Two novel drug-nutraceutical cocrystal hydrates based on the antiepileptic carbamazepine (CBZ) with isomeric trihydroxybenzoic acids, including 3,4,5-trihydroxybenzoic acid (345THBA) and 2,3,4-trihydroxybenzoic acid (234THBA), are reported. A comparative analysis of the [CBZ + 345THBA + H2O] (4:1:2) and [CBZ + 234THBA + H2O] (1:0.25:0.5) crystal structures, determined by single crystal X-ray diffraction, revealed that both solids belong to a channel-type cocrystals and exhibit the same 3D stacking of the CBZ homodimers. In spite of the isostructural nature of the novel cocrystal hydrates, significant discrepancies were observed in their physicochemical and pharmacokinetics properties. The dehydration process, occurring in one- or two-steps, resulted in the conversion of the multicomponent crystals. The cocrystal hydrates demonstrated pH-dependent solubility, whereby only [CBZ + 234THBA + H2O] (1:0.25:0.5) exhibited enhanced solubility in comparison with the parent drug at all pH values studied. Despite the different thermodynamic solubility and stability in solution, both cocrystal hydrates demonstrated an insignificant influence on the dissolution and diffusion behavior of the drug. However, it was determined that the cocrystallization of CBZ with 345THBA enhances its pharmacokinetic parameters, thereby rendering this cocrystal hydrate a viable alternative to the existing commercial dosage form.
