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.
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Kearney, A.S., Crawford, L.F., Mehta, S.C. et al. The Interconversion Kinetics, Equilibrium, and Solubilities of the Lactone and Hydroxyacid Forms of the HMG-CoA Reductase Inhibitor, CI-981. Pharm Res 10, 1461–1465 (1993). https://doi.org/10.1023/A:1018923325359
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DOI: https://doi.org/10.1023/A:1018923325359