Simplification of pharmacopoeial liquid chromatography methods for related substances of statins by hyphenated ultraviolet and charged aerosol detection

Abstract

For a more comprehensive characterization of a drug substance and its impurities, multidetector approaches are a helpful tool in liquid chromatography. In particular, the relatively inexpensive hyphenation of the ultraviolet (UV) with the charged aerosol detector (CAD) extends the scope from UV-active to non- or weak chromophore analytes, respectively. In this study, the chromatographic methods of the test for related substances of simvastatin and lovastatin in the European Pharmacopoeia were adapted to UV-CAD and thus allowing a more sophisticated detection of the weak chromophore dihydro impurity besides the other UV-active impurities. The compendial gradient program for simvastatin had to be modified (lowered initial acetonitrile percentage and increased gradient slope) because an additional critical peak pair emerged with the Hypersil C₁₈ BDS column used here. Therefore, a Plackett-Burman design with 11 factors (including 4 dummy factors) was chosen to evaluate robustness of the adapted method. The flow rate, initial acetonitrile percentage, and column temperature were identified as three critical parameters that had to be carefully observed. Finally, the validity of the method for simultaneous detection of dihydrosimvastatin with CAD and of lovastatin and simvastatin as examples of UV detection was verified according to ICH Q2 (R1). In the case of lovastatin, the direct comparison with the pharmacopoeial method reveal that a determination with CAD is the more sensitive method.

Keywords: Hyphenated LC-UV-CAD method; Inverse gradient compensation; Lovastatin; Plackett-Burman design; Simvastatin.