Crystal engineering of the cystic fibrosis drug ivacaftor: salts, solvates and hydrate forms with solubility and stability studies

Abstract

Ivacaftor (IVA) is a selective small-molecule potentiator used to treat cystic fibrosis in patients with certain genetic mutations. It is a BCS class II drug having poor aqueous solubility. The European Commission has granted orphan status to IVA. It is considered to be highly polymorphic based on literature, and several solvates have been reported in patents. To address the solubility and identify the most stable solid forms of IVA, crystal engineering strategies were employed in the present work to prepare new multicomponent solid forms, including cocrystals, salts, and solvates/hydrates. Eight new multicomponent solid forms of IVA were reported, along with the crystal structure of the polymorphic form of IVA (form-B). The eight new forms comprise one dihydrate form (IVA–2H₂O), two salt forms with hydrochloride and hydrobromide (IVA–HCl–EA and IVA–HBr–ACA), and five solvates with geraniol (GER), acetic acid (ACA, in two different stoichiometries), ethanolamine (ETA), and ethylene glycol (EGL). The solvates of monoacetic acid (IVA–ACA) and diacetic acid (IVA–DACA) were produced concomitantly during the crystallization experiments. IVA–GER crystallized as a monohydrate, whereas IVA–ETA and IVA–EGL crystallized in anhydrous forms. The prepared multicomponent solids displayed different conformations compared with the neutral IVA form-B; in particular, the protonated form exhibited twist conformations at the amide group. Four of the multicomponent solids were reproduced on the bulk scale and further characterized by thermal and spectroscopic analyses. Further, the solubility of the prepared multicomponent solids was evaluated in pH 1.2 and 6.8 buffers. All the prepared multicomponent solids showed enhanced solubility profiles in the buffer solutions. Notably, IVA–DACA exhibited a 2.5-fold increased solubility in the pH 1.2 buffer, while a 37-fold increase in solubility was observed for IVA–ETA in the pH 6.8 buffer. The IVA–GER solid form exhibited solid-state stability in both the pH media, while the remaining multicomponent solids were found to be unstable and converted to either their hydrate or solvate forms. The present study paves the way for modulating the solubility profile and solid-state stability of IVA via the crystal engineering strategy.