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]center dot H2O. Reactions with other mineral acids (HI and HBF4) gave ionic cocrystalline (ICC) forms (CBZ center dot[acridinium] [I-3]center dot 2.5I(2) and CBZ center dot[H5O2](0.25) [BF4](0.25)H2O) as well as the salt form CBZ center dot CBZ(H)][BF4]center dot 0.5H2O. Reaction of CBZ with a series of sulfonic acids also gave salt forms, namely, [CBZ(H)][O3SC6H5], [CBZ(H)][O3SC6H4(OH)]center dot 0.5H(2)O [CBZ(H)](2)[O3SCH2CH2SO3], and [CBZ(H)] [O3SC6H3(OH) (COOH)]center dot 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.