Ionic, Neutral, and Hybrid Acid–Base Crystalline Adducts of Lamotrigine with Improved Pharmaceutical Performance

Lamotrigine (L) is a known drug in the treatment of epilepsy and bipolar disorder. Due to its unique structure and functionalities, L is able to form both salts and cocrystals. The present study reports ionic, neutral, and hybrid crystalline forms of L with improved material properties and modified drug release rates. Novel forms of L with cinnamic acid (CA), ferulic acid (FRA), salicylic acid (SAC), and vanillin (VN) were successfully prepared and characterized using single crystal XRD, SEM, FT–IR, DSC, TGA, and powder XRD. LCA and LVN crystallized in P21/c space group, whereas LSAC crystallized in P1̅ space group. Pseudo-quadruple hydrogen bond with R42 (16) graph set notation were observed in all three crystal structures of L. The characteristic FT–IR stretching peaks at 3326.53, 3341.53, and 3340.65 cm–1 corresponding to N+–H bond were observed in LCA, LFRA, and LSAC. Comparison of dissolution profiles using similarity factor (f2) analysis revealed that the dissolution profiles of LCA, LFRA, and LVN were significantly different from that of L. LVN exhibited improved dissolution rate compared to L and LCA revealed a sustained release profile. Both these properties are important in designing oral dosage forms for neuropathic pain and bipolar disorder therapy. Further, LCA can be used in the development of extended release drug delivery systems for treating epileptic disorders.

拉莫三嗪（Lamotrigine，下文简称L）是一款用于治疗癫痫与双相情感障碍的临床常用药物。鉴于其独特的结构与功能特性，拉莫三嗪可同时形成盐类与共晶。本研究报道了拉莫三嗪的离子型、中性及杂化晶型，此类晶型具备更优异的材料性能，并可实现药物释放速率的精准调节。本研究成功制备了拉莫三嗪与肉桂酸（cinnamic acid，CA）、阿魏酸（ferulic acid，FRA）、水杨酸（salicylic acid，SAC）及香兰素（vanillin，VN）的新型复合晶型，并通过单晶X射线衍射（single crystal XRD）、扫描电子显微镜（SEM）、傅里叶变换红外光谱（FT–IR）、差示扫描量热法（DSC）、热重分析（TGA）及粉末X射线衍射（powder XRD）完成了系统表征。LCA与LVN的晶胞空间群为P2₁/c，而LSAC的空间群为P1̅。在拉莫三嗪的三种晶型结构中，均观测到带有R4²(16)图记的准四重氢键。在LCA、LFRA及LSAC样品中，可观测到对应于N⁺–H键的特征傅里叶变换红外伸缩振动峰，其波数分别为3326.53、3341.53及3340.65 cm⁻¹。通过相似因子（f2）分析法对溶出曲线进行对比分析，结果显示LCA、LFRA及LVN的溶出曲线与原料药拉莫三嗪存在显著差异。其中LVN的溶出速率较原料药L有所提升，而LCA则呈现出缓释特性。上述两项特性在开发用于治疗神经病理性疼痛与双相情感障碍的口服制剂方面具有重要价值。此外，LCA可用于开发治疗癫痫疾病的长效释药递送系统。