The Interconversion Kinetics, Equilibrium, and Solubilities of the Lactone and Hydroxyacid Forms of the HMG-CoA Reductase Inhibitor, CI-981

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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 pKa 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, the equilibrium reaction is no longer detectable and greatly favors the hydroxyacid form. The rate constant for lactone formation, k1 is well described by specific acid-catalyzed and spontaneous lactonization pathways, whereas the rate constant for lactone hydrolysis (or hydroxyacid formation), k2, is well described by specific acid-, water-, and specific base-catalyzed pathways.