Salt and Ionic Cocrystalline Forms of Amides: Protonation of Carbamazepine in Aqueous Media.
journal contributionposted on 2015-12-02, 00:00 authored by Amanda R. Buist, David S. Edgeley, Elena A. Kabova, Alan R. Kennedy, Debbie Hooper, David G. Rollo, Kenneth Shankland, Mark J. Spillman
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.