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Eur J Pharm Sci. 2017 Nov 15;109:31-39. doi: 10.1016/j.ejps.2017.07.025. Epub 2017 Jul 26.

Cocrystal formation, crystal structure, solubility and permeability studies for novel 1,2,4-thiadiazole derivative as a potent neuroprotector.

Author information

1
Institution of Russian Academy of Sciences, G.A. Krestov Institute of Solution Chemistry RAS, 153045 Ivanovo, Russia.
2
Institute of General and Inorganic Chemistry RAS, Leninsky Prosp. 31, 119991 Moscow, Russia.
3
Institute of Physiologically Active Compounds of Russian Academy of Sciences, 142432 Chernogolovka, Russia.
4
Institution of Russian Academy of Sciences, G.A. Krestov Institute of Solution Chemistry RAS, 153045 Ivanovo, Russia. Electronic address: glp@isc-ras.ru.

Abstract

The cocrystallization approach has been applied to modify the poor solubility profile of the biologically active 1,2,4-thiadiazole derivative (TDZ). Extensive cocrystal screening with a library of coformers resulted in formation of a new solid form of TDZ with vanillic acid in a 1:1 molar ratio. The cocrystalline phase was identified and characterized by thermal and diffraction analyses including single-crystal X-ray diffraction. The energies of intermolecular interactions in the crystal were calculated by solid-state DFT and PIXEL methods. Both calculation schemes show good consistency in terms of total energy of the intermolecular interactions and suggest that the cocrystal is mainly stabilized via hydrogen bonds, which provide ca. 44% of the lattice energy. Since the cocrystal contained the hydroxybenzoic acid derivative as a coformer, the solubility profile of the cocrystal was investigated at different pHs using eutectic concentrations of the components. Furthermore, the influence of the cocrystallization on the permeability performance of the 1,2,4-thiadiazole through an artificial regenerated cellulose membrane was also evaluated. In addition, the thermodynamic functions of the cocrystal formation were estimated from the solubility of the cocrystal and the corresponding solubility of the pure compounds at various temperatures. The cocrystal formation process was found to have a relatively small value of the driving force (-5.3kJ·mol-1). The most significant contribution to the Gibbs energy was provided by the exothermic enthalpy of formation.

KEYWORDS:

1,2,4-Thiadiazole; Cocrystal; Formation thermodynamics; Permeability; Solubility

PMID:
28756204
DOI:
10.1016/j.ejps.2017.07.025
[Indexed for MEDLINE]

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