Ketoconazole

Pharmaceutical product stability is an important issue in pharmaceutical industry. The rheological behavior of a pharmaceutical product affects its stability and performance characteristics such as, foaming properties and filling process during production. Ketoconazole, imidazole antifungal agent, is a weak base with two pKa-values 6.15 and 2.94. It is unstable in aqueous medium and vulnerable to degradation if not properly formulated. Oxidation and hydrolysis are the most degradation routes affecting its stability. The aim of this study to assess the effect of formulation factors such as, pH, the amount of the rheology modifier, rheological behavior and temperature on the stability of ketocona-zole in aqueous media. Different formulations of 2 gm% ketoconazole were prepared, using different percent concentrations of the rheology modifier (NaCl) as 0.8 gm%, 0.2 gm%, 0.4 gm%, 0.1 gm% at different pH values 5.5, 6.5 and 7.5. Experimental formulations were prepared at different temperature and time intervals. The measurements of pH and viscosity of the prepared shampoo were evaluated during stability. Stability studies were carried out as per ICH guidelines for 18 months and monitored by validated stability indicating HPLC method (linearity: 60-140 μg/mL; R 2 =0.9995; acceptable accuracy and precision %RSD < 1.0%). The rheological behavior of the system possess a yield point (minimum shear stress for flow to commence) and time dependency. A reduction in viscosity occurs on shearing with time and rebuilding of viscosity on standing. The key is the rate at which the structure is rebuilt. This is a function of the nature of the thixotropic agent, its concentration in the vehicle or medium, and the amount of agitation before use. The prepared ketoconazole shampoo was high stable at high pH (6.5-7.5) and at temperature < 30 °C during the manufacturing process. Furthermore, the amount of rheology modifier had a high significant effect on the stability of ketoconazole. Formulations containing 0.1 gm% NaCl showed better stability and exhibited ideal thixotropic rheological behavior.

To develop media simulating human colonic fluids (HCFs), to evaluate their use in predicting intracolonic solubility of ketoconazole, danazol and felodipine and to compare solubilities in HCFs with previously determined solubilities in gastric (HGFs) and small intestinal (HIFs) fluids. Fasted state simulated colonic fluid (FaSSCoF) and fed state simulated colonic fluid (FeSSCoF) were designed to reflect fluids previously collected from the ascending colon in healthy adults. Solubilities of the three model compounds were determined in HCFs, simulated HCFs, and plain buffers. For ketoconazole, solubilities in FaSSCoF and FeSSCoF were closer than those in the corresponding plain buffers to the solubility in HCFs. For danazol and felodipine, solubilities in FaSSCoF and FeSSCoF predicted solubilities in HCFs. In the fasted state, solubilities of danazol and felodipine in HCFs were higher than or similar to in HGFs or HIFs, while the ketoconazole solubility was lower. In the fed state, solubilities of all three model compounds in HCFs were lower than in HGFs or HIFs. FaSSCoF and FeSSCoF more closely predict solubility of poorly soluble compounds in HCFs than plain buffers. In most cases, solubility in HCFs differs from those in HGFs and HIFs.

Ketoconazole, an anti-fungal agent, is often incorporated in several pharmaceutical forms and in shampoo formulation it is known to be effective against fungal infection on the scalp. This paper describes a method to quantify ketoconazole in shampoo by comparing the cylinder plate assay and the HPLC method. The test organism used for the agar diffusion assay was Candida albicans ATCC 10231. Three different concentrations of ketoconazole were used for the diffusion assay. A mean zone diameter was obtained for each concentration. A standard curve was obtained by plotting the three values derived from the zone diameters. A prospective validation of the method showed that the method was linear (r = 0.9982), precise (R.S.D. = 2.57%) and accurate. The results obtained by the two methods were statistically evaluated by analysis of variance (ANOVA) and the results obtained indicate that there is no significant difference between these two methods.