Application of HPTLC, spectrofluorimetry and differential pulse voltammetry for determination of the antifungal drug posaconazole in suspension dosage form.

This work presents the development, validation and application of three simple and direct analytical methods for determination of posaconazole (PSZ) in its pure form and in suspension dosage form. Method I is based on high performance thin layer chromatography (HPTLC) where effective separation of PSZ and the internal standard (itraconazole) was achieved using Merck HPTLC plates (20×10cm aluminium plates with 250µm layer thickness precoated with silicagel 60 F254) and a mobile phase composed of acetone and chloroform (1:2, by volume), followed by densitometric measurement of the drugs' spots at 262nm. Method II involves measurement of the native fluorescence of PSZ in 0.1M H2SO4 at excitation and emission wavelengths of 260 and 365nm, respectively. Method III depends on the voltammetric analysis of PSZ. A well-defined cathodic wave was obtained for PSZ in Britton-Robinson buffer pH 6.5 using the differential-pulse mode at the hanging mercury drop electrode (HMDE). The developed methods were validated according to the International Conference on Harmonization (ICH) guidelines regarding linearity, ranges, accuracy, precision, robustness and limits of detection and quantification. The proposed methods showed good linearity over the concentration ranges 5-50, 0.05-0.3, 0.005-0.05µg/mL PSZ for methods I, II, and III respectively. Intra and inter-day precision were verified by the RSD% values which were less than 2%. The proposed methods were successfully applied for the quantification of PSZ in suspension dosage form with no observable interferences. Assay methods were favorably compared with those obtained by previously reported HPLC method.

Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat.

Valspodar is a P-glycoprotein inhibitor widely used in preclinical and clinical studies for overcoming multidrug resistance. Despite this, the pharmacokinetics of valspodar in rat, a commonly used animal model, have not been reported. Here, we report on the pharmacokinetics of valspodar in Sprague-Dawley rats following intravenous and oral administration of its Cremophor EL formulation, which has been used for humans in clinical trials. After intravenous doses, valspodar displayed properties of slow clearance and a large volume of distribution. Its plasma unbound fraction was around 15% in the Cremophor EL formulation used in the study. After 10 mg kg(-1) orally it was rapidly absorbed with an average maximal plasma concentration of 1.48 mg l(-1) within approximately 2 h. The mean bioavailability of valspodar was 42.8%. In rat, valspodar showed properties of low hepatic extraction and wide distribution, similar to that of its structural analogue cyclosporine A.