CQC, Coimbra Chemistry Center, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
CQC, Coimbra Chemistry Center, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
Eur J Pharm Sci. 2019 Mar 1;129:148-162. doi: 10.1016/j.ejps.2019.01.007. Epub 2019 Jan 9.
In this work, a crystal engineering and thermodynamic based approach has been used aiming at contributing to a deeper knowledge of lamotrigine multicomponent solid forms. Two types of co-molecules have been chosen that can give rise to co-crystals with lamotrigine through different supramolecular heterosynthons: the xanthines, theophylline and caffeine, and the three isomeric pyridinecarboxamides. Association with diflunisal, which may result in a salt, was also investigated. Mechanochemistry, differential scanning calorimetry, thermogravimetry, X-ray powder and single crystal diffraction, infrared spectroscopy were the methods used. For all the systems, exploratory neat mechanochemistry experiments, carried out on lamotrigine + co-molecule binary mixtures of different compositions, were not successful in promoting association. From differential scanning calorimetry data and the binary solid-liquid phase diagrams, co-crystals/salts were identified as well as their respective stoichiometry, and a methodology of synthesis was established. For pyridinecarboxamides, molecular recognition is dependent on the position of the amide group in the pyridine ring: co-crystallization did not occur with picolinamide co-former. Both xanthines form co-crystals with lamotrigine, (1:1) with theophylline and (2:1) lamotrigine:caffeine. Additionally, the crystalline structure of a lamotrigine:theophylline 1:1 monohydrate was solved. The (1:1) lamotrigine:theophylline co-crystal converts to this monohydrate in accelerated stability tests. A (1:1) lamotrigine:diflunisal salt was identified, which proved to be stable in accelerated stability assays.
在这项工作中，采用了晶体工程和热力学方法，旨在深入了解拉莫三嗪多组分固体形式。选择了两种可以通过不同超分子杂合键与拉莫三嗪生成共晶的共分子：黄嘌呤、茶碱和咖啡因，以及三种异构体吡啶甲酰胺。还研究了与可能形成盐的 diflunisal 的缔合。使用的方法有机械化学、差示扫描量热法、热重分析、X 射线粉末和单晶衍射、红外光谱。对于所有系统，在不同组成的拉莫三嗪+共分子二元混合物上进行的探索性纯机械化学实验都未能成功促进缔合。从差示扫描量热法数据和二元固液相图中，确定了共晶/盐及其各自的化学计量比，并建立了合成方法。对于吡啶甲酰胺，分子识别取决于酰胺基在吡啶环上的位置：与 picolinamide 共形成剂没有发生共结晶。两种黄嘌呤均与拉莫三嗪形成共晶，茶碱与拉莫三嗪的比例为 1:1，咖啡因与拉莫三嗪的比例为 2:1。此外，还解决了拉莫三嗪：茶碱 1:1 一水合物的晶体结构。在加速稳定性测试中，（1:1）拉莫三嗪：茶碱共晶转化为一水合物。鉴定出（1:1）拉莫三嗪：diflunisal 盐，在加速稳定性试验中证明是稳定的。
