Purification of Dirithromycin. Impurity Reduction and Polymorph Manipulation

The manufacture of dirithromycin [9S(R)-9-deoxo-11-deoxy-9,11-[imino[2-(2-methoxyethoxy)ethylidene]oxy]erythromycin] from commercially available erythromycin A results in a drug substance containing impurities at the level of several percent. A five-step plan for the development of a commercial-scale recrystallization procedure is presented. A purification system for dirithromycin which utilizes the crystalline acetone solvate and exemplifies this plan is described. Physical characterization data for this solvate are included. The solubility of the acetone solvate in water−acetone mixtures is at a maximum at a ratio of 1:9 v/v and exhibits a parabolic relationship with temperature such that, in a solvent composition of 2:1, its solubility is at a minimum at 40 °C. The adduct of erythromycylamine and acetone was found to exist in solution as an equilibrium between the tetrahydro-1,3-oxazine and imine forms.