We report the discovery of two new forms (II and III) of a potential non-steroidal anti-inflammatory and thyroid drug, 2-((2,6-dimethylphenyl)amino)benzoic acid (HDMPA) through solution growth and thermal treatment of crystals. Form II has been discovered through crystal growth in a variety of solvents, and characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), FT-IR, and Raman spectroscopy. Form II converts into form III upon thermal treatment, as indicated by the phase behavior study of form II with differential scanning calorimetry (DSC). Form III has been characterized by IR, Raman and PXRD. Conformational flexibility of the molecule seems to lead to the polymorphism of the system. A conformational scan shows the conformational minima correspond to the conformers in the polymorphs. Lattice energy calculations show energies of À48.14 and À50.31 kcal mol À1 for forms I and II, providing information on the relative stability for each form. Hirshfeld analysis revealed that

A lactam−lactam dimer (LLD) and lactam NH•••OC (amide) catemer (LAC) are two competing motifs in N-phenyl-2-hydroxynicotinanilides (PHNAs). Steric effects play an important role in determining the outcome of this competition, and in general, PHNAs with no or negligible steric hindrance take on a near-planar conformation and form LLDs, rather than the widely observed amide NH•••OC hydrogen-bond chains. Conversely, those with significant steric hindrance are forced to take on a twisted conformation and form a lactam NH•••OC (amide) hydrogen bond. Nevertheless, steric factors are not the only criteria, as an LLD and an LAC have been observed in the two polymorphs (1-I and 1-II) of 2-hydroxy-N-m-tolyl-nicotinamide (namely 2-oxo-1,2-dihydropyridine-3-carboxylic acid m-tolylamide, compound 1), although the molecules in both forms have a nearly identical conformation, in contrast to five other newly synthesized PHNAs (2−6), whose crystal structures are sustained on the LLD. Thus, synthon polymorphism is possible in conformationally planar PHNAs. Theoretical studies were performed to provide an explanation for this observation. The lattice energies of the two forms of 1 showed only an insignificant difference. A Hirshfeld analysis revealed that the loss of stability due to less hydrogen bonding in 1-II is compensated by the participation of π−π stacking. Other than the commonly observed LLD in the crystals, π−π stacking provides a significant stabilization for each crystal, with its particular effects being dependent on the substitution pattern of the compound. A noncovalent interaction (NCI) analysis further provided a visual demonstration of the important intermolecular interactions. Potentially the other planar compounds could behave in a similar manner.

Substitution on both aromatic rings of fenamic acid led to a highly polymorphic system in 5-methyl-2-m-tolylamino-benzoic acid, in contrast to the two mono-substituted analogs, which had only one or two forms obtained.

A series of homologues (1–4) of fenamic acid have been synthesized by varying the length of the linker between the two aromatic rings, and their polymorphism has been investigated. Under the same crystallization conditions, each of the newly synthesized compounds leads to two forms, except for compound 1, which indicates that additional flexibility due to homologation does not necessarily lead to more polymorphs. The molecules in each polymorphic system show different conformations due to the rotation about specific sigma bonds. Phase transitions are observed between the polymorphs of each system. Conformational analysis and Hirshfeld surface analysis were applied to investigate the effect of conformational flexibility on the polymorphism of these compounds.

2-((2,6-Dichlorophenyl)amino)benzoic acid (2-DCABA), a potential non-steroidal anti-inflammatory drug and an analog of 2-((2,6-dimethylphenyl)amino)benzoic acid (HDMPA) was synthesized and its polymorphism was studied to investigate the effect of double Cl-CH3 exchange....