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)

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-2H-1,4-benzodiazepin-2-one) are reported. The bio logically active molecule forms isostructural clathrates with diaquadiethan olbis(isothiocyanato) complexes of both cobalt(II) and nickel(II) in molar ratios of 1:2 [M(NCS)(2)(C2H5OH)(2)(H2O)(2)]. 2C(15)H(11)N(3)O(3) (M = Co2, 1, and M = Ni2+, 2). Detailed analyses of the structures, the secondary i nteractions, the neutral drug conformations, the FTIR spectra and thermal s tabilities of the clathrates, in comparison with those of the crystalline n itrazepam, 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-gu est secondary interactions occur. In the first thermal decomposition step a parallel release of ethanol and water was observed by simultaneous thermog ravimetric and differential thermal analysis measurements. This indicates t hat some bonds of the metal complex unit and the host-guest secondary inter actions in 1 and 2 are weaker than interactions in the pure drug. If an eas y release of ethanol and water occurs during dissolution of 1 and 2, it mig ht result in an improved bioavailability of the drug, which is soluble only in aqueous ethanol. (C) 2001 Elsevier Science B.V. All rights reserved.