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

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, the competitive grinding in the presence of structurally related vanillic acid led to 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 acetonitrile/water mixture, which may indicate the presence of a transitional stage. According to the 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 ºC. 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 the solid state DFT calculations.

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Publication details

The article was received on 20 Apr 2018, accepted on 09 May 2018 and first published on 09 May 2018


Article type: Paper
DOI: 10.1039/C8CP02532K
Citation: Phys. Chem. Chem. Phys., 2018, Accepted Manuscript
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    Cocrystals of 1,2,4-thiadiazole-based potent neuroprotector with gallic acid: solubility, thermodynamic stability relationships and formation pathways

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

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