title: Nanoparticle formation and growth during in vitro dissolution of ketoconazole solid dispersion.
abstract: The aim of this study is to examine the physical mechanisms during the dissolution of a solid dispersion, so as to provide further understanding behind the enhanced dissolution properties. X-ray amorphous solid dispersions of ketoconazole (KC), a poorly aqueous soluble drug, were prepared by melt extrusion with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer. Prior to dissolution, Raman mapping showed a fully homogeneous spatial distribution of KC in polymer and possible drug dispersion at molecular level, whereas Fourier transform infrared spectroscopy revealed no drug-polymer chemical interaction. During in vitro dissolution test, a burst release followed by a gradual decline in dissolution could be explained by the release of KC in molecular form followed by formation of drug nanoparticles and their subsequent growth to micron size range as shown by dynamic light scattering analysis. Observations using transmission electron microscopy and cryogenic scanning electron microscopy provided support to the suggested mechanisms. The results suggested that the release of KC from the solid dispersions was carrier controlled initially, and PVP 17 PF is more efficient in inhibiting particle growth as compared with PVP-VA64. The particle growth inhibition during dissolution may be an important consideration to achieve the full benefits of dissolution enhancement of solid dispersions.
authors.affiliation: Institute of Chemical and Engineering Sciences, Jurong Island, Singapore 627833. parijat_kanaujia@ices.a-star.edu.sg
authors.forename: Parijat
authors.initials: P
authors.lastname: Kanaujia
authors.forename: Grace
authors.initials: G
authors.lastname: Lau
authors.forename: Wai Kiong
authors.initials: WK
authors.lastname: Ng
authors.forename: Effendi
authors.initials: E
authors.lastname: Widjaja
authors.forename: Andrea
authors.initials: A
authors.lastname: Hanefeld
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischbach
authors.forename: Mario
authors.initials: M
authors.lastname: Maio
authors.forename: Reginald B H
authors.initials: RB
authors.lastname: Tan
mesh_terms: D002626:Chemistry, Pharmaceutical; D020285:Cryoelectron Microscopy; D003460:Crystallization; D018360:Crystallography, X-Ray; D007654:Ketoconazole / Q000737:chemistry*; D007700:Kinetics; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010316:Particle Size; D011205:Povidone / Q000737:chemistry; D033362:Powder Diffraction; D011759:Pyrrolidines / Q000737:chemistry; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D013678:Technology, Pharmaceutical / Q000379:methods; D014753:Vinyl Compounds / Q000737:chemistry
chemical_list: D011759:Pyrrolidines; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate); D011205:Povidone; D007654:Ketoconazole