title: Development of a discriminating in vitro dissolution method for a poorly soluble NO-donating selective cyclooxygenase-2 inhibitor.
abstract: A discriminating dissolution method using a USP apparatus 2 dissolution tester was developed for a nitric oxide donating selective COX-2 inhibitor to support phase I and II formulation development, clinical supplies release and stability testing of an immediate release oral tablet. The BCS class II compound showed very low aqueous solubility and required the use of surfactant-containing (sodium lauryl sulfate (SLS)) dissolution medium in order to achieve an appropriate release profile. The dissolution method utilized 900 mL of 2% SLS (w/v). Samples were withdrawn at five specified time-points over 60 min, at a paddle speed of 75 rpm. Analysis of samples was performed using a validated HPLC method. Despite the use of high levels of SLS, the ability to discriminate variations in physical properties such as drug particle size, granule particle size and tablet compression force was demonstrated. In order to confirm the relationship between these physical parameters and the tablet in vivo release profile, oral dosing of the formulations in fasted beagle dogs was performed to determine if the changes observed in the dissolution profiles were biorelevant. The results of the dissolution and corresponding in vivo experiments helped identify the critical processing parameters likely to influence product bioavailability.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Merck Frosst Center for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1. robert_papp@merck.com
authors.forename: Robert
authors.initials: R
authors.lastname: Papp
authors.forename: Pauline
authors.initials: P
authors.lastname: Luk
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Mullett
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kwong
authors.forename: Smita
authors.initials: S
authors.lastname: Debnath
authors.forename: Roch
authors.initials: R
authors.lastname: Thibert
mesh_terms: D000818:Animals; D001682:Biological Availability; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D020030:Nitric Oxide Donors / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D020030:Nitric Oxide Donors