Is the Fenamate Group a Polymorphophore? Contrasting the Crystal Energy Landscapes of Fenamic and Tolfenamic Acids

The concept of a polymorphophore was investigated by contrasting the crystal energy landscapes of monomorphic fenamic acid (2-(phenylamino)-benzoic acid, FA) and one of its highly polymorphic derivatives, tolfenamic acid (2-[(3-chloro-2-methylphenyl)amino]-benzoic acid, TA). The crystal energy landscapes of both molecules show that the benzoic acid R-2(2)(8) dimer motif is found in all low energy crystal structures, but conformational flexibility of the phenyl rings leads to a wide range of crystal structures with different packings of this dimer. Many of the observed fenamate crystal structures can overlay a significant proportion of the coordination environment with other observed or calculated structures, but the substituents of the phenyl group affect the ordering of the related low energy crystal structures. The crystal energy landscape of tolfenamic acid has several crystal structures, including the observed polymorphs, tightly clustered around the global minimum, whereas the corresponding cluster contains only the observed and a closely related structure for fenamic acid. Hence, the fenamate fragment is potentially permissive of a large number of structures because of the conformational flexibility, but the substituents determine whether a specific fenamate will be polymorphic. Thus, a polymorphophore promotes but does not guarantee polymorphism.