Applications of oxygen polarography to drug stability testing and formulation development: solution-phase oxidation of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.
The kinetics of oxidation of the HMG-CoA reductase inhibitors lovastatin, simvastatin, L-157,012, and L-647,318 were studied in an aqueous surfactant solution. A thermally labile free radical initiator was used to attain measurable reaction rates at 40 degrees C and rate constants were determined by measuring oxygen consumption using an oxygen electrode. The stability of the drugs was found to increase in the order lovastatin = simvastatin less than L-157,012 less than L-647,318. The addition of butylated hydroxyanisole (BHA) was found to stabilize the drugs. For the oxidation of lovastatin, the effectiveness of antioxidants increased in the order propyl gallate less than BHA less than alpha-tocopherol. It is concluded that the stability of oxidizable drugs can be rapidly and conveniently assessed by the techniques described herein.
Kaufman
M J
MJ
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
D000975:Antioxidants; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000032:analysis; D010101:Oxygen Consumption / Q000187:drug effects; D011048:Polarography; D019821:Simvastatin
D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C064145:L 157012; C064146:L 647318; D008148:Lovastatin; D019821:Simvastatin; D010100:Oxygen