Investigation of Alcaftadine using a Double Oxidation Process by Eliminating Column Chromatography

Abstract

Alcaftadine is an active pharmaceutical ingredient (API) used as an ophthalmic solution for the prevention of itching associated with allergic conjunctivitis. The originally reported synthesis uses a time-consuming column chromatography technique for the isolation of hydroxymethylated product alcohol (10). A simple yet effective double oxidation strategy is developed using oxidation grade manganese dioxide to avoid tedious chromatographic purification. Firstly, a partial oxidation of hydroxymethylated crude mass (mixture of compounds 9, 10 and 16) was carried out using a limited amount of MnO2 to get rid of critical diol impurity (16) and to allow crystallization of alcohol (10) crude, followed by its second oxidation using additional MnO2 to provide alcaftadine via a scale-up friendly process. This synthetic approach has been proven to be cost effective and commercially viable. Various impurities formed during the process were also identified and eliminated to obtain ICH guideline purity of alcaftadine API. The process was validated in plant scale and US DMF was filed to manufacture alcaftadine API.