Molecular Salts of Drug Famotidine with Isomeric Dihydroxybenzoic Acids

The space to find new stable solid-state formulations with value-added properties for the labile drug famotidine (FAM) exploiting its conformational flexibility and ionizable nature has been reconnoitered by isolating at least six molecular salts with isomeric dihydroxybenzoic acids (DHBA). These solid forms were synthesized via a mechanochemical grinding method followed by slow evaporation of solvents and characterized. They exhibit better physical stability under aqueous and various physiological pH conditions, which is attributed to the drug conformational change in the solid state. Such conformational modification eventually leads to strong hydrogen bonding synthons with the coformers. Except for the anhydrous molecular salt with 2,6-DHBA, all others display enhanced physiochemical properties viz. solubility, membrane permeation, drug flux, and essentially drug bioavailability. The improvement of drug properties is endorsed by the formation of stronger ionic guanidinium···carboxylate interactions between the active pharmaceutical ngredients (API) and the coformers as well as solute···solvent interactions. The difference in the isomeric position of OH groups and the lattice water molecule(s) guided the formation of different auxiliary hydrogen bonds, resulting in unique molecular packing with properties and emphasized.