Salt Forms of Amides: Protonation and Polymorphism of Carbamazepine and Cytenamide

In
situ generation of HCl or HBr in alcohol leads to O-protonation
of the amide group of carbamazepine. Six salt phases have been produced
using this method and their crystal structures determined by single
crystal diffraction. A new polymorph of carbamazepine hydrochloride
is described as are two polymorphs of carbamazepine hydrobromide.
All are protonated at the amide O atom to give RC­(OH)­NH2 cations. Prolonged exposure to air results in addition of water
to the solid salt forms. Such hydration of carbamazepine hydrobromide
simply gives a monohydrated phase, but similar treatment of the equivalent
hydrochloride results in partial loss of HCl and the transfer of the
remaining proton from the amide group to water to give [carbamazepine]­[H3O]0.5[Cl]0.5·H2O. A
similar hydronium chloride species is the only product isolated after
reaction of the carbamazepine analogue cytenamide with HCl generated
in methanol.