title: Preparation of nanoparticles by solvent displacement for drug delivery: a shift in the "ouzo region" upon drug loading.
abstract: As biodegradable nanoparticles meet with increasing interest for drug delivery applications, a series of investigations were carried out to understand the mechanism of the formation of drug-loaded nanoparticles using the solvent displacement method. Although previous explanations referred to Marangoni convection as the driving force for nanoprecipitation, recent publications describing the so-called "ouzo effect" sparked these current studies using a novel negatively charged polymer, poly(vinyl sulfonate-co-vinyl alcohol)-graft-poly(D,L-lactide-co-glycolide) (P(VS-VA)-g-PLGA), and a positively charged model drug, salbutamol. Interfacial tension did not influence the nanoparticle formation as would be expected if governed by Marangoni convection, but ternary phase diagrams outlined the so-called "ouzo regions" defining the polymer and solvent concentrations leading to stable nanoparticle suspensions for both this novel polymer and unmodified poly(D,L-lactide-co-glycolide) (PLGA). Physicochemical properties, morphology and drug loading of the nanoparticles were analyzed, and stable P(VS-VA)-g-PLGA nanoparticles with and without salbutamol ranged in size from 59-191nm. The "ouzo region" phase diagram boundaries shifted considerably upon drug loading, which can be explained by the increased solubility of the polymer-drug complex. This behavior necessitated a substantial adjustment of polymer concentrations required to produce drug-loaded nanoparticles with characteristics comparable to blank nanoparticles. In conclusion, the use of "ouzo diagrams" is a beneficial tool to manufacture nanoparticles with specified physicochemical properties by the solvent displacement method.
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps-Universität Marburg, Ketzerbach 63, Marburg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Beck-Broichsitter
authors.forename: Erik
authors.initials: E
authors.lastname: Rytting
authors.forename: Tobias
authors.initials: T
authors.lastname: Lebhardt
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Kissel
mesh_terms: D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D018625:Microscopy, Atomic Force; D053758:Nanoparticles; D012997:Solvents; D013500:Surface Tension; D014783:Viscosity
chemical_list: D012997:Solvents