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 i...

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Bibliographic Details
Published in:International journal of pharmaceutics 2004-05, Vol.275 (1), p.19-27
Main Authors: Euler, Danielle, Frech, Patricia, Karki, Shyam, Cowden, Cameron, Pearce, Gareth, Mehta, Pratik, Lindemann, Christopher, Byway, Paul, Wang, Michael, Gibson, Todd, Cheng, Yu, Kwei, Gloria, Rose, Jayna
Format: Article
Language:English
Subjects:
Acetamides
Animals
Anticoagulants - blood
Anticoagulants - chemistry
Anticoagulants - pharmacokinetics
Biological and medical sciences
Caco-2 Cells
Crystallization
Dogs
Drug Compounding
General pharmacology
Humans
In Vitro Techniques
Intestinal absorption
Intestinal Absorption - drug effects
Intestines - anatomy & histology
Intestines - metabolism
Male
Medical sciences
Pharmaceutical Solutions
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Polymorphism
Pyrazines
Solubility
Surface area
Surface Properties
Suspensions
Thrombin - antagonists & inhibitors
Time Factors
Water
X-Ray Diffraction
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Summary: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.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2003.12.021