Simple and rapid quantification of deuterium isotopologues in a deuterated drug substance deuremidevir using Fourier-transform infrared spectroscopy and partial least squares

Abstract

Deuterated drugs are increasingly becoming a prominent focus in drug design and development. The level of deuterium isotopologues (isotopic impurities) is the critical quality attribute of deuterated active pharmaceutical ingredients (APIs), especially for those synthesized by isotopic exchange approaches. However, existing analytical strategies rely on high-end instruments such as LC-MS and NMR, which are not routinely equipped in quality control (QC) laboratories. Herein, we developed a QC-friendly quantitative method for determining the deuterium isotopologue in deuremidevir hydrobromide (VV116), a deuterated drug substance synthesized by isotope exchange, using Fourier-transform infrared (FTIR) spectroscopy integrated with partial least squares (PLS) regression. A gradient series of solid mixtures with defined levels of the deuterium isotopologue was designed for FTIR acquisition, and the quantitative model was optimized through a combinatorial strategy that simultaneously screens various spectral preprocessing and wavenumber variables. Ultimately, a PLS model with max–min normalization preprocessing and wavenumber variables selected using backward interval PLS followed by competitive adaptive reweighted sampling offered optimal performance, and could be directly applied for the rapid and straightforward release testing of VV116 in QC laboratories. This work provides a simpler alternative to complex analytical techniques for deuterium isotopologues determination in a deuterated API.