Salt and ionic cocrystalline forms of amides : protonation of carbamazepine in aqueous media

The products of reactions of the pharmaceutical amide carbamazepine (CBZ) with strong acids under aqueous conditions were investigated by both powder and single crystal X-ray diffraction. Despite previous claims to the contrary, it was found that salt forms with CBZ protonated at the amide O atom could be isolated from reactions with both HCl and HBr. These forms include the newly identified hydrate phase [CBZ(H)][Cl].H2O. Reactions with other mineral acids (HI and HBF4) gave ionic cocrystalline (ICC) forms (CBZ.[acridinium][I3].2.5I2 and CBZ.[H5O2]0.25[BF4]0.25.H2O) as well as the salt form CBZ.[CBZ(H)][BF4].0.5H2O. Reaction of CBZ with a series of sulfonic acids also gave salt forms, namely [CBZ(H)][O3SC6H5], [CBZ(H)][O3SC6H4(OH)].0.5H2O, [CBZ(H)]2[O3SCH2CH2SO3] and [CBZ(H)][O3SC6H3(OH)(COOH)].H2O. CBZ and protonated CBZ(H) moieties can be differentiated in the solid state both by changes to molecular geometry and by differing packing preferences