Thermodynamic and Crystallization of Lamotrigine Cocrystal

Two novel lamotrigine cocrystals, namely, lamotrigine (LAM) phthalimide (PTL) cocrystal (1) and lamotrigine (LAM) succinimide (SUC) cocrystal monohydrate (1:1:1) (2), were successfully synthesized by liquid-assisted grinding and evaporative crystallization, and their structures were determined by XRD (power and single-crystal X-ray diffraction) and FT-IR. Ternary phase diagrams of LAM–PTL were constructed for the obtained cocrystal in isobutanol and ethyl propionate at two different temperatures, i.e., 298.15and 303.15 K. A narrow stability region was found for the pure LAM–PTL cocrystal in the phase diagram at both temperatures. The solubility of LAM–PTL was measured by suspending cocrystal in solutions of varying PTL concentrations in ethyl propionate and isobutanol. The mathematical model described by the solubility product of cocrystal components K_sp and by solution complexation constants K₁₁ was used to fit the solubility of LAM–PTL cocrystal. It can be concluded that K_sp values increase as the cocrystal solubility increases, while K₁₁ values decrease. Graphical representation of the cocrystal solubility dependence on ligand concentration will serve as a diagnostic tool for the stoichiometry of solution complexes. The results of the stability study demonstrated that 1 and 2 are stable under the conditions of both 85% and 98% RH at 25 °C.