Identification and Synthesis of Oxidative-Degradation and Starting Materials-Attributed Impurities in Lisdexamfetamine Dimesylate

Impurities are an integral part of drug substances, even though they have not been studied in the pharmacological evaluation of the Benefit-Risk (BR) profiles. Hence, understanding their origin and controlling them have prime importance during drug substance development. The structures of some of the impurities in lisdexamfetamine dimesylate, a central nervous system stimulant drug, have been confirmed based on literature and analytical data. The study has been undertaken to evaluate impurities arising from oxidative degradation and impurities due to material attributes. All the listed impurities have been identified, synthesized, and characterized by spectral tools. We have, herein, reported the synthesis of two oxidative degradant impurities, 2-hydroxylisdexamfetamine dimesylate and 4-hydroxylisdexafetamine dimesylate. In addition, chiral isomeric impurities of lisdexamfetamine dimesylate as (S,R), (R,S) and (R,R)-lisdexamfetamine dimesylate have also been reported. These impurities have been identified, synthesized and a control strategy for mitigating risk in lisdexamfetamine dimesylate is provided.