Taking Advantage of Polymorphism To Effect an Impurity Removal: Development of a Thermodynamic Crystal Form of (R,R)-Formoterol Tartrate

The development and large-scale implementation of a novel technology utilizing polymorphic interconversion and crystalline intermediate formation of ( R, R )-formoterol l -tartrate (( R, R )-FmTA, 1 ) as a tool for the removal of impurities from the final product and generation of the most thermodynamically stable crystal form is reported. The crude product was generated by precipitation of the free base as the l -tartrate salt in a unique polymorphic form, form B. Warming the resultant slurry effected the formation of a partially hydrated stable crystalline intermediate, form C, with a concomitant decrease in the impurity levels in the solid. Isolation and recrystallization of form C provided 1 in the thermodynamically most stable polymorph, form A.