A New 1:1 Cocrystal of Lamotrigine and 1,2,3,6-4hydrophthalimide:Discovery,Characterization, and Construction of Ternary Phase Diagrams

ABSTRACT 1:1 cocrystal of lamotrigine (LAM) with 1,2,3,6-4 hydrophthalimide (HTHP) was first successfully synthesized and was characterized by XRD (power and single-crystal X-ray diffraction), FT-IR, DSC TG. Molecular Hirshfeld surfaces and the corresponding two-dimensional (2D) fingerprint plots have been evaluated and hirshfeld surface analysis indicated that hydrogen bonding N···H and O···H mainly constitutes the connection between cocrystal molecules.Ternary phase diagrams (TPDs) of LAM-HPHT in isobutanol was constructed at 293.15 K and 313.15K. The result indicated that pure cocrystal preparation or stability region became larger as temperature increasing without changing the TPDS shape. And meanwhile, the solubility of LAM-HPHT in isobutanol was measured, the solubility product (Ksp) and solution complexation constants (K11) were proposed to illustrate the solubility of LAM-HPHT. The result indicated that Ksp gradually increases while K11 decreases with the cocrystal solubility increasing. Dissolution results indicated LAM-HPHT was found to exhibit improved aqueous solubility when compared to pure LAM. Stability study demonstrated that LAM-HPHT were much more stable than original LAM crystal under the condition of 98% RH (25℃) or 85% RH (25℃).