Modelling of release kinetics of mebendazole from solid dispersion based formulations in simulted gastric fluid

Mebendazole (MBZ) is the main treatment of human echinococcosis caused by the larval forms of the parasite Echinococcus granulosus or E. multilocuralis, which enter in blood and contaminate internal organs, and has been shown active also in various cancer types. Due to its poor solubility in intestinal fluid, in both cases its bioavailability is a critical factor in determining the extent and duration of effect. Tablets based on solid mebendazole dispersions in polyethylene glycol 6000 (PEG) by melting method were prepared in the ratios of 1: 1 and 1: 2.5, with croscarmellose and Ludiflash as excipients, in order to increase its bioavailability. In vitro release assays were performed in simulated gastric fluid. The release was performed using USP apparatus 2 (paddles) model using an ERWEKA DT800 HH device at a rotational speed of 75 rpm. The resulting samples were quantitatively analyzed using a validated HPLC method. Release kinetics was performed using Noyes-Whitney, Higuchi, Siepmann Peppas, Weibull and Immediate Release in Semi-infinite Medium model (IR-SIM). Swelling and disaggregation excipients led to a release in two, well separated, phases: pre-disaggregation and post- disaggregation. Release after three hours decreased following inclusion of MBZ as solid dispersion in PEG from 100 % in absence of PEG to approximately 50 % in case of 1:1 MBZ-PEG proportion and to some, 20 % in case of 1: 2.5 MBZ-PEG proportion. In both phases, the kinetics of release fitted well the law of the radical and the law of Noyes Whitney. Since the site of the action / absorption of mebendazole is not at the gastric but at the intestinal level, as well as the fact that mebendazole has the tendency to precipitate in the passage from the gastric fluid to the intestine fluid, it was considered that the slower gastric release may partially cancel out its tendency to precipitate. Square root type behavior can appear in case of dissolution of active substance in solvent penetrating the tablet matrix (Higuchi model) or in case of release outside the matrix acting as an infinite reservoir. Since Noyes Whitney model suppose the release in a limit layer outside the matrix, it was considered an argument for IR-SIM model. The conclusion has a general methodological significance in conditions of quasi-total acceptance in literature of Higuchi model even in conditions far of those used in its deduction.