cis-2-sec-Butyl-4-{4-[4-(4-{[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)-1-piperazinyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (Itraconazole)

Abstract

The molecular structure of itraconazole, C35H38C12-N804, has been determined from single-crystal X-ray diffraction data. The two molecules in the asymmetric unit differ mainly in the conformation of the methoxyt Internal code of the Janssen Research Foundation: R51211.Acta Crystallographica Section C ISSN 0108-2701ISSN 0108- © 1996 2226 C35H38CI2NsO4 phenylpiperazine moiety. Apart from a 180 ° rotation of the triazole ring, the geometry of the dichlorophenylethoxytriazole moiety is almost the same as the dichlorophenylethoxyimidazole geometry found in miconazole, econazole and ketoconazole. CommentItraconazole, (I), is an oral antifungal triazole registered in most countries of the world. In comparison with miconazole and ketoconazole, itraconazole is essentially a more potent antifungal agent with a wider spectrum, a slower clearance and reduced toxicity. All antifungal azoles probably act by an identical mechanism of inhibition of the fungal cytochrome P-450 enzymes. The potency seems to be determined by the affinity and geometric orientation of the nitrogen heterocycle to the heme iron ion, by protonation of the N3 or N4 atom in the imidazole or triazole ring, and by the affinity of the non-ligand portion for the apoprotein of cytochrome P-450 (Vanden Bossche, Marichal, Gorrens, Geerts & Janssen, 1988). The crystal structure of itraconazole has been determined for comparison with the structures of ketoconazole (Peeters, Blaton & De Ranter, 1979a), miconazole (Peeters, Blaton & De Ranter, 1979b) and econazole (Freer, Pearson & Salole, 1986). The asymmetric unit contains two molecules (A and B) partly related by a pseudo-inversion centre at ca 0.25,0.49,0.25 (Fig. 1). The sec-butyl side chain is statistically disordered in both molecules implying that both the R and S configurations are present. The main difference between the two molecules is the orientation of the methoxyphenylpiperazine moiety. In molecule A, the methoxy group is almost perpendicular to the phenyl ring, whereas in molecule B, it is almost coplanar with the phenyl ring. As a consequence, the C70--O71--C72 and O71--C72---C77 angles are enlarged by ca 4 °.Each molecule contains seven rings of which the triazole and benzene rings are essentially planar with a maximum deviation of 0.014 (5) t Partial occupancies (see below). .353 (7) N51--N52 .326 (7) N51---C55 .458 (7) N51--C56 .320 (9) N52---C53 .333 (8) C53--N54 .33 (1) N54----C55 .531 (7) C56--C57 .411 (5) C57--O58 .392 (6) C57--O61 .543 (8) C57--C62 1.444 (7) O58--C59 1.518 (7) C59--C60 1.507 (9) C59---C70 1.423 (6) C60--O61 1.390 (7) C62--C63 1.387 (6) C62--C67 1.395 (8) C63---C64 1.722 (5) C63--C168 1.366 (7) C64--C65 1.377 (8) C65--C66 1.729 (6) C65---C169 1.378 (8) C66--C67 1.426 (6) C70--O71 1.404 (8)2228 C35H38C12N804 N92 -0.9180 (6) 0.2246 (3) 0.1045 (2) N93 -0.9247 (7) 0.2081 (3) 0.1730 (2O71---C72 1.384 (9) C72--C73 1.358 (8) C72---C77 1.382 (9) C73---C74 1.386 (8) C74--C75 1.384 (9) C75--C76 1.427 (8) C75--N78 1.38 ( 1 ) C76--C77 1.452 (7) N78--C79 1.434 (8) N78---C8...

A Solid-State Approach to Enable Early Development Compounds: Selection and Animsal Bioavailability Studies of an Itraconazole Amorphous Solid Dispersion

“…ITZ is an anhydrous, crystalline solid form with the XRPD pattern (Fig. 2) displaying sharp peaks indicative of the form reported in the Cambridge Structural Database (TEHZIP) 50. By DSC (data not shown), a single endotherm at 166°C (onset; Δ H f : 84 J/g) corresponds to a solid to liquid transition confirmed by hot stage microscopy.…”

A SAXS-WAXS study of the endothermic transitions in amorphous or supercooled liquid itraconazole

“…<10. For itraconazole, which contains 87 atoms, initial distance parameters were obtained by fits to the crystal structure [6] and the Debye-Waller thermal factors σ are estimated within an empirical algorithm. Details of our algorithm for fitting the intra-molecular x-ray scattering are given in references [7] and [8].…”

“…Details of our algorithm for fitting the intra-molecular x-ray scattering are given in references [7] and [8]. The crystal structure of itraconazole is triclinic and there are 4 molecules in each unit cell volume of 3447.3 Å -3 [6]. Each molecule contains seven rings in which the triazole and benzene rings are essentially planar, but there two conformations of the methoxy group which are either orientated perpendicular or almost co-planar to the phenyl ring.…”

Nuances in the Calculation of Amorphous Solubility Enhancement Ratio

“…However, 1 of the 2 chiral centers leads to R and S configurations of the sec-butyl chain that are present at the same location in the crystal. 51 Thus, the 4 stereoisomers really behave as only 2 distinguishable stereoisomers. Assuming that the 2 distinguishable stereoisomers are randomly mixed in the amorphous form, the entropy of the amorphous form should be increased by the entropy of ideal mixing of the 2 molecules, which is Rln2.…”