In situ formation of nanoparticles upon dispersion of melt extrudate formulations in aqueous medium assessed by asymmetrical flow field-flow fractionation

Abstract

In recent years melt extrudates (e.g. Meltrex ®) have proven to be a promising formulation tool for poorly water-soluble and poorly bioavailable drugs. During the hot-melt extrusion process solid dispersions are formed. For several of these formulations improved bioavailabilities have been reported; the mechanism behind, however is still not very well understood. The aim of this study was to investigate whether solid dispersions prepared by melt extrusion upon dispersion in aqueous medium form particles and/or supramolecular assemblies. The formulation investigated here contained the human immunodeficiency virus (HIV) protease inhibitors lopinavir and ritonavir, polyvinylpyrrolidone–vinyl acetate copolymer (Kollidon ® VA64), sorbitan monolaurate (Span ® 20) and hydrophilic fumed silica (Aerosil ® 200). The aqueous dispersions originating from both, API-containing and placebo formulation were investigated using photon correlation spectroscopy (PCS) and asymmetrical flow field-flow fractionation (AsFlFFF) with subsequent online multi-angle light-scattering (MALS) particle size analysis. The content of both APIs in the AsFlFFF-fractions was quantified using high performance liquid chromatography–mass spectrometry. PCS indicated sub-micron particles. AsFlFFF revealed the co-existence of up to three different types of colloidal to nanoparticulate assemblies in the aqueous dispersions. Even though a complete resolution of the composition of the sub-fractions could not be achieved, the following types could be clearly distinguished: The first fraction eluting from AsFlFFF, appears to be colloidal polymer. Only marginal amounts of the APIs were found associated with the polymer. Secondly, API-rich nanoparticles eluted. Thirdly, nanoparticulate assemblies assigned to sorbitan monolaurate and/or hydrophilic fumed silica were identified. A limited amount of drug was found associated with this fraction. Using AsFlFFF–MALS the size of particles in fractions could be determined. From this experience AsFlFFF is regarded as promising technique for investigation of particles/structures originating during dispersion of melt extrudates in aqueous medium in terms of size and type of nanoparticles and their API-content.