Preparation of Deuterium-Labeled Armodafinil by Hydrogen–Deuterium Exchange and Its Application in Quantitative Analysis by LC-MS

Armodafinil, the R enantiomer of modafinil, was approved in 2007 by the US Food and
Drug Administration as a wake-promoting agent for excessive sleepiness treatment. Due to its
abuse by students and athletes, there is a need of its quantification. Quantitative analysis by liquid
chromatography-mass spectrometry, however, though very common and sensitive, frequently cannot
be performed without isotopically labeled standards which usually have to be specially synthesized.
Here we reported our investigation on the preparation of deuterated standard of armodafinil based
on the simple and inexpensive hydrogen–deuterium exchange reaction at the carbon centers. The
obtained results clearly indicate the possibility of introduction of three deuterons into the armodafinil
molecule. The introduced deuterons do not undergo back exchange under neutral and acidic
conditions. Moreover, the deuterated and non-deuterated armodafinil isotopologues revealed coelution
during the chromatographic analysis. The ability to control the degree of deuteration using
different reaction conditions was determined. The proposed method of deuterated armodafinil
standard preparation is rapid, cost-efficient and may be successfully used in its quantitative analysis
by LC-MS.