A. Kearney, S. Mehta, G. Radebaugh
Aug 1, 1992
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Influential Citations
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Quality indicators
Journal
Pharmaceutical Research
Abstract
The aqueous solubility and solution stability of the N-methylglucamine and sodium salts of CI-988 (CI-988 NMG and CI-988 Na) were evaluated to aid in the development of a parenteral formulation for preclinical and clinical testing. CI-988 ([R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.13,7]dec-2-yloxy)-carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid) is a selective “dipeptoid” cholecystokinin-B receptor antagonist. The shape of the pH-solubility profile, generated at 30°C, is consistent with the ionization of the terminal carboxyl group (pKa of 4.34). The pH-rate profile is independent of the salt form and is well described by two reaction pathways: spontaneous or water-catalyzed degradation of the nonionized form and specific base-catalyzed degradation of the ionized form. The primary mechanism of degradation from the former pathway is consistent with intramolecular, carboxyl-assisted, amide-bond cleavage, whereas the primary mechanism of degradation from the latter pathway appears to be intramolecular cyclization to a hydantoin product with expulsion of 2-adamantanol. The pH dependencies of the solubility and stability show that a simple aqueous buffered solution of CI-988 has a predicted t90 of 2.1 years and a solubility of 0.94 mg/ml at pH 6.5, the theoretical pH of maximum stability, and 30°C.