Tizoxanide pyridine monosolvate

Huaqin Zheng; Hui Deng; Yunyun Chen; Ding Li

doi:10.1107/S1600536812016133

. 2012 Apr 21;68(Pt 5):o1453–o1454. doi: 10.1107/S1600536812016133

Tizoxanide pyridine monosolvate

Huaqin Zheng ^a, Hui Deng ^a, Yunyun Chen ^a, Ding Li ^a,^*

PMCID: PMC3344569 PMID: 22590331

Abstract

In the title compound [systematic name: 2-hydroxy-N-(5-nitro-1,3-thiazol-2-yl)benzamide pyridine monosolvate], C₁₀H₇N₃O₄S·C₅H₅N, the dihedral angle between the pyridine and benzamide rings is 80.55 (7)°. An intamolecular O—H⋯N hydrogen bond occurs in the tizoxanide. In the crystal, the components are linked by an O–H⋯N hydrogen bond, forming a zigzag chain along the c axis. Aromatic π–π interactions between inversion-related pyridine rings [centroid–centroid distance = 3.803 (6) Å] are also observed.

Related literature

For the biological activity of tizoxanide, see: Rao et al. (2009 ▶); Gargala et al. (2000 ▶); Dubreuil et al. (1996 ▶); Ashton et al. (2010 ▶); Korba, Elazar et al. (2008 ▶); Zhao et al. (2010 ▶). For related structures and background to the bioactivity of tizoxanide, see: Pankuch & Appelbaum (2006 ▶); Stettler et al. (2003 ▶); Broekhuysen et al. (2000 ▶). For details on experimental methods used to obtain this form and analogues, see: Navarrete-Vazquez et al. (2011 ▶). For a pyridine-solvated forms, see: Dong et al. (2011 ▶). For additional literature on related tizoxanide thiazolide compounds, see: Megraud et al. (1998 ▶); Chan-Bacab et al. (2009 ▶); Korba, Montero et al. (2008 ▶); Stachulski et al. (2011a ▶ b ▶). For the biological activity of the anti-parasitic agent nitazoxanide {systematic name: [2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl]ethanoate}, see: Hemphill et al. (2006 ▶); Rossignol et al. (2006 ▶). For the structure of nitazoxanide, see: Bruno et al. (2010 ▶). For the effect of crystallization from different solvents on drug properties, see: Trask et al. (2004 ▶).

Experimental

Crystal data

C₁₀H₇N₃O₄S·C₅H₅N
M _r = 344.35
Triclinic,
a = 6.9826 (3) Å
b = 10.0462 (5) Å
c = 11.8387 (7) Å
α = 102.998 (5)°
β = 99.037 (5)°
γ = 104.367 (4)°
V = 763.69 (7) Å³
Z = 2
Cu Kα radiation
μ = 2.16 mm⁻¹
T = 293 K
0.20 × 0.15 × 0.10 mm

Data collection

Agilent Xcalibur Onyx Nova diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.712, T _max = 0.806
4493 measured reflections
2481 independent reflections
2349 reflections with I > 2σ(I)
R _int = 0.016

Refinement

R[F ² > 2σ(F ²)] = 0.028
wR(F ²) = 0.075
S = 1.08
2481 reflections
265 parameters
All H-atom parameters refined
Δρ_max = 0.20 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: OLEX2.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812016133/qm2062sup1.cif

e-68-o1453-sup1.cif^{(20.8KB, cif)}

Supplementary material file. DOI: 10.1107/S1600536812016133/qm2062Isup2.mol

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812016133/qm2062Isup3.hkl

e-68-o1453-Isup3.hkl^{(124.7KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812016133/qm2062Isup4.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
N7—H7⋯O1	0.85 (2)	1.95 (2)	2.6248 (16)	135.9 (18)
O1—H25⋯N8	0.94 (2)	1.64 (2)	2.5671 (16)	175 (3)

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Acknowledgments

We thank Sun Yat-sen University for financial support of this work. We also thank Professor Xiaopeng Hu for the data collection.

supplementary crystallographic information

Comment

Nitazoxanide was first developed as an anti-parasitic agent, and marketed in the USA since 2002 (Stachulski et al., 2011a). In humans, once orally administered, nitazoxanide is hydrolyzed in plasma to its active metabolite tizoxanide (TIZ), which is 99% protein bound (Broekhuysen et al., 2000; Ashton et al., 2010). Nitazoxanide exhibits a broad spectrum of activities against intracellular and extracellular protozoa, helminthes, aerobic and anaerobic bacteria, and viruses infecting humans and animals (Hemphill et al., 2006; Rossignol et al., 2006; Korba, Montero et al., 2008; Zhao et al., 2010; Stachulski et al., 2011b).

In the present study, tizoxanide was prepared via deacetylation of nitazoxanide in pyridine and it crystallized as a 1:1 ratio complex with pyridine as crystals. Thermogravimetric analysis was performed to study the thermal stability of the title complex, which indicated a one-step molecular weight loss of 22.43% corresponding to one pyridine molecule in the temperature range of 333–373 K, confirming a 1:1 ratio complex of tizoxanide-pyridine (theoretical weight loss 22.97%).

The tizoxanide and pyridine are linked through hydrogen bond O1–H···N8 (bond distance = 2.567 Å). A stable crystal was formed through intramolecular O1—H···N7 (bond distance = 2.625 Å) and intermolecular O1—H···N8 hydrogen-bonding interactions involving the benzamide group and the pyridine molecule. It is arresting that π–π interactions play an important role in the molecular packing. Inversion-related pyridine molecules are linked by π-π interactions [centroid-centroid distance = 3.803 (6) Å], which stabilize the crystal. By comparison with X-ray of prodrug nitazoxanide (Bruno et al., 2010), tizoxanide has stronger intramolecular hydrogen bonds. These hydrogen bonds may be useful for pharmaceutical preparation of tizoxanide. The molecular and crystal structures are stabilized by intra- (O1—H···N7) and intermolecular (O1—H···N8, π-stacking) interactions respectively, which give a great stability to the crystal building.

When the drug crystallized from different solvents, the crystal form may be changed and then altering a drug's properties, such as melting point and solubility (Trask et al., 2004). We speculated that the replacement of a weak alkaline solvent or solid compound containing the pyridine ring may form the corresponding crystals made of different formulations of active drugs for tizoxanide. Obviously, crystal form of the title compound is different from prodrug nitazoxanide, which suggests that changing solvent or pyridine derivatives may form new crystals and new dosage forms of drugs. This is our future work.

Experimental

A solution of 80 mg of nitazoxanide in 250 ul of pyridine was stirred for 15 min at 333 K and left to crystallize at 293 K overnight. A size suitable flaxen needle was attained for X-ray analysis.

Thermogravimetric analysis for the title complex was performed using a NETZSCH STA409 instrument with sample. The sample was placed in an aluminium cell, heated at 5 °C min^-1 and purged with nitrogen gas flowing at 20 cm³ min^-1.