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.
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.
Euler
Danielle
D
Department of Pharmaceutical Research and Development, Merck & Co., Inc., West Point, PA 19486, USA.
Frech
Patricia
P
Karki
Shyam
S
Cowden
Cameron
C
Pearce
Gareth
G
Mehta
Pratik
P
Lindemann
Christopher
C
Byway
Paul
P
Wang
Michael
M
Gibson
Todd
T
Cheng
Yu
Y
Kwei
Gloria
G
Rose
Jayna
J
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
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