Solid Form Selection and Process Development of KO-947 Drug Substances

KO-947 is a potent, selective extracellular signal-regulated kinases (ERK) inhibitor that was investigated in the clinic for the treatment of various solid tumors. KO-947 free base, form E, was originally recommended out of 10 identified crystalline forms for the development of an oral solid dosage product. Change of clinical need shifted the focus to aqueous solubility enhancement through salt formation. Mesylate salt demonstrated remarkably increased aqueous solubility and also profound polymorphism. Anhydrous form III was initially recommended but later dropped, primarily due to the manufacturing difficulties. In the end, form IX was discovered through close collaboration between preformulation and process scientists. An elaborate manufacturing process was then devised to successfully produce mesylate salt, form IX in kilogram scale supplied for the clinical use.