title: The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility.
abstract: Amorphous solid dispersions (ASDs) are a promising formulation approach for poorly soluble active pharmaceutical ingredients (APIs), because they ideally enhance both dissolution rate and solubility. However, the mechanism behind this is not understood in detail. In the present study, we investigated the supramolecular and the nano/microparticulate structures that emerge spontaneously upon dispersion of an ASD in aqueous medium and elucidated their influence on solubility. The ASD, prepared by hot melt extrusion, contained the poorly soluble ABT-102 (solubility in buffer, 0.05 μg/mL), a hydrophilic polymer, and three surfactants. The apparent solubility of ABT-102 from the ASD-formulation was enhanced up to 200 times in comparison to crystalline ABT-102. At the same time, the molecular solubility, as assessed by inverse equilibrium dialysis, was enhanced two times. Asymmetrical flow field-flow fractionation in combination with a multiangle light-scattering detector, an ultraviolet detector, and a refractometer enabled us to separate and identify the various supramolecular assemblies that were present in the aqueous dispersions of the API-free ASD (placebo) and of binary/ternary blends of the ingredients. Thus, the supramolecular assemblies with a molar mass between 20,000 and 90,000 could be assigned to the polyvinylpyrrolidone/vinyl acetate 64, while two other kinds of assemblies were assigned to different surfactant assemblies (micelles). The amount of ABT-102 remaining associated with each of the assemblies upon fractionation was quantified offline with high-performance liquid chromatography-ultraviolet-visible. The polymeric and the micellar fraction contributed to the substantial increase in apparent solubility of ABT-102. Furthermore, a microparticulate fraction was isolated by centrifugation and analyzed by scanning electron microscopy, X-ray scattering, and infrared spectroscopy. The microparticles were found to be amorphous and to contain two of the surfactants besides ABT-102 as the main component. The amorphous microparticles are assumed to be the origin of the observed increase in molecular solubility ("true" supersaturation).
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark.
authors.forename: Kerstin J
authors.initials: KJ
authors.lastname: Frank
authors.forename: Ulrich
authors.initials: U
authors.lastname: Westedt
authors.forename: Karin M
authors.initials: KM
authors.lastname: Rosenblatt
authors.forename: Peter
authors.initials: P
authors.lastname: Hölig
authors.forename: Jörg
authors.initials: J
authors.lastname: Rosenberg
authors.forename: Markus
authors.initials: M
authors.lastname: Mägerlein
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
authors.forename: Martin
authors.initials: M
authors.lastname: Brandl
mesh_terms: D003102:Colloids / Q000737:chemistry*; D004058:Diffusion; D007191:Indazoles / Q000737:chemistry*; D008422:Materials Testing; D008863:Microspheres; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure*; D010316:Particle Size; D052638:Particulate Matter / Q000737:chemistry*; D012995:Solubility; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: C528492:ABT 102; D003102:Colloids; D007191:Indazoles; D052638:Particulate Matter; D014867:Water; D014508:Urea