The Impurity That Was Not: A Persistent Efinaconazole Signal Revealed as an Isotopologue

Abstract Identification of process-related impurities is a routine task in the optimization and manufacturing of APIs. The identification of these contaminants enables researchers to develop appropriate strategies to purge them or prevent their formation. In many cases, impurity identification is straightforward, relying on an understanding of the synthetic process and the reactivity of the reagents, which allows researchers to hypothesize the formation of specific byproducts that are often indeed generated during synthesis. In other instances, however, certain impurities are extremely difficult to characterize, and their identification becomes a challenging and demanding task, particularly when present at very low levels. This article describes the time- and resource-intensive effort required to identify and characterize a nonpurging impurity in efinaconazole that elutes in close proximity to the API peak and is consistently detected at 0.06% (a/a), posing a potential Out of Specification risk during industrial production. The impurity was ultimately identified as an isotopologue of efinaconazole exhibiting subtly distinct physicochemical properties, an uncommon behavior for isotopologue species.