title: Stabilisation of amorphous furosemide increases the oral drug bioavailability in rats.
abstract: A glass solution of the amorphous sodium salt of furosemide (ASSF) and polyvinylpyrrolidone (PVP) (80:20 w/w%) was prepared by spray drying. It was investigated if PVP was able to stabilise ASSF during storage and dissolution and whether this influenced the in vivo performance of the glass solution after oral dosing to rats. The glass solution had a glass transition temperature of 121.3 ± 0.5°C, which was significantly higher than that of the pure drug (101.2°C). ASSF in the glass solution was stable for at least 168 days when stored at 20°C and 0% relative humidity. The glass solution exhibited fast dissolution in simulated intestinal medium, pH 6.5; the intrinsic dissolution rate was found to be 10.1 ± 0.6 mg/cm(2)/min, which was significantly faster than the pure ASSF. When investigating the stability during dissolution in stimulated intestinal medium at pH 6.5, the ASSF in the glass solution showed signs of crystallinity after 1 min of dissolution, but crystallised to a lesser extent than pure ASSF. The stabilising effect of PVP on ASSF, led to improved relative oral bioavailability in rats of 263%, when compared to the pure ASSF.
authors.affiliation: Department of Micro- and Nanotechnology, Technical University of Denmark, Ørsteds Plads 345B, 2800 Kongens Lyngby, Denmark.
authors.forename: Line Hagner
authors.initials: LH
authors.lastname: Nielsen
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: thomas.rades@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Bioneer:FARMA, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D005665:Furosemide / Q000008:administration & dosage* / Q000737:chemistry*; D005898:Glass / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008297:Male; D019999:Pharmaceutical Solutions / Q000008:administration & dosage / Q000737:chemistry; D011205:Povidone / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D044366:Transition Temperature
chemical_list: D019999:Pharmaceutical Solutions; D005665:Furosemide; D011205:Povidone
keywords: Amorphous; Furosemide; Glass solution; Oral bioavailability; Polyvinylpyrrolidone; Solid dispersion