Interpreting Lattice Water Incorporation in the Enhancement of Solubility and Membrane Permeability of Trimethoprim Molecular Salts

Solubility is a significant concern for most drugs administered orally, particularly BCS class II drugs. One such poorly soluble antibiotic drug, trimethoprim (TRM), is commonly used to treat urinary tract infections. The TRM and six isomeric dihydroxybenzoic acids are used in a 1:1 ratio, resulting in six molecular salts that demonstrate improved drug solubility and membrane permeability. The inclusion of water molecules in the crystal lattice of the TRM molecular salts uncontrollably influences the overall performance of the drug in various pH environments. All six molecular salts of TRM were isolated using liquid-assisted grinding followed by slow evaporation of solvents and characterized. The in vitro determination of solubility and membrane permeability under different physiological pH conditions reveals a direct correlation with crystal packing, water inclusion, and represented energies. Results are corroborated with the quantitative measure of lattice water supported by a CSD survey, supramolecular synthons, Hirshfeld surface analysis, molecular packing, conformational energies, and packing indices (%).