Crystal Structures and Physicochemical Properties of Four New Lamotrigine Multicomponent Forms

In the present study, four new multicomponent forms of
lamotrigine
(LTG) with selected carboxylic acids, viz. acetic acid, propionic
acid, sorbic acid, and glutaric acid, have been identified. Preliminary
solid-state characterization was done by differential scanning calorimetry/thermogravimetric,
infrared, and powder X-ray diffraction techniques. X-ray single-crystal
structure analysis confirmed the proton transfer, stoichiometry, and
the molecular composition, revealing all of these to be a new salt/salt-cocrystal/salt
monosolvate monohydrate of LTG. All four compounds exhibited both
the aminopyridine dimer of LTG (motif 4) and cation–anion dimers
between protonated LTG and the carboxylate anion in their crystal
structures. Further, these new crystal forms were subjected to solubility
studies in water, powder dissolution studies in 0.1 N HCl, and stability
studies under humid conditions in comparison with pure LTG base. The
solubility of these compounds in water is significantly enhanced compared
with that of pure base, which is attributed to the type of packing
motifs present in their crystal structures as well as to the lowering
of the pH by the acidic coformers. Solid residues of all forms remaining
after solubility and dissolution experiments were also assessed for
any transformation in water and acidic medium.

本研究中，研究人员成功鉴定出四种与选定羧酸（即乙酸、丙酸、山梨酸及戊二酸）形成的拉莫三嗪（lamotrigine, LTG）新型多组分晶型。初步固态表征采用差示扫描量热法/热重分析法、红外光谱法以及粉末X射线衍射技术完成。X射线单晶结构分析证实了质子转移过程、化学计量比与分子组成，结果表明上述四种晶型均为拉莫三嗪的新型盐/盐-共晶/单溶剂化物单水合物。四种化合物的晶体结构中，均同时存在拉莫三嗪的氨基吡啶二聚体（基序4）以及质子化拉莫三嗪与羧酸根阴离子之间的阴-阳离子二聚体。进一步地，相较于纯拉莫三嗪碱型，研究人员对这些新型晶型开展了水中溶解度实验、0.1 N盐酸中的粉末溶出实验以及潮湿环境下的稳定性实验。结果显示，此类化合物在水中的溶解度较纯碱型有显著提升，这一现象可归因于其晶体结构中存在的堆积基序类型，以及酸性共晶形成剂对pH值的降低作用。此外，研究人员还对溶解度与溶出实验后剩余的各类固体残留物，在水相及酸性介质中的结构转变情况进行了评估。