Inclusion compounds containing a drug: structure and thermal stability of the first clathrates of nitrazepam and isothiocyanato ethanol complexes of Co(II) and Ni(II)

Abstract

Syntheses, crystal structures and comparative analytical investigations on the first two inclusion compounds of an antiepileptic drug, nitrazepam (1,3-dihydro-7-nitro-5-phenyl-2 H-1,4-benzodiazepin-2-one) are reported. The biologically active molecule forms isostructural clathrates with diaquadiethanolbis(isothiocyanato) complexes of both cobalt(II) and nickel(II) in molar ratios of 1:2 [M(NCS) 2(C 2H 5OH) 2(H 2O) 2]·2C 15H 11N 3O 3 (M=Co 2+, 1, and M=Ni 2+, 2). Detailed analyses of the structures, the secondary interactions, the neutral drug conformations, the FTIR spectra and thermal stabilities of the clathrates, in comparison with those of the crystalline nitrazepam, have been carried out. In the crystal structures there are only host–guest hydrogen bonds of O⋯H, N⋯H and S⋯H type. Owing to the comparable size of the two constituents neither host–host nor guest–guest secondary interactions occur. In the first thermal decomposition step a parallel release of ethanol and water was observed by simultaneous thermogravimetric and differential thermal analysis measurements. This indicates that some bonds of the metal complex unit and the host–guest secondary interactions in 1 and 2 are weaker than interactions in the pure drug. If an easy release of ethanol and water occurs during dissolution of 1 and 2, it might result in an improved bioavailability of the drug, which is soluble only in aqueous ethanol.