Experimental and topological determination of the pressure-temperature phase diagram of racemic etifoxine, a pharmaceutical ingredient with anxiolytic properties.

Information about the solid-state properties of etifoxine has been lacking, even if the active pharmaceutical ingredient has been used for its anxiolytic properties for decennia. The crystal structure of the racemic compound possesses a monoclinic space group P21/n with cell parameters a = 8.489(2) Å, b = 17.674(2) Å, c = 20.883(3) Å, ß = 98.860(10)° and a unit-cell volume of 3095.8(9) Å3 at 293 K. The unit cell contains 8 molecules, while 2 independent molecules with different conformations are present in the asymmetric unit. The density of the crystal is 1.291 g/cm3 and its melting point was found at 362.6 ±â€¯0.3 K with a melting enthalpy of 85.6 ±â€¯3.0 J g-1. Its thermal expansion in the liquid and the solid state and the change in volume on melting and between the vitreous state and the crystalline solid have been studied. The results confirm the tendency of small organic molecules to increase about 11% in volume on melting, while the volume difference between the glass and the crystal at the glass transition temperature is about half this value at 6%. These values can be used in the construction of phase diagrams in the case that the experimental data for a given system is incomplete.

Pharmacokinetics and metabolism of the novel anticonvulsant agent N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in rats and humans.

N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) belongs to a new series of experimental anticonvulsants related to lidocaine. This study was undertaken to understand the pharmacokinetics and metabolism of D2624 in rats and humans, with emphasis on the possible formation of 2,6-dimethylaniline (2,6-DMA). After oral administration of stable isotope-labeled parent drug to rats and GC/MS analysis of plasma samples, two metabolites were identified: D3017, which is the primary alcohol, and 2,6-DMA, formed by amide bond hydrolysis of either D2624 or D3017. In urine, three metabolites of D2624 were identified: namely D3017,2,6-DMA, and D3270 (which is the carboxylic acid derivative of D3017). Based on plasma AUC analysis, D3017 and 2,6-DMA accounted for > 90% of the dose of D2624. After oral administration, D2624 was found to be well absorbed (93%), but underwent extensive first-pass metabolism in the rat, thus resulting in 5.3% bioavailability. Rat and human liver microsomal preparations were capable of metabolizing D2624 to D3017 and 2,6-DMA. The formation of D3017 was NADPH-dependent, whereas 2,6-DMA formation was NADPH-independent and probably was catalyzed by amidase(s) enzymes. In a single-dose (25-225 mg) human volunteer study, the parent drug (D2624) was not detected in plasma at any dose, whereas 2,6-DMA was detected only at the two highest doses (150 and 225 mg). D3017 was detected after all doses of parent drug, with approximate dose proportionality in AUC and a half-life of 1.3-2.2 hr. The metabolic behavior observed in humans suggests there is a marked species difference in the oxidative and hydrolytic pathways of D2624.