ISSN:
1573-904X
Keywords:
CI-981
;
HMG-CoA reductase inhibitor
;
stability
;
solubility
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract The pH dependence of the interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981 ([R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-hepatonic acid), are important considerations when chosing and developing one of the forms of these compounds. Over a pH range of 2.1 to 6.0 and at 30°C, the apparent solubility of the sodium salt of CI-981 (i.e., the hydroxyacid form) increases about 60-fold, from 20.4 µg/mL to 1.23 mg/mL, and the profile yields a pK a for the terminal carboxyl group of 4.46. In contrast, over a pH range of 2.3 to 7.7 and also at 30°C, the apparent solubility of the lactone form of CI-981 varies little, and the mean solubility is 1.34 (±0.53) µg/mL. The kinetics of interconversion and the equilibrium between the hydroxyacid and the lactone forms have been studied as a function of pH, buffer concentration, and temperature at a fixed ionic strength (0.5 M) using a stability-indicating HPLC assay. The acid-catalyzed reaction is reversible, whereas the base-catalyzed reaction can be treated as an irreversible reaction. More specifically, at pH 〈6, an equilibrium favoring the hydroxyacid form is established, whereas at pH 〉6, the equilibrium reaction is no longer detectable and greatly favors the hydroxyacid form. The rate constant for lactone formation, k 1 is well described by specific acid-catalyzed and spontaneous lactonization pathways, whereas the rate constant for lactone hydrolysis (or hydroxyacid formation), k 2, is well described by specific acid-, water-, and specific base-catalyzed pathways.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1018923325359
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