Hydrogen bonding features of amide functionalities in four novel salts of an antiemetic drug domperidone

Abstract

Domperidone, 5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo-[d] imidazol-1-yl)propyl]-piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one, C22H24ClN5O2, is an antiemetic drug, used to relieve the patients from nausea and vomiting sickness. In the present study, four novel domperidone salts viz., domperidone chloride hydrate methanol solvate, (I), bis(domperidone nitrate nitric acid) hydrate, (II), domperidone nitrate 1.046 hydrate (III) and domperidone methylsulfate hemihydrate, (IV) are reported. Structure (I) crystallized in the monoclinic space group P21/n, while, structures of (II) - (IV) crystallized in the triclinic space group P1¯. In all four structures the N atom of piperidine ring is protonated and further confirmed by IR and 1H NMR analyses. In (I), (II) and molecule B of (III), the orientation of chlorine-substituted oxobenzimidazolyl and non-substituted oxobenzimidazolyl rings are in anti-clinal conformations, while molecule A of (III) and (IV), are in syn-clinal conformations. The protonated piperidine ring adopts a chair conformation in all four structures. In (I), inversion-related domperidone molecules are involved in forming a R22(28) dimer, while in (II), symmetry independent domperidone molecules A and B are involved in constructing the R22(28) dimer. In (III) and (IV), two sets of amide R22(8) dimer are observed. In all four structures, the anions and solvent molecules play a crucial role in aggregating the domperidone dimers into three-dimensional hydrogen bonded networks. It is interesting to note that the characteristic feature of domperidone, amide R22(8) dimer is observed in (III) and (IV), while, in (I) and (II), a very different and unique R22(28) dimer is observed between the domperidone molecules. The formation of this R22(28) dimer appears to be influenced by the conformations of the chlorine-substituted oxobenzimidazolyl and non-substituted oxobenzimidazolyl groups.