Polymorphism Of Clonixin And Its Analogs

Ever since Ulle and Lebedk discovered the polymorphism of benzamide compounds in 1832,scientists have been more and more interested in the phenomenon of polymorphism.Polymophism is of particular importance in pharmaceuticals since different crystals of the same active pharmaceutical ingredient may have different solubility,dissolution rate and thus bioavailability.In this thesis,we investigate the polymorphism of a non-steroidal anti-inflammatory drug(NSAID)clonixin and its derivatives through the combination of theoretical and experimental approaches,hoping to provide insight into the formation of different crystal forms of each compound and offer some potential new NSAIDs.Firstly,clonixin was synthesized by reacting 2-chloronicotinic acid with 3-chloro-2-methyl-phenylamine with p-TsOH as catalyst under a nucleophilic aromatic substitution(SNAr)mechanism according to the literature,and confirmed by nuclear magnetic resonance.Different crystal forms were obtained in a variety of solvents by slow evaporation and slow cooling.In the course of this process,we obtained two new solvate in N,N-dimethylformamide and N,N-dimethylacetamide in addition to the four solvent-free forms.The structures of the different polymorphs were solved by single-crystal X-ray diffraction and each form was further characterized by UV,IR and Raman spectroscopy.A series of thermodynamic tests were run with differential scanning calorimetry(DSC),thermogravimetric analysis and hot-stage microscopy to study the relative stability of these forms.Quantum chemistry calculations such as lattice energy computation and Hirshfeld analysis were performed to provide further insight into the relative stability and formation of the different forms.In due time,we will test the potential of the new forms of clonixin as NSAIDs.Next,we designed a series of clonixin derivatives using the structure of clonixin as a model.Similarly,four derivatives of clonixin were synthesized by replacing the chlorine with fluorine,bromine,iodine and hydrogen to investigate the effect of substituents on the polymorphic behavior of these compounds.A variety of crystal forms were obtained by various crystallization methods.The structures of the crystals of each compound were also solved by single-crystal X-ray diffraction.Each form of the clonixin derivatives was characterized by UV,IR and Raman spectroscopy.The thermal behaviors of each polymorphic system were investigated by DSC.In due time,the potential of the new forms of clonixin and the polymorphs of the new compounds as NSAIDs will be investigated.