Solubilty and dissolution studies of antifungal drug:hydroxybutenyl-β-cyclodextrin complexes

The solubilities of voriconazole, ketoconazole, and clotrimazole with and without hydroxybutenyl-β-cyclodextrin (HBenBCD) in aqueous media were examined. The solubility of these antifungal drugs was significantly improved by complexation with HBenBCD. Both the pH and the type of buffer used to adjust the medium pH had a very significant effect on drug solubilities and the apparent binding constants of the drug:cyclodextrin complexes. Additionally, the stereochemistry of tartrate buffers was found to influence both the electrostatic interaction between drug and tartrate as well as complexation of the drug-tartrate aggregate by HBenBCD. We also compared the solubilization of these antifungal drugs by HBenBCD to other cyclodextrin derivatives with different substituents under identical experimental conditions and found that the amount of drug solubilized was in some cases influenced strongly by the nature of the cyclodextrin. Solid antifungal drug:HBenBCD complexes were prepared and their dissolution profiles were obtained which showed that HBenBCD improved both the rate of dissolution and the amount of drug dissolved.     

Spectrophotometric determination of clotrimazole and Phenylephrine-HCl in pharmaceutical formulation using 1, 2-naphthoquinone-4-Sulphonic acid sodium salt (NQS) as a chromogenic reagent

A sensitive, rapid and economical spectrophotometric method based on their interaction with NQS reagent in basic medium, which produces orange-colored complexes, has been devised to identify many drugs with amino groups (clotrimazole and phenylephrine-HCl). The maximum absorption for the complexes of clotrimazole and phenylephrine-HCl is 455 and 484 nm, respectively. Beer's law is applicable in the concentration ranges of (2–40) μg/ml for clotrimazole and (0–20) μg/ml for phenylephrine-HCl. The molar absorptivity values are 3931.1760 L/mol.cm and 4521.4074 L/mol.cm of clotrimazole and phenylephrine-HCl respectively with accuracy of 100.0285%–103.1456% and RSD better than 3.3211%. The method has been successfully used to determine these medications in pharmaceutical formulations, and it has been found to be superior to British Pharmacopeia standard procedures. At a 95% confidence level, F and t-tests are less than the tabulated values.     

Application of dispersive liquid–liquid microextraction followed by HPLC–MS/MS for the trace determination of clotrimazole in environmental water samples

A method for the analysis of clotrimazole was developed with dispersive liquid–liquid microextraction for sample pre‐concentration and HPLC–MS/MS for analysis. A linear ion trap was used for the confirmation of clotrimazole identity in the samples. The developed method enables the analysis of clotrimazole in river water and sewage effluent from wastewater treatment plants with a LOQ of 0.7 ng/L. Environmental monitoring of clotrimazole was undertaken. Samples from river water and sewage effluents were analysed over a one‐year period. Clotrimazole was found in every tested sample with concentration range from 1 to 31 ng/L. The amount of clotrimazole in tested samples was highly dependent on sampling season. The highest results were obtained in summer and autumn.     

Development and validation of HPLC method for determination of clotrimazole and its two degradation products in spray formulation

A novel simple isocratic HPLC method with UV detection for the determination of three compounds in spray solution (active component clotrimazole and two degradation products imidazole and (2-chlorophenyl)diphenylmethanol) using ibuprofen as an internal standard was developed and validated. The complications with different acido-basic properties of the analysed compounds in HPLC separation - while clotrimazole has pK_a 4.7, imidazole has pK_a 6.9 compared to relatively more acidic (2-chlorophenyl)diphenylmethanol - were finally overcome using a 3.5 μm Zorbax^® SB-Phenyl column (75 mm × 4.6 mm i.d., Agilent Technologies).The optimal mobile phase for separation of clotrimazole, degradation products imidazole and (2-chlorophenyl)diphenylmethanol and ibuprofen as internal standard consists of a mixture of acetonitrile and water (65:35, v/v) with pH* conditioned by phosphoric acid to 3.5. At a flow rate of 0.5 ml min⁻¹ and detection at 210 nm, the total time of analysis was less than 6 min.The method was applied for routine analysis (batch analysis and stability tests) in commercial spray solution.     

Analysis,fate studies and monitoring of the antifungal agent clotrimazole in the aquatic environment

The analysis and presence of clotrimazole, an antifungal agent with logK _OW > 4, was thoroughly studied in the aquatic environment. For that reason analytical methods based on gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry were developed and validated to quantify clotrimazole with limits of quantification down to 5 and 1 ng/L, respectively. Both methods were compared in an intercalibration exercise. The complete mass-spectrometric fragmentation pattern could be elucidated with the aid of quadrupole time of flight mass spectrometry. Since clotrimazole tends to adsorb to laboratory glassware, studies on its adsorption behaviour were made to ensure the appropriate handling of water samples, e.g. pH, storage time, pretreatment of sampling vessels or material of the vials used for final extracts. The phenomena of adsorption to suspended matter were investigated while analysing different waste-water samples. Application of the methods in various investigated wastewater and surface water samples demonstrated that clotrimazole could only be detected in the low nanogram per litre range of anthropogenic influenced unfiltered water samples after acidification to pH 2.