title: Assessment of oral bioavailability enhancing approaches for SB-247083 using flow-through cell dissolution testing as one of the screens.
abstract: SB-247083 is a potent, nonpeptidic, orally active, ETA-selective, endothelin receptor antagonist. The diacid form and three salts (monoarginine, diarginine and disodium) of SB-247083 were evaluated during the pre-clinical phase of development. The developability attributes (i.e. hygroscopicity, thermal behavior, aqueous solubility, and drug-excipient compatibility) of these compounds were evaluated. In addition to these attributes, the flow-through cell (FTC) dissolution testing (using USP Apparatus 4) was used as a screening technique to evaluate several SB-247083 formulations of the diacid and its salts. FTC dissolution testing offers two distinct advantages over the more traditional static-condition dissolution testing: (1) maintenance of sink conditions; and (2) the ability to change the dissolution medium during a dissolution run. The former advantage is especially important for poorly aqueous soluble drugs having associated dissolution-rate-limitations, and the latter advantage allows one to more closely simulate the pH gradient associated with transit through the GI tract. Based on the comparative dissolution data, three formulations were chosen for oral dosing in dogs. The reasonable correlation found between the FTC dissolution results and the oral bioavailability data demonstrate that FTC dissolution testing can be a valuable tool for aiding in salt (solid-state form) and formulation selection in the early stages of development of drug candidates.
authors.affiliation: Pharmaceutical Development, GlaxoSmithKline plc, 709 Swedeland Road, King of Prussia, PA 19406, USA. david_perng-1@gsk.com
authors.forename: Cherng-Yih
authors.initials: CY
authors.lastname: Perng
authors.forename: Albert S
authors.initials: AS
authors.lastname: Kearney
authors.forename: Nagesh R
authors.initials: NR
authors.lastname: Palepu
authors.forename: Brian R
authors.initials: BR
authors.lastname: Smith
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Azzarano
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D005079:Excipients; D008297:Male; D011422:Propionates / Q000737:chemistry / Q000493:pharmacokinetics*; D044022:Receptor, Endothelin A; D012995:Solubility
chemical_list: D001572:Benzofurans; D065128:Endothelin Receptor Antagonists; D005079:Excipients; D011422:Propionates; D044022:Receptor, Endothelin A; C113045:SB 247083