title: Dissolution and coarsening of polydisperse, polymorph drug particles liberated from a disintegrating finished dosage form: Theoretical considerations.
abstract: In order to improve the bioavailability of substances with limited water-solubility, they are often formulated as nanoparticles. Nanoparticles show enhanced dissolution properties when compared to large particles. In this paper a dissolution theory is presented that comprehensively describes the dissolution properties of both large- and nanoparticles. It comprises non-sink conditions and arbitrary shaped isometrically dissolving particles, considering particle-size-independent dissolution layer thickness and several polymorphic drug forms. The known root-laws of dissolution kinetics happen to be special cases that depend on particle-size in relation to the diffusion layer thickness i.e. whether the particles are much larger, comparable, or much smaller than the diffusion layer thickness. The presented theory explains the improved dissolution properties of nanoparticles, such as their increased solubility, almost immediate dissolution, and the dissolution kinetics which is independent from hydrodynamic conditions. For polydisperse, polymorphic particles of arbitrary shapes that are liberated from a disintegrating finished dosage form, the Ostwald ripening (coarsening of particles and transition of metastable polymorphic forms into a more stable crystalline form) is described as water mediated mass transport. The presented theory points to certain limitations of the Ostwald-Freundlich equation for nanoparticles and provides their better characterization. This way it may contribute to a more specifically targeted development of finished dosage forms and may help to reduce the bias of toxicological and environmental assessments especially for drugs that are formed as nanoparticles.
authors.affiliation: Sandoz GmbH, Biochemiestr. 10, A-6250 Kundl, Austria. Electronic address: stefan.horkovics-kovats@sandoz.com.
authors.forename: Stefan
authors.initials: S
authors.lastname: Horkovics-Kovats
mesh_terms: D004304:Dosage Forms; D065546:Drug Liberation; D007700:Kinetics; D008962:Models, Theoretical; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D012995:Solubility
chemical_list: D004304:Dosage Forms
keywords: Dissolution kinetics; Effective diffusion layer thickness; Nanoparticles; Ostwald-Freundlich equation; Particle size-independent diffusion layer thickness; Polymorphic forms; Solubility