High speed development work by preparation of an “in-hand” library of NMR-quantified degradation products

Standard materials of impurities are needed in pharmaceutical development such as for validating impurity analytical methods. Most often the impurities possess structures, which are difficult and very time consuming to synthesize. In the present work, we demonstrate that a library of degradation products of ragaglitazar-a novel tricyclic-γ-alkyloxyphenylpropionic acid with hypolipidemic and antidiabetic activity-observed in stability indicating samples of a solid dosage formulation by LC-MS can be produced in a one pot oxidation reaction. The library entities were isolated in small quantities (µg-mg) by preparative HPLC and structurally characterized by NMR spectroscopy and mass spectrometry. The concentrations of the library entities were determined in solution by NMR using an internal standard method. The library was successfully used in the validation work of a newly developed purity method for the drug product providing useful response factors and relative retention times (RRTs) of the degradation products.