From Solution to Sublimation: Thermodynamic Evaluation of Iproniazid Multicomponent Crystals for Robust...

To comprehensively characterize the solution and sublimation thermodynamics of 1:1 multicomponent crystals of the antidepressant drug iproniazid (IPN) with six positional isomers of dihydroxybenzoic acid (DHBA) in acetonitrile, and to establish structure-thermodynamic relationships guiding coformer selection in pharmaceutical development.

Temperature-dependent solubilities were measured over 293.15-313.15 K using the shake-flask method. Activity coefficients were derived via the Schrӧder-van Laar equations. Standard formation thermodynamic parameters were calculated from solubility data. Sublimation parameters were indirectly evaluated using a thermodynamic cycle linking dissolution, solvation, and sublimation.

Activity coefficients showed positive deviations from ideality for most compounds, while 25DHBA and 35DHBA exhibited negative deviations, indicating favorable solute-solvent interactions. All stable systems formed spontaneously through an enthalpy-driven mechanism. Sublimation enthalpies were highly endothermic (233.2-266.5 kJ·mol^-1) and correlated with the calculated total lattice energies, providing a quantitative measure of crystal lattice strength relevant to pharmaceutical processing and storage.

Positional isomerism of the DHBA coformer governs the thermodynamic stability of IPN multicomponent crystals through a balance of intra- and intermolecular interactions. The integrated thermodynamic cycle approach offers an experimentally accessible framework for evaluating sublimation parameters, providing practical guidance for coformer selection, solid form screening, and predicting physical stability in pharmaceutical development.