Investigation of various impurities in febuxostat

Febuxostat is a novel, non-purine, selective inhibitor of xanthine oxidase for hyperuricemia in patients with gout. The drug reduces uric acid production by inhibiting the activity of xanthine oxidase, an enzyme that, in the last step of purine metabolism, converts xanthine to uric acid. Research has shown febuxostat to be well tolerated in long-term treatment in patients with hyperuricemia. While various febuxostat synthesis routes starting from 4-hydroxybenzonitrile have been reported, far less information on isomeric, carryover, and byproduct impurities is available. The impurity profile of a drug substance is of increasing importance for ensuring the quality of drug products. However, it is extremely challenging for an organic chemist to identify impurities that form in small quantities and particularly burdensome if the product is non-pharmacopoeial. This article describes the identification and synthesis of various impurities that form during the production of febuxostat and its intermediates as well as strategies for minimizing the formation of all isomeric, carryover, and by-product impurities of febuxostat and its intermediates.