Bioavailability enhancement of an active substance by supercritical antisolvent precipitation

Abstract

Oxeglitazar is a new orally administered poorly water soluble active substance used in the treatment of type II diabetes. Our research aimed to improve the bioavailability of this active substance using Supercritical Antisolvent (SAS) process. Oxeglitazar was coprecipitated with various solubilizing excipients: polyoxyethylene–polyoxypropylene block copolymers (Poloxamer 188 and 407), polyethylene glycol (PEG 8000) and polyvinilpyrrolidone (PVP K17) from six different solvents: ethanol (EtOH), tetrahydrofuran (THF), dichloromethane (DCM), chloroform (CHCl 3), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) and two binary solvent mixtures: EtOH/THF (50:50%, v/v) and EtOH/CHCl 3 (50:50%, v/v). Formulations were compared in terms of particle morphology, crystallinity, polymorphic purity, residual solvent content, precipitation yield and dissolution kinetics. SAS formulations of oxeglitazar–PEG 8000, Poloxamer 188 and 407 contained acicular drug crystals that were partly embedded in polymeric spheres while experiments with PVP K17 resulted in quasi amorphous solid dispersions with high density and good flowability. In spite of the greater particle size, SAS formulations exhibited significantly greater dissolution rate compared to raw drug and physical mixtures. More than twice as much active substance was dissolved at 5 min from Poloxamer 407 and PVP K17 formulations than from unprocessed drug. In addition, SAS prepared Poloxamer 407 formulation from DCM solution exhibited high polymorphic purity, good flow properties, acceptable precipitation yield and low residual solvent content.