Epimerization and hydrolysis of dalvastatin, a new hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.
In aqueous solutions, dalvastatin (1) undergoes epimerization as well as hydrolysis. The transformation of the drug was studied as a function of pH at 25 degrees C in aqueous solutions containing 20% acetonitrile. At all pH values, first-order plots for the conversion are biphasic, indicating rapid equilibration of 1 with its epimer (2) and slower hydrolysis of 1 to the corresponding beta-hydroxy acid (3). Apparent first-order rate constants for the biexponential equation are given as a function of pH. The alkyl-oxygen cleavage of the lactone ring results in the epimerization of 1 to 2, whereas the acyl-oxygen cleavage results in the hydrolysis of 1 to 3. The epimerization is an SN1 reaction reaching an equilibrium of [1]eq/[2]eq = 1.27. The epimerization rate is increased with an increase in the water content of the solvent. The hydrolysis of 1 to 3 is acid and base catalyzed. The hydrolysis is reversible in acidic media and irreversible in neutral and basic media. At pH values greater than 9, the hydrolysis reaction proceeds more rapidly than the epimerization.
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Analytical and Physical Chemistry Department, Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426-0107.
D000097:Acetonitriles; D000924:Anticholesteremic Agents / Q000737:chemistry*; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003510:Cyclohexanes / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007536:Isomerism; D007700:Kinetics; D007783:Lactones / Q000737:chemistry*
D000097:Acetonitriles; D000924:Anticholesteremic Agents; D003510:Cyclohexanes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; C071481:dalvastatin