (6)	−0.0126 (6)
C25	0.0238 (8)	0.0277 (9)	0.0303 (9)	−0.0016 (6)	−0.0041 (7)	−0.0095 (7)
C11	0.0215 (8)	0.0256 (8)	0.0261 (8)	−0.0047 (6)	−0.0002 (6)	−0.0063 (7)
N11	0.0217 (6)	0.0211 (7)	0.0229 (7)	0.0003 (5)	−0.0005 (5)	−0.0043 (5)
N12	0.0266 (7)	0.0233 (7)	0.0268 (7)	0.0042 (5)	−0.0008 (6)	−0.0077 (6)
C13	0.0266 (8)	0.0248 (8)	0.0288 (9)	−0.0004 (6)	−0.0022 (7)	−0.0072 (7)
N14	0.0238 (7)	0.0248 (7)	0.0296 (8)	−0.0001 (5)	−0.0033 (6)	−0.0066 (6)
C15	0.0250 (8)	0.0234 (8)	0.0244 (8)	0.0035 (6)	−0.0024 (6)	−0.0035 (6)

Geometric parameters (Å, º)

C10—O1	1.4149 (18)	C3S—H3S	0.9300
C10—C1	1.531 (2)	C4S—C5S	1.389 (2)
C10—C21	1.541 (2)	C4S—H4S	0.9300
C10—C11	1.544 (2)	C5S—C6S	1.382 (2)
O1—H1	0.8200	C5S—H5S	0.9300
F2—C2	1.3610 (18)	C6S—H6S	0.9300
F4—C4	1.3611 (19)	C21—N21	1.456 (2)
C1—C6	1.388 (2)	C21—H21A	0.9700
C1—C2	1.389 (2)	C21—H21B	0.9700
C2—C3	1.374 (2)	N21—C25	1.331 (2)
C3—C4	1.374 (3)	N21—N22	1.3641 (19)
C3—H3	0.9300	N22—C23	1.315 (2)
C4—C5	1.364 (2)	C23—N24	1.360 (2)
C5—C6	1.390 (2)	C23—H23	0.9300
C5—H5	0.9300	N24—C25	1.326 (2)
C6—H6	0.9300	C25—H25	0.9300
O1S—C11S	1.2351 (19)	C11—N11	1.4531 (19)
O2S—C11S	1.3043 (18)	C11—H11A	0.9700
O2S—H2S	0.8200	C11—H11B	0.9700
C11S—C1S	1.483 (2)	N11—C15	1.334 (2)
O21S—C2S	1.3551 (19)	N11—N12	1.3635 (18)
O21S—H21S	0.8200	N12—C13	1.313 (2)
C1S—C6S	1.400 (2)	C13—N14	1.358 (2)
C1S—C2S	1.404 (2)	C13—H13	0.9300
C2S—C3S	1.393 (2)	N14—C15	1.324 (2)
C3S—C4S	1.380 (2)	C15—H15	0.9300
O1—C10—C1	111.57 (12)	C5S—C4S—H4S	119.6
O1—C10—C21	109.56 (12)	C6S—C5S—C4S	119.32 (15)
C1—C10—C21	114.49 (13)	C6S—C5S—H5S	120.3
O1—C10—C11	103.97 (12)	C4S—C5S—H5S	120.3
C1—C10—C11	109.65 (12)	C5S—C6S—C1S	120.98 (15)
C21—C10—C11	106.99 (12)	C5S—C6S—H6S	119.5
C10—O1—H1	109.5	C1S—C6S—H6S	119.5
C6—C1—C2	115.91 (14)	N21—C21—C10	112.27 (13)
C6—C1—C10	121.15 (13)	N21—C21—H21A	109.1
C2—C1—C10	122.61 (14)	C10—C21—H21A	109.1
F2—C2—C3	116.63 (14)	N21—C21—H21B	109.1
F2—C2—C1	119.05 (15)	C10—C21—H21B	109.1
C3—C2—C1	124.30 (15)	H21A—C21—H21B	107.9
C4—C3—C2	116.42 (15)	C25—N21—N22	109.90 (14)
C4—C3—H3	121.8	C25—N21—C21	128.99 (15)
C2—C3—H3	121.8	N22—N21—C21	121.07 (13)
F4—C4—C5	118.57 (16)	C23—N22—N21	101.93 (14)
F4—C4—C3	118.22 (16)	N22—C23—N24	115.47 (16)
C5—C4—C3	123.21 (16)	N22—C23—H23	122.3
C4—C5—C6	118.08 (16)	N24—C23—H23	122.3
C4—C5—H5	121.0	C25—N24—C23	102.08 (14)
C6—C5—H5	121.0	N24—C25—N21	110.62 (15)
C1—C6—C5	122.08 (15)	N24—C25—H25	124.7
C1—C6—H6	119.0	N21—C25—H25	124.7
C5—C6—H6	119.0	N11—C11—C10	110.92 (12)
C11S—O2S—H2S	109.5	N11—C11—H11A	109.5
O1S—C11S—O2S	123.05 (14)	C10—C11—H11A	109.5
O1S—C11S—C1S	121.94 (14)	N11—C11—H11B	109.5
O2S—C11S—C1S	115.01 (13)	C10—C11—H11B	109.5
C2S—O21S—H21S	109.5	H11A—C11—H11B	108.0
C6S—C1S—C2S	118.98 (14)	C15—N11—N12	110.02 (13)
C6S—C1S—C11S	121.00 (14)	C15—N11—C11	129.44 (13)
C2S—C1S—C11S	119.92 (14)	N12—N11—C11	120.12 (13)
O21S—C2S—C3S	117.50 (14)	C13—N12—N11	102.48 (12)
O21S—C2S—C1S	122.78 (14)	N12—C13—N14	114.48 (14)
C3S—C2S—C1S	119.70 (14)	N12—C13—H13	122.8
C4S—C3S—C2S	120.16 (15)	N14—C13—H13	122.8
C4S—C3S—H3S	119.9	C15—N14—C13	103.38 (13)
C2S—C3S—H3S	119.9	N14—C15—N11	109.63 (14)
C3S—C4S—C5S	120.84 (15)	N14—C15—H15	125.2
C3S—C4S—H4S	119.6	N11—C15—H15	125.2

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2S—H2S···N14	0.82	1.79	2.6012 (17)	168
O21S—H21S···O1S	0.82	1.89	2.6082 (16)	146
O1—H1···N24^i	0.82	2.07	2.8190 (18)	152
C15—H15···O21S^ii	0.93	2.31	3.2077 (19)	163
C25—H25···F4^iii	0.93	2.32	3.184 (2)	155

Symmetry codes: (i) −x, −y+1, −z+1; (ii) −x−1, −y+1, −z; (iii) x, y+1, z.