COCRYSTALLIZATION TO IMPROVE THE DISSOLUTION AND PHARMACOKINETICS OF A POORLY SOLUBLE DRUG
Issue Date
2010-04-12Author
Stanton, Mary Katherine
Publisher
University of Kansas
Format
166 pages
Type
Thesis
Degree Level
M.S.
Discipline
Pharmaceutical Chemistry
Rights
This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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Show full item recordAbstract
Improving the dissolution and pharmacokinetics of the poorly soluble active pharmaceutical ingredient, AMG 517, through cocrystallization was investigated. Correlations between the in vitro powder and intrinsic dissolution in fasted simulated intestinal fluid and the in vivo rat pharmacokinetics of 16 cocrystals were examined. A detailed exploration of the behaviors of corresponding carboxylic acid and amide cocrystal pairs utilizing single crystal structure analysis to elucidate results is also performed. All cocrystals exhibit increased intrinsic and powder dissolution rates as well as area under the concentration-time curve and maximum plasma concentration in rat pharmacokinetic investigations compared to the free base. Linear regression analysis leads to a moderate in vitro/in vivo correlation. The incorporation of an amide rather than the more common carboxylic acid cocrystal former affords unique properties in one case. In silico tools describing the crystal faces, attachment energy and crystal morphology, are constructive in relating the crystals physical properties.
Collections
- Pharmaceutical Chemistry Dissertations and Theses [141]
- Theses [3940]
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