title: Influence of physicochemical properties and intestinal region on the absorption of 3-fluoro-2-pyrimidylmethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide, a water insoluble thrombin inhibitor, in dogs.
abstract: In this paper, we describe the physicochemical and biopharmaceutical properties of 3-fluoro-2-pyrimidylmethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide, a direct thrombin inhibitor (1, Fig. 1). Three crystalline forms were characterized and studies were planned to investigate the absorption characteristics of the three selected crystalline forms. Due to the short half-life observed in preclinical species, regional absorption studies were also conducted to support potential controlled release formulation development. Results showed that the absorption of 1 was dependent on the surface area of the particles administered as suspensions and was independent of the crystal forms. From Caco-2 cell transport studies, it was determined that the permeability of 1 was high. Based on the low aqueous solubility it would be classified as a class 2 compound in the Biopharmaceutics Classification System. Regional absorption results suggested that the compound was absorbed along the gastrointestinal tract in Beagle dogs, however colonic absorption appeared to be reduced by slower dissolution.
authors.affiliation: Department of Pharmaceutical Research and Development, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Euler
authors.forename: Patricia
authors.initials: P
authors.lastname: Frech
authors.forename: Shyam
authors.initials: S
authors.lastname: Karki
authors.forename: Cameron
authors.initials: C
authors.lastname: Cowden
authors.forename: Gareth
authors.initials: G
authors.lastname: Pearce
authors.forename: Pratik
authors.initials: P
authors.lastname: Mehta
authors.forename: Christopher
authors.initials: C
authors.lastname: Lindemann
authors.forename: Paul
authors.initials: P
authors.lastname: Byway
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Todd
authors.initials: T
authors.lastname: Gibson
authors.forename: Yu
authors.initials: Y
authors.lastname: Cheng
authors.forename: Gloria
authors.initials: G
authors.lastname: Kwei
authors.forename: Jayna
authors.initials: J
authors.lastname: Rose
mesh_terms: D000081:Acetamides; D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D003460:Crystallization; D004285:Dogs; D004339:Drug Compounding; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000033:anatomy & histology; D008297:Male; D019999:Pharmaceutical Solutions; D011719:Pyrazines; D012995:Solubility; D013499:Surface Properties; D013535:Suspensions; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014867:Water; D014961:X-Ray Diffraction
chemical_list: C488415:3-fluoro-2-pyrimidylmethyl 3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide; D000081:Acetamides; D000925:Anticoagulants; D019999:Pharmaceutical Solutions; D011719:Pyrazines; D013535:Suspensions; D014867:Water; D013917:Thrombin