title: The interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981.
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)- beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl ]- 1H-pyrrole-1-hepatonic acid), are important considerations when choosing 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 micrograms/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 degrees C, the apparent solubility of the lactone form of CI-981 varies little, and the mean solubility is 1.34 (+/- 0.53) micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmaceutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Morris Plains, New Jersey 07950.
authors.forename: A S
authors.initials: AS
authors.lastname: Kearney
authors.forename: L F
authors.initials: LF
authors.lastname: Crawford
authors.forename: S C
authors.initials: SC
authors.lastname: Mehta
authors.forename: G W
authors.initials: GW
authors.lastname: Radebaugh
mesh_terms: D000069059:Atorvastatin; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006538:Heptanoic Acids / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D007783:Lactones / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry*; D012995:Solubility; D013696:Temperature
chemical_list: D002021:Buffers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D011758:Pyrroles; D000069059:Atorvastatin