Lamotrigine: Design and synthesis of new multicomponent solid forms

• Published in: European journal of pharmaceutical sciences Vol. 129; pp. 148 - 162
• Main Authors: Évora, António O.L., Castro, Ricardo A.E., Maria, Teresa M.R., Ramos Silva, M., Canotilho, João, Eusébio, M. Ermelinda S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-03-2019
• Subjects: Co-crystals and salts; Diflunisal; Lamotrigine; Pyridinecarboxamides; Stability assay; Xanthines; Diflunisal; Co-crystals and salts; Pyridinecarboxamides; Stability assay; Xanthines; Lamotrigine
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2019.01.007

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.
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