Poor water solubility of drugs fuels complex formulations and jeopardizes patient access to medication. Simplifying these complexities we systematically synthesized a library of 36 sterically demanding counterions and mapped the pharmaceutical design space for amorphous ionic liquid strategies for Selurampanel, a poorly water soluble drug used against migraine. Patients would benefit from a rapid uptake after oral administration to alleviate migraines symptoms. Therefore we probed the ionic liquids for the flux, supersaturation period and hygroscopicity leading to algorithms linking molecular counterion descriptors to predicted pharmaceutical outcome. By that, 30- or 800-fold improvements of the supersaturation period and fluxes were achieved as were immediate to sustained release profiles through structural counterions' optimization compared to the crystalline free acid of Selurampanel. Guided by ionic liquid structure, in vivo profiles ranged from rapid bioavailability and high maximal plasma concentrations to sustained patterns. In conclusion, the study outlined and predicted the accessible pharmaceutical design space of amorphous ionic liquid based and excipient-free formulations pointing to the enormous pharmaceutical potential of ionic liquid designs.
In conclusion, the ionic liquid strategy advances the suite of formulation strategies of poor water soluble drugs by an excipient free alternative. Controlling the fluxes within a broad design space comes in reach without using complex pharmaceutical formulations or the need of changing the drug structure. In vivo proof of concept detailed the control of key pharmacokinetic parameters, spanning from rapid bioavailability to sustained profiles rigorously deploying the design space introduced by and easily accessible through amorphous ionic liquid strategies. Further studies are needed, to proof the safety profiles of these new counterions and expanding this approach to other weakly acidic drugs.