A new 1:1 cocrystal of lamotrigine and 1,2,3,6-hydrophthalimide: discovery, characterization, and construction of ternary phase diagrams

摘要

A 1:1 cocrystal of lamotrigine (LAM) and 1,2,3,6-hydrophthalimide (HPHT) was successfully synthesized for the first time and was characterized by XRD (powder and single-crystal X-ray diffraction), FT-IR, DSC and TG. Molecular Hirshfeld surfaces and the corresponding two-dimensional (2D) fingerprint plots have been evaluated and Hirshfeld surface analysis indicated that hydrogen bonds (N center dot center dot center dot H and O center dot center dot center dot H) mainly constitute the connection between the cocrystal molecules. The ternary phase diagrams (TPDs) of LAM-HPHT in isobutanol were constructed at 293.15 K and 313.15 K. The results indicated that as the temperature increases, the pure LAM-HPHT cocrystal preparation region became larger without changing TPD shape. Meanwhile, the solubility of LAM-HPHT in isobutanol was measured, and the solubility product (K-sp) and solution complexation (K-11) constants were proposed to illustrate the solubility of LAM-HPHT. The result indicated that K-sp gradually increases while K-11 decreases with the cocrystal solubility increasing. The dissolution results indicated that LAM-HPHT was found to exhibit improved aqueous solubility when compared to pure LAM. The stability study demonstrated that LAM-HPHT was much more stable than the original LAM crystal under the condition of 98% RH (25 degrees C) or 85% RH (25 degrees C).