title: Effect of physicochemical and formulation variables on the in vivo absorption of ABT-761.
abstract: ABT-761 is a 5-lipoxygenase inhibitor developed for the treatment of asthma. The present study was undertaken to evaluate different crystal forms of ABT-761 and their impact on in vitro and in vivo performance in capsule formulations. Two crystal forms of ABT-761, hemihydrate and non-solvate from different sources, were characterized by thermal analysis, x-ray powder diffraction, moisture sorption, and intrinsic dissolution studies. An in vitro test was performed to assess the effect of formulation and drug from different sources on drug release. Crossover design was also used to evaluate oral bioavailability of ABT-761 hemihydrate formulations in beagle dogs. Plasma concentrations of ABT-761 were analyzed using a reverse-phase high-performance liquid chromatography (HPLC) assay. It was found that in vivo oral absorption as well as in vitro dissolution of ABT-761 were influenced by different formulations. Capsule formulations of ABT-761 hemihydrate are bioequivalent to the solution formulation in terms of extent of absorption, butformulation and the method of granulation preparation can have a major impact on the absorption rate. In conclusion, a single crystal form of ABT-761, i.e., hemihydrate, is preferred for subsequent product development. However, exposure of the drug to conditions that may facilitate phase transformation should be avoided.
authors.affiliation: Pharmaceutical and Analytical Research and Development, Abbott Laboratories, North Chicago, Illinois 60064, USA. Qiu.yihong@abbott.com
authors.forename: Yihong
authors.initials: Y
authors.lastname: Qiu
authors.forename: James J
authors.initials: JJ
authors.lastname: Fort
authors.forename: Jay
authors.initials: J
authors.lastname: Trivedi
authors.forename: Armin H
authors.initials: AH
authors.lastname: Gerhardt
authors.forename: Peter
authors.initials: P
authors.lastname: Mayer
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Briskin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schilling
mesh_terms: D000042:Absorption / Q000187:drug effects / Q000502:physiology; D000818:Animals; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D004285:Dogs; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000097:blood* / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: C096921:atreleuton; D006918:Hydroxyurea