Fluconazole–malonic acid (1/1)

Jože Kastelic; Danijel Kikelj; Ivan Leban; Nina Lah

doi:10.1107/S1600536813003656

. 2013 Feb 13;69(Pt 3):o378–o379. doi: 10.1107/S1600536813003656

Fluconazole–malonic acid (1/1)

Jože Kastelic ^a, Danijel Kikelj ^b, Ivan Leban ^c, Nina Lah ^c,^*

PMCID: PMC3588488 PMID: 23476565

Abstract

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 ▶,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 _r = 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
Δρ_max = 0.32 e Å⁻³
Δρ_min = −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 ▶).

Supplementary Material

Click here for additional data file.^{(24.7KB, cif)}

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

e-69-0o378-sup1.cif^{(24.7KB, cif)}

Click here for additional data file.^{(192.8KB, hkl)}

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

e-69-0o378-Isup2.hkl^{(192.8KB, hkl)}

Click here for additional data file.^{(7.3KB, cml)}

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

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

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

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

Acknowledgments

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.

supplementary crystallographic information

Comment

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 (pK_a 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.

Experimental

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.