Crystalline forms of selected agrochemical actives : design and synthesis of cocrystals

Abstract

The research described in this disseration covers the crystal form screening of two analogous agrochemical actives, thiophanate-methyl and thiophanate-ethyl, as well as the discovery of seven 4-hydroxybenzoic acid cocrystals of selected agrochemical actives. Polymorphs are crystal forms of a compound that have the same composition, but a different arrangement of molecules. Cocrystals are molecular crystals composed of two or more compounds, and refer mainly to crystals which contain compounds that are solids at standard conditions. Solvates are forms that have molecules of solvent in the crystal lattice and these include hydrates, in which the solvent is water. The crystal forms of organic compounds are investigated especially in the pharmaceutical and other specialty chemical industries for better processing and activity of the compounds as well as for intellectual property reasons. Thiophanate-methyl was found to crystallize as two polymorphs and fourteen solvates, while thiophanate-ethyl was found to crystallize as four polymorphs and seven solvates. Identification of the forms was achieved mostly with powder X-ray diffraction, but methods such as IR spectroscopy, solid state NMR spectroscopy and thermogravimetric analysis were also used. The crystal structures of most of the crystal forms were determined by single crystal X-ray diffraction, allowing the inspection of intermolecular interactions such as hydrogen bonding. Reliable hydrogen bonding motifs were identified and used as supramolecular synthons in the design of new cocrystal forms. Three cocrystals of thiophanate-methyl and eight cocrystals of thiophanateethyl were found. The seven cocrystal forms of agrochemical actives with 4- hydroxybenzoic acid show better properties in comparison to the pure forms, and highlight the importance of cocrystallization in industrial applications. The design and synthesis of cocrystals as well as the analysis of packing and hydrogen bonding in crystal structures is reviewed in the literature part of this thesis.