Simvastatin was forced degraded and a composite sample was analyzed with the goal
to develop an impurity profile. An unknown impurity was discovered using a high pH
mobile phase in combination with a methanol gradient during the course of a QbD method
development process. The aim of this study was to identify the unknown impurity and
characterize potential points of origin or relationship to the API.
Analysis of the unknown impurity yielded MS spectral results of [M+H]+=451.3057 Da and major fragment ions of m/z=299.1997, 317.2104, 335.2187, and 357.2029
Da. The elemental composition analysis for [M+H]+=451.3057 proposed a structure having a composition consisting of C26 H43 O6 with a mass accuracy of -0.3 ppm and an isotopic fit confidence of 93.83%. A known
related impurity of simvastatin, simvastatin methyl ester, has the same elemental
composition. Investigative experiments confirmed zero presence of [M+H]+=451.3057
when utilizing all other LC chromatographic conditions used in the QbD method development
process, thus suggesting on-column degradation of simvastatin when employing methanol
and high pH conditions. Replacing methanol with ethanol as the elution solvent confirmed
this hypothesis by producing the simvastatin ethyl ester degradation product on-column.
The results suggest the on-column transesterfication of simvastatin through attack
of the lactone ring with alcohol-based solvents and high pH buffer as the mobile phases.
This is a consideration for LC methods developers employing lower cost alternatives
to acetonitrile.
