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Issue 21, 2018
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Cocrystals of a 1,2,4-thiadiazole-based potent neuroprotector with gallic acid: solubility, thermodynamic stability relationships and formation pathways

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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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Article information


Submitted
20 Apr. 2018
Accepted
09 Maijs 2018
First published
09 Maijs 2018

Phys. Chem. Chem. Phys., 2018,20, 14469-14481
Article type
Paper

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

A. O. Surov, A. V. Churakov, A. N. Proshin, X. Dai, T. Lu and G. L. Perlovich, Phys. Chem. Chem. Phys., 2018, 20, 14469
DOI: 10.1039/C8CP02532K

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