THE INTERCONVERSION KINETICS, EQUILIBRIUM, AND SOLUBILITIES OF THE LACTONE AND HYDROXYACID FORMS OF THE HMG-COA REDUCTASE INHIBITOR, CI-981

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)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-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-degrees-C, the apparent solubility of the sodium salt of CI-981 (i.e., the hydroxyacid form) increases about 60-fold, from 20.4 mug/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-degrees-C, the apparent solubility of the lactone form of CI-981 varies little, and the mean solubility is 1.34 (+/-0.53) mug/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, 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.