Application of Quantitative NMR (qHNMR) towards Establishment of Pharmaceutical Reference Standard; A Case of a Ticagrelor Process Impurity

Quantitative proton NMR (qHNMR) methodology was employed for the stoichiometric (free base and the corresponding counterion) assessment of a ticagrelor process impurity, also referred to in the United States Pharmacopeia (USP), Pharmacopeial Forum as Ticagrelor Related Compound A (RC A), [(1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine (R)-mandelate], also called as Tica amine mandelate, a critical impurity that, when present during manufacturing, has a limit of not more than 0.0008%. The Tica amine is also a listed impurity E in the Ticagrelor monograph, in European Pharmacopeia. Because there was no existing NMR spectroscopic method in the literature specific to quantify the counterion (mandelic acid) in Ticagrelor RC A, this study aimed to fill the gap. Accurate stoichiometric measurement of this impurity serves to enhance product quality in the manufacturing of the ticagrelor active pharmaceutical ingredient (API). Using ethylene carbonate as an internal standard (IS), the qHNMR analysis on Ticagrelor impurity, revealed many key characteristics of the test mixture composition, including (free base and counterion). The results demonstrate that qHNMR has great potential for addressing several key quality attributes associated with chemical analyses such as detection, identification, quantification, and purity determination, as well as deriving molecular stoichiometry, all from the single proton spectrum.