Synthesis, pharmacology, crystal properties, and quantitative solvation studies from a drug transport perspective for three new 1,2,4‐thiadiazoles

A novel 1,2,4‐thiadiazoles were synthesized. Crystal structures of these compounds were solved by X‐ray diffraction experiments and comparative analysis of molecular conformational states, packing architecture, and hydrogen bonds networks were carried out. Thermodynamic aspects of sublimation processes of studied compounds were determined using temperature dependencies of vapor pressure. Thermophysical characteristics of the molecular crystals were obtained and compared with the sublimation and structural parameters. Solubility and solvation processes of 1,2,4‐thiadiazoles in buffer, n‐hexane and n‐octanol were studied within the wide range of temperature intervals and thermodynamic functions were calculated. Specific and nonspecific interactions of molecules resolved in crystals and solvents were estimated and compared. Distribution processes of compounds in buffer/n‐octanol and buffer/n‐hexane systems (describing different types of membranes) were investigated. Analysis of transfer processes of studied molecules from the buffer to n‐octanol/n‐hexane phases was carried out by the diagram method with evaluation of the enthalpic and entropic terms. This approach allows us to design drug molecules with optimal passive transport properties. Calcium‐blocking properties of the substances were evaluated. © 2010 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3754–3768, 2010