Aqueous stability and solubility of CI-988, a novel "dipeptoid" cholecystokinin-B receptor antagonist.
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[3.3.1.1(3,7)]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 degrees 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 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 degrees C.
Kearney
A S
AS
Department of Pharmaceutics, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Morris Plains, New Jersey 07950.
Mehta
S C
SC
Radebaugh
G W
GW
D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007211:Indoles / Q000737:chemistry*; D008536:Meglumine / Q000031:analogs & derivatives* / Q000737:chemistry; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012995:Solubility
D007211:Indoles; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D008536:Meglumine