Cocrystals of a 1,2,4-thiadiazole-based potent neuroprotector with gallic acid: solubility, thermodynamic stability relationships and formation pathways?

Physical Chemistry Chemical Physics Pub Date: 2018-05-09 DOI: 10.1039/C8CP02532K

Abstract

Three distinct solid forms, namely anhydrous cocrystals with 2?:?1 and 1?:?1 drug/acid ratios ([TDZ?:?GA] (2?:?1), [TDZ?:?GA] (1?:?1)), and a hydrated one having 1?:?1?:?1 drug/acid/water stoichiometry ([TDZ?:?GA?:?H2O] (1?:?1?:?1)), have been formed by cocrystallization of the biologically active 1,2,4-thiadiazole derivative (TDZ) with gallic acid (GA). The thermodynamic stability relationships between the cocrystals were rationalized in terms of Gibbs energies of the formation reactions and further verified by performing a set of competitive and exchange mechanochemical reactions. Interestingly, competitive grinding in the presence of the structurally related vanillic acid led to the formation of a new polymorphic form of the [TDZ?:?Vanillic acid] (1?:?1) cocrystal, which was promoted by gallic acid. The mechanochemical method was also applied to elucidate the alternative pathways of the [TDZ?:?GA?:?H2O] (1?:?1?:?1) cocrystal formation. Direct cocrystallization of TDZ with GA monohydrate was found to proceed much faster than the reaction of TDZ and anhydrous GA in the presence of an acetonitrile/water mixture, which may indicate the presence of a transitional stage. According to dissolution studies, the [TDZ?:?GA?:?H2O] (1?:?1?:?1) cocrystal was ca. 6.6 times more soluble than the parent 1,2,4-thiadiazole at pH 2.0 and 25.0 °C. The apparent two-step dehydration behavior of the [TDZ?:?GA?:?H2O] (1?:?1?:?1) cocrystal monohydrate was clarified by analyzing the intermolecular interactions of water molecules with the crystalline environment derived from solid state DFT calculations.

Graphical abstract: Cocrystals of a 1,2,4-thiadiazole-based potent neuroprotector with gallic acid: solubility, thermodynamic stability relationships and formation pathways
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