Characterization and relative response factor determination of process related impurity in Naproxen by nuclear magnetic resonance spectroscopy

In the impurity profile of naproxen around 0.6% unknown polar impurity was detected by high performance liquid chromatography (HPLC). The product ion spectrum of the impurity and Naproxen was recorded in LCMS/MS and the fragmentation pattern of the impurity was observed to be similar to the fragmentation pattern of Naproxen with only a difference of two atomic mass units. The high resolution mass spectrum (HRMS) of the impurity displayed a protonated molecular ion at m/z 229.0863, which corresponds to the pseudomolecular formula C14H13O3+. Based on LC/MS/MS, HRMS, 1D and 2D NMR data, the structure of the impurity was characterized as 2-(6-methoxynaphthalen-2-yl)acrylic acid. The acrylic acid impurity was synthesized in the laboratory and co injected in HPLC to confirm the retention time. RRF of the impurity was determined by 1H NMR method and also by conventional HPLC slope method and the RRF values are found to be 6.11 and 5.64, respectively. The values are comparable and 1H NMR method of RRF determination is complimentary and can be effectively used as an alternative method to conventional HPLC method especially in early stages of development when availability of impurity standards is not possible.