A General Strategy to Rapid and Sensitive Determination of Five High Boiling Point Solvents in Pharmaceuticals by RP-HPLC Combined with Precipitation Method.

This article focuses on the development and validation of a fast, sensitive high-performance liquid chromatography (HPLC) method combined with a matrix precipitation sample preparation technique for the simultaneous determination of five high boiling point solvents (HBPS)—N-methylpyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and N,N-dimethylformamide (DMF)—in pharmaceutical active pharmaceutical ingredients (APIs). The method addresses challenges associated with traditional headspace gas chromatography (HSGC), such as low vapor pressure of HBPS and residual solvent interference, by minimizing matrix effects and improving sensitivity within a 14.5-minute analysis time. Validated according to ICH Q2 (R1) guidelines, the method demonstrated excellent linearity, precision, accuracy, and lower limits of detection compared to existing techniques, and was successfully applied to three representative APIs: apalutamide, baloxavir marboxil, and baricitinib. This strategy offers a practical alternative for quality control of HBPS in pharmaceutical development, overcoming limitations of prior GC and HPLC methods.