Deuterated Drugs: Isotope Distribution and Impurity Profiles.

A recent review identified the problem of lower isotopologues in deuterated active pharmaceutical ingredients (APIs) as a critical issue in this area of medicinal chemistry. In this Perspective, the relationship between overall enrichment and isotope distribution for deuterated APIs is discussed. Deuterated APIs are divided into single deuterium, methyl-d3, and polydeuterated compounds. For the latter category, distribution calculations demonstrate that the parent deuterated API contains significant quantities of the lower isotopologues. As an alternative to the use of overall enrichment to describe these compounds, it is suggested that describing these compounds with a distribution profile should be preferred, giving an accurate and defensible description of the API. Using this approach, the lower isotopologues become an integral part of the API and not an impurity.