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.