Polymer-Induced Heteronucleation of Tolfenamic Acid: Structural Investigation of a Pentamorph

The nonsteroidal anti-inflammatory drug (NSAID) tolfenamic acid (TA), previously thought to be dimorphic, is demonstrated to have at least five polymorphs. The new forms were uncovered through the emerging screening technique of polymer-induced heteronucleation (PIHn). The presence of conformational changes among forms, whole molecule disorder, space group diversity, and varying number of molecules in the asymmetric unit occurring within a very narrow free energy window (approximately 0.3 kcal/mol) make the solid-state chemistry of this molecule uniquely complex among pharmaceuticals. These aspects make it a particularly suitable benchmark compound for crystal structure prediction methods.