Versatile supramolecular architectures in lamotrigine multicomponent crystalline materials (2011)

The structural organization at the molecular scale determines the physicochemical properties of bulk materials. Thus, control of material properties should rely on precise understanding of the assembly of the molecular components. The design of multicomponent crystalline molecular materials offers the opportunity to modify target properties of a specific compound without modifying its basic molecular structure. This is especially relevant in the context of pharmaceutical materials, where the molecular structure of the active pharmaceutical ingredient must remain intact in order to preserve its fundamental pharmacological properties. The assembly of different molecular components in the same crystal lattice can be achieved from a careful selection of specific molecular components by considering their potential supramolecular interactions. By following this strategy, the molecular components in multicomponent crystals can be exchanged in order to produce a systematic modification of a specific property. Thus multicomponent crystals represent a versatile approach for the construction of functional materials with tailor made properties. This thesis is focused on the design and synthesis of multicomponent crystals based on the pharmaceutical compound lamotrigine (LM) as a potential route for the control of its physical properties. The present thesis is divided in six chapters, the contents of which are briefly summarized hereafter. Chapter 1 aims to provide a general introduction to the thesis and to set out the context for the research work described. It introduces the concepts of supramolecular chemistry and crystal engineering, describing the various types of intermolecular interactions, multicomponent crystals and the concepts of polymorphism and isostructurality. The chapter finishes with a brief description of the main objectives of the thesis. In Chapter 2 the crystal structures of the anhydrous crystalline form and three new solvates of LM have been determined by single crystal X-ray diffraction. The analysis of the crystal structures has shown that the marked tendency of LM to form solvates is driven by the preferential formation of bifurcated NH2...O hydrogen bonds between LM and the oxygen atoms of solvent molecules. In Chapter 3 the formation of multicomponent crystals of LM has been studied by solution crystallizations of LM with different dicarboxylic acids (DC), using different solvents and initial stoichiometries. A total of 21 novel LMDC multicomponent crystalline phases have been identified and characterized by X-ray diffraction, thermal and spectroscopic analyses. It is shown that the use of different solvents and initial stoichiometries can give rise to different multicomponent crystals for a particular acid. The evaluation of the melting points has shown a direct correlation between the melting points of the DC and its corresponding LMDC multicomponent crystal. The analysis of crystal structures of LMDC multicomponent crystals has shown that several hydrogen bonding motifs and structural patterns can be identified as common features across the studied structures. In addition, two different series of isostructural LMDC multicomponent crystals have been identified. In Chapter 4 a set of LM salts with four different counterions have been prepared by solution crystallization and the influence of the counterion on the salt solubility has been investigated. These LM salts have been characterized and identified by X-ray diffraction, thermal and spectroscopic analyses. While isostructural LMDC salts were obtained for the dicarboxylic acids succinic, fumaric and DL-tartaric, the counterion saccharin produced a non-isostructural anhydrous salt. The determination of the water solubility of these salts has shown that the solubility of isostructural LMDC salts can be directly related to the solubility of the corresponding precursor acid. In addition, it has been shown that the LM tartrate salt has a solubility of up to four times that of the LM free base. In Chapter 5 the formation of isostructural inclusion host architectures based on the combination of LM with 1,4-butanedicarboxylic acids (DCs) has been explored and the modification of the inclusion properties along these hosts has been investigated. It has been shown that the exposure of solid mixtures of LM and a range of different saturated and unsaturated DCs to a third molecule in the gas, solid or liquid state results in the self-assembly of a family of isostructural LMDC host frameworks. The frameworks are based on a hydrogen bonded molecular salt structure and exhibit unprecedented robustness to changes in the structure of the DC. This isostructurality allowed for the systematic variation of substituents on the DC building block, resulting in 12 inclusion hosts which show a systematic modification of the size, shape, topology and surface of the inclusion cavity. Chapter 6 summarizes the main conclusions presented throughout the thesis.