Extending the Range of Nitrofurantoin Solid Forms: Effect of Molecular and Crystal Structure on Formation Thermodynamics and Physicochemical Properties

In this work, four novel pharmaceutical cocrystals of nitrofurantoin, an antibacterial drug, with isonicotinamide, picolinamide, 2-hydroxybenzamide, and 2-aminobenzamide have been obtained and thoroughly characterized by various analytical techniques. The crystal structures of the solid forms have been elucidated by single-crystal X-ray diffraction, and the energy distribution of intermolecular interactions has been further quantified on the basis of QTAIMC analysis. Eight distinct supramolecular heterosynthons of hydrogen bonding have been identified in the studied crystals, and their relative stability has been ranked in terms of total interaction energies. The thermodynamics of the cocrystallization reactions has been systematically investigated using two independent experimental techniques, namely solution calorimetry and phase solubility diagram, which allowed us to assess both the enthalpic and the entropic contributions to the cocrystal formation driving force. The pH-solubility behavior of the cocrystals has been investigated at different pH values using eutectic concentrations of the components. Although all of the cocrystals reported here were found to be more soluble than the parent drug, their advantage in thermodynamic solubility did not translate into enhanced dissolution performance due to a rapid solution-mediated phase transformation in aqueous media. In addition, the effect of cocrystallization on other pharmaceutically relevant properties of nitrofurantoin, including photostability and membrane permeability, has been considered and analyzed.