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

Abstract

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.

Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers

“…Second, three MEK inhibitors: trametinib, cobimetinib, and binimetinib have been approved in combination with B-RAF inhibitors. Third, the inhibitors of the final downstream kinase, ERK, are currently in clinical development, including LY3214496 (NCT02857270) [35], BVD-523 (NCT03417739) [36], MK-8353 (NCT01358331) [37], and KO-947 (NCT03051035) (Figure 5) [1,38].…”

“…Third, the inhibitors of the final downstream kinase, ERK, are currently in clinical development, including LY3214496 (NCT02857270), [35] BVD-523 (NCT03417739), [36] MK-8353 (NCT01358331), [37] and KO-947 (NCT03051035) (Figure 5). [1] , [38]…”

Application of Twin Screw Extrusion to Scale Polymorphs, a Salt, and the Amorphous Phase for Various Drug Substances

“…Our previous work successfully demonstrated that twin screw extrusion (TSE) could be used to scale up polymorphs of active pharmaceutical ingredients (APIs) . Polymorphism occurs when two or more crystals have the same chemical composition but different internal structures (molecular packing), while polymorph screening and the formation of crystalline salts/cocrystals are approaches used for optimization of physical properties such as melting point, hygroscopicity, chemical stability, and dissolution rate. − Because of this, it is vital to develop robust crystallization processes for the isolation of the thermodynamically most stable form at room temperature. − Therefore, one of the goals of this work was to see if TSE could again be utilized to apply mechanochemistry to generate gram-scale quantities of polymorphs of 1 to support phase mapping and crystallization to ensure form control. TSE has also become a popular way for generating pharmaceutical cocrystals and salts; − thus, another goal was to determine if the hemihydrate of 2 could be isolated via liquid-assisted extrusion in an aqueous free environment via green chemistry.…”