Conformational and Intermolecular Interaction Analysis of Tiaprofenic Acid: A X-Ray Powder Diffraction and First Principle Modeling Analysis

(±)-tiaprofenic acid (TA), marketed as (Surgam®), belongs to the family of NSAIDs, with the peculiarity of a reduced incidence of ulcer induction in rats compared with parent drugs. However, some adverse effects were observed, and better knowledge of its interaction with biologic substrates is needed. Unfortunately, unlike most commercial NSAIDs, suitable single crystals for an X-ray diffraction study could not be obtained. To fill the gap, the crystal structure of TA was solved by X-ray powder diffraction, and the molecular interactions stabilizing the structure were analyzed by Hirshfeld surface and energy framework analysis. TA crystallizes in the P21/c space group, with its two enantiomers in the asymmetric unit, further confirming the peculiarity of the crystal structure and the difficulty of solving it. TA packing is characterized by alternating enantiomers connected through hydrogen bonds, forming chains, arranged in layers, stabilized by π-stacking. First principle modeling revealed several stable conformations within 4 kJ/mol of the global minimum and the relaxed potential energy scans revealed modest (8 kJ/mol–15 kJ/mol) energy barriers. Such flat energy landscape suggests flexible and dynamic behavior of tiaprofenic acid in solution and in vivo conditions, with multiple suitable docking sites.