Determination of Naproxen Impurities’ Relative Response Factors by qNMR-HPLC Using DMSO-d6 Solvent as an Internal Calibrant

Quantitative nuclear magnetic resonance coupled with HPLC (qNMR-HPLC) is a rapid and non-destructive approach. It does not require accurate sample weights and purification of reference substances. However, when determining the relative response factors (RRFs) of multiple drug impurities, spectral overlap may be a problem. As naproxen and its impurities are similar in structure, it is difficult to determine the corresponding characteristic signal peaks of each component in the 1H NMR spectrum of the principal component and impurities. This study aimed to develop a qNMR-HPLC method using the δ 2.5 ppm signal of DMSO-d6 as an internal calibrant to determine the RRFs of six naproxen impurities (I–VI). Each component was analyzed by qNMR separately and the ratio relationship was linked by DMSO-d6 calibrant. The obtained RRFs (0.30, 0.76, 1.14, 1.00, 0.59, and 0.51, respectively) were consistent with those determined using the HPLC standard curve method (0.30, 0.78, 1.04, 1.05, 0.59, and 0.51, respectively). The method showed a linear R2 of 1 in the 1–12 mg·mL−1 range, the RSD precision of five replicates was 0.10%, and the RSD of solution stability within 24 h was 0.10%. The method is well suited for scenarios involving minimal sample quantities that cannot be accurately weighed and for the simultaneous determination of multiple impurity RRFs in cases where spectral overlap is a challenge.