Simultaneously enhancing the in vitro/in vivo performances of acetazolamide using proline as a zwitterionic coformer for cocrystallization

With the objective to improve the physicochemical properties and optimize pharmacokinetic performances of acetazolamide (ACA), a new zwitterionic cocrystal of ACA with proline (PRO), namely, ACA-PRO, was synthesized and characterized. The single-crystal X-ray diffraction analysis revealed that the cocrystal has a component ratio of 1:1 and is dominated by a three dimensional hydrogen bonding supramolecular structure. The water solubility and permeability of ACA in the cocrystal were simultaneously enhanced compared with pure ACA in physiological pH environments. The in vivo pharmacokinetic evaluation indicated that the relative bioavailability of ACA from the cocrystal was enhanced by 2.68-fold. The present investigation not only provides an alternative approach for optimizing physicochemical and pharmacokinetic properties of BCS class-IV drugs without changing the molecular structures and intrinsic bioactivities, but also enriches the current understanding of the structures of zwitterionic cocrystals and their behaviors in vitro and in vivo.