The comparative study of cocrystal/salt in simultaneously improving solubility and permeability of acetazolamide

Abstract With the purpose of improving solubility and permeability of acetazolamide (ACZ), two new solid forms including one salt with piperazine (PPZ), and one cocrystal with theophylline (THP), namely, ACZ-PPZ-H 2 O ( 1 ) and ACZ-THP ( 2 ), were synthesized and structurally characterized. The single-crystal X-ray diffraction analysis revealed that the three-dimensional structure of both 1 and 2 are maintained by abundant hydrogen bonding interaction. In molecular salt 1 , PPZ 2+ cations locate in and link to the cavities formed by ACZ − anions and solvent water molecules, while in cocrystal 2 , the hydrogen bonding chains assembled by ACZ molecules weave the hydrogen bonding layer of THP molecules to a three-dimensional supramolecular structure. The powder dissolution and in vitro permeation experiments indicated that both solubility and permeability of ACZ were simultaneously improved after the formation of cocrystal and salt. Comparatively, the cocrystallization could remarkably enhance the permeability of ACZ, while the salt formation is more advantageous in increasing its solubility. The present study provides a new strategy of screening and prediction for simultaneously enhancing solubility and permeability of ACZ, which will be beneficial for the development of drugs with low solubility and poor permeability.