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

• Published in: Physical chemistry chemical physics : PCCP Vol. 20; no. 21; pp. 14469 - 14481
• Main Authors: Surov, Artem O., Churakov, Andrei V., Proshin, Alexey N., Dai, Xia-Lin, Lu, Tongbu, Perlovich, German L.
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 2018
• Subjects: Acetonitrile; Acids; Cocrystallization; Dehydration; Gallic acid; Molecular chains; Stability; Stoichiometry; Thiadiazoles; Water chemistry
• ISSN: 1463-9076; 1463-9084; 1463-9084
• DOI: 10.1039/C8CP02532K

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.