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.