Fluconazole–malonic acid (1/1)

Kastelic, J.; Kikelj, D.; Leban, I.; Lah, N.

doi:10.1107/S1600536813003656

Volume 69
Part 3
Pages o378-o379
March 2013

Received 24 January 2013
Accepted 5 February 2013
Online 13 February 2013

Key indicators
Single-crystal X-ray study
T = 150 K
Mean (C-C) = 0.002 Å
R = 0.038
wR = 0.100
Data-to-parameter ratio = 14.6
Details

Fluconazole-malonic acid (1/1)

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

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

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-HN and O-HO hydrogen bonds. Such aggregates are further connected into (001) layers by further O-HN hydrogen bonds. The structure also features weak non-classical C-HO and C-HN 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, 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 K radiation
= 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 > 2(I)
R_int = 0.024

Refinement

R[F² > 2(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
_max = 0.32 e Å^-3
_min = -0.29 e Å^-3

Table 1
Hydrogen-bond geometry (Å, °)

D-HA	D-H	HA	DA	D-HA
O1-H1O11M	0.89 (2)	1.94 (2)	2.8057 (14)	166.2 (18)
O12M-H11N14ⁱ	0.88 (2)	1.86 (2)	2.6830 (17)	156 (2)
O21M-H12N24ⁱⁱ	0.88 (3)	1.89 (3)	2.7606 (17)	171 (2)
C6-H6N14ⁱ	0.93	2.61	3.484 (2)	156
C12M-H12BO11Mⁱⁱⁱ	0.97	2.44	3.3880 (18)	165
C13-H13O12M^iv	0.93	2.54	3.3144 (19)	141
C25-H25O11M	0.93	2.40	3.2018 (18)	144
C25-H25O22Mⁱⁱⁱ	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); 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 data and figures for this paper are available from the IUCr electronic archives (Reference: GK2552 ).

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

Brittain, H. G. (2012a). Cryst. Growth Des. 12, 1046-1054.
Brittain, H. G. (2012b). Cryst. Growth Des. 12, 5823-5832.
Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.
Kastelic, J., Hodnik, Z., Sket, P., Plavec, J., Lah, N., Leban, I., Pajk, M., Planinsek, O. & Kikelj, D. (2010). Cryst. Growth Des. 10, 4943-4953.
Kastelic, J., Lah, N., Kikelj, D. & Leban, I. (2011). Acta Cryst. C67, o370-o372.
Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.
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.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.
Spek, A. L. (2009). Acta Cryst. D65, 148-155.
US Food and Drug Administration (2011). Guidance for Industry; Regulatory Classification of Pharmaceutical Co-crystals. Silver Spring, MD.

organic compounds