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 so lubilities of the lactone and hydroxyacid forms of the HMG-CoA reducta se inhibitor, CI-981 l-4-[(phenylamino)carbonyl]-1H-pyrrole-1-hepatoni c 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 va ries little, and the mean solubility is 1.34 (+/-0.53) mug/mL. The kin etics of interconversion and the equilibrium between the hydroxyacid a nd the lactone forms have been studied as a function of pH, buffer con centration, and temperature at a fixed ionic strength (0.5 M) using a stability-indicating HPLC assay. The acid-catalyzed reaction is revers ible, whereas the base-catalyzed reaction can be treated as an irrever sible reaction. More specifically, at pH <6, an equilibrium favoring t he hydroxyacid form is established, whereas at pH >6, the equilibrium reaction is no longer detectable and greatly favors the hydroxyacid fo rm. The rate constant for lactone formation, k1, is well described by specific acid-catalyzed and spontaneous lactonization pathways, wherea s the rate constant for lactone hydrolysis (or hydroxyacid formation), k2, is well described by specific acid-, water-, and specific base-ca talyzed pathways.