Investigations into the HPLC Retention Behavior of Simvastatin and Structurally Related Compounds

Abstract

The HPLC retention behavior of simvastatin and its β,δ‐dihydroxy acid and methylester forms were investigated. The retention of the lactone and the methylester was found to be highly dependent on the eluent composition and mildly dependent on temperature at low temperatures. The retention of the β,δ‐dihydroxy acid was found to be highly dependent on eluent pH and temperature as well as the composition. Atypical dependence of the retention of the β,δ‐dihydroxy acid on temperature prompted further investigation. It was determined that the observed temperature–retention relationship for the β,δ‐dihydroxy acid was caused by a shift in the _w ^s pK of the acid under the elution conditions. As the elution temperature increases, the _w ^s pK of the acid changes resulting in an increase in retention at low temperatures. Thermodynamic analysis shows that retention of simvastatin and the methyl ester is predominantly enthalpy driven. Similar analysis for the β,δ‐dihydroxy acid shows that retention is entropy driven at low temperatures at all pH's, but it is enthalpy driven at higher temperatures.

Keywords:

• Retention behavior
• Simvastatin
• HPLC
• Related compounds

Acknowledgments

The authors would like to thank Dr. Andy Clausen, Dr. Rosario Lobrutto, Dr. Anant Vailaya, Dr. Peter Sajonz, Dr. Jean Wyvratt, Mr. Gary Bicker, and Mrs. Kathi Price for their helpful discussions throughout the preparation of this manuscript.