Identification and comparison of impurities in fluoxetine hydrochloride synthesized by seven different routes

Fluoxetine HCl was prepared by seven different synthetic routes, all previo usly reported. The major impurities in each route were identified by GC/MS, HPLC/MS, and gradient HPLC analysis. Impurities were classified as being d erived from impurities in 4-chlorobenzotrifluoride, those arising during th e SNAr reaction of this compound and 3-methylamino-1-phenylpropanol, and th ose arising during the synthesis of this alcohol. Fifteen impurities belong ing to the latter two categories were identified, and their structures were confirmed by synthesis of authentic material for most of the compounds. It was found that a variety of analytical tools was needed for complete chara cterization of the impurity profile of fluoxetine HCl and that purification of the intermediate and recrystallization of the drug itself are highly ef fective in minimizing the levels of the impurities.