Controlled release of a highly hydrophilic API from lipid microspheres obtained by prilling: Analysis of drug and water diffusion processes with X-ray-based methods

This study deals with the development of an oral controlled-release dosage form of a highly water-soluble antiepileptic drug. In this respect, drug-loaded spheroid particles close to 380 mu m in diameter and composed of lipid binders were prepared by prilling. The purpose here was to thoroughly characterize the controlled-release mechanism of the drug in aqueous pH-6.8 buffered dissolution medium. Water and drug diffusion pathways as well as related kinetic parameters were determined by theoretical analysis of experimental data. Conventional in-vitro experiments performed by analytical high performance liquid chromatography showed that the released fraction reaches 90 wt.% only after a 24-hour immersion in the dissolution medium, pointing out an effective sustained release mechanism. Interpretation of these data was strengthened by the implementation of an innovative methodology involving X-ray diffraction and microtomography to follow the structural evolution of the drug-loaded microspheres at molecular and microscopic scales. This approach allowed to explicit that water and drug transports obey to Fickian diffusion behaviours in good agreement with Crank's and non-simplified Higuchi's equations, respectively. In the latter case, independent modelling of drug release assimilating the microspheres to a variable-geometry reservoir was considered to refine the kinetic analysis of the diffusion process. The water diffusion coefficient D-w was found equal to 6.3 x 10(-9) cm(2)/s and the API apparent diffusion coefficient reduced to the tortuosity of the matrix D-API/tau equal to 2 x 10(-9) cm(2)/s. This study ranks among the rare examples of monolithic dispersion device constituted by a highly soluble drug incorporated inside a perfectly inert lipid matrix. The dissolution liquid penetrates the particles through channels progressively created by the solubilization of the drug itself which occurs instantaneously at the inner front of the liquid. (C) 2011 Elsevier B. V. All rights reserved.