Double Substitution Leads to A Highly PolymorphicSystem in 5-Methyl-2-m-tolylamino-benzoic Acid

By instilling methyl group(s) to either or both aromatic rings of fenamic acid (FA), three FA derivatives (1-3) were synthesized to investigate the effect on the polymorphic behavior of these compounds exerted by substitution. A relatively comprehensive polymorph screen led to the discovery of four polymorphs for compound 3, for which substitution took place on both aromatic rings, in contrast to the harvest of either two or one form(s) for compounds 1 and 2, both of which are mono-substituted. The observation indicates both substitution position and pattern are important in the polymorphism of these compounds. The thermal properties of each system are investigated by differential scanning calorimetry (DSC). Conformational scan and Hirshfeld analysis are performed to study the mechanism of polymorphism and the intermolecular interactions contributing to the stability of each crystal form.