Effects of the crystal structure and thermodynamic stability on solubility of bioactive compounds: DFT study of isoniazid cocrystals

摘要

Intrinsic solubility of the isoniazid-carboxylic acid cocrystals is explored using thermodynamic cycle of transferring from crystal to gas and then to solution. The enthalpy/Gibbs free energy of phase transitions is computed by solid-state DFT (crystal) and DFT methods with/without accounting for polar solvent (aqueous solution/gas). The dissolution process of the isoniazid-dicarboxylic acid 2:1 cocrystals is found to be enthalpy-determined. The linear correlation between the theoretical sublimation enthalpies and experimental Gibbs energy of solution is established. According to it, the increase of stability causes the decrease of the considered cocrystals solubility. We conclude that a soluble and relatively stable cocrystal of isoniazid should be characterized by the sublimation enthalpy varying from 185 to 200 kJ.mol(-1). Bader analysis of theoretical periodic electron density enables us to quantify the non covalent interactions and clarify their role in formation of the isoniazid cocrystals. The sublimation enthalpy of the cocrystals is defined by the structure of the coformer molecule. Its value is less 150 kJ.mol(-1) in the case of aromatic acids and larger than 180 kJ.mol(-1) for the aliphatic dicarboxylic acids. The sublimation enthalpy increases with the increase of the dicarboxylic acid hydrocarbon chain. (C) 2016 Elsevier B.V. All rights reserved.