Isomeric Coformer Responsive Conformational Adjustment to Recuperate Stability, Solubility, and In Vitro Permeation Behavior of Drug Molecular Salts

The N–H or O–H systems are highly electron-deprived, and hence they easily interact with lone pairs usually on other N or O atoms in an extra bonding interaction. Such steering interactions stimulate the drug conformation to reposition that mounts well with all interactions and the packing in the lattice. Conformationally flexible histamine H 2 -receptor inhibitor drug famotidine (FAM) that shows low bioavailability and rapid degradation in an acidic environment was picked from the shelves. Six molecular salts of FAM with coformers of isomeric aminobenzoic acids (ABAs) and isomeric hydroxybenzoic acids (HBAs) from the GRAS list were synthesized via mechanochemical grinding. The obtained multicomponent solids show enhanced phase stability when compared to the parent drug in different pH media. The FAM molecular salts with ortho -HBA, ortho -ABA, and para -ABA show comparable solubility at pH 1.2, whereas the rest exhibited superior solubility and membrane permeation behavior in simulated physiological pH environments. This improvement of the drug properties is attributed to (i) the formation of directional hydrogen bond heterosynthons between the drug and coformers and the (ii) solute···solvent interactions. The change in the functional group(s), i.e., OH to −NH 2, and the isomeric position variation aided in altering drug conformation leading to unique crystal packing in the solid states and corroborating with improved properties.