Dosable solvates of ivacaftor with high boiling point liquids

Abstract

Ivacaftor (also known as VX-770) is a small molecule currently in development for treatment of cystic fibrosis. In the present work, we describe an effort to create novel solvates, formed with 2-methylbutyric acid and isobutyric acid respectively, in pursuit of a more robust and reliable scale-up process. The solvates were characterized by X-ray crystallography, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and dynamic vapor sorption. The vapor sorption analysis showed the isobutyric acid solvate to be less stable than the 2-methylbutyric acid solvate, which became the focus of subsequent investigations. The 2-methylbutyric acid solvate was administered to rats and dogs in a series of pharmacokinetic studies, and showed excellent in vivo bioavailability. Thus, using liquid-state co-formers led to a solid form that is bioavailable, as well as stable and processable, suggesting that using such liquid-state co-formers could potentially benefit pharmaceutical development more broadly.