title: 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.
abstract: 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 μm 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 × 10(-9) cm(2)/s and the API apparent diffusion coefficient reduced to the tortuosity of the matrix D(API)/τ equal to 2 × 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.
authors.affiliation: Université Paris-Sud XI, UMR CNRS 8612, 5 rue JB Clément, 92290 Châtenay Malabry, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Pivette
authors.forename: Vincent
authors.initials: V
authors.lastname: Faivre
authors.forename: Lucia
authors.initials: L
authors.lastname: Mancini
authors.forename: Claire
authors.initials: C
authors.lastname: Gueutin
authors.forename: Georges
authors.initials: G
authors.lastname: Daste
authors.forename: Michel
authors.initials: M
authors.lastname: Ollivon
authors.forename: Sylviane
authors.initials: S
authors.lastname: Lesieur
mesh_terms: D000927:Anticonvulsants / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004058:Diffusion; D004339:Drug Compounding / Q000379:methods*; D005079:Excipients / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008863:Microspheres; D010232:Paraffin / Q000737:chemistry; D014635:Valproic Acid / Q000737:chemistry; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D005079:Excipients; D005227:Fatty Acids; D014867:Water; C086409:glyceryl behenate; D014635:Valproic Acid; D010232:Paraffin