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

Area of Science:

• Crystallography
• Molecular modeling
• Pharmacology

Background:

• Tiaprofenic acid (TA) is a nonsteroidal anti-inflammatory drug (NSAID) with a lower incidence of ulcer induction in rats compared to other NSAIDs.
• Despite its therapeutic use, some adverse effects necessitate a deeper understanding of TA's interactions with biological molecules.
• Obtaining single crystals for X-ray diffraction studies, common for NSAIDs, has been challenging for TA.

Purpose of the Study:

• To elucidate the crystal structure of tiaprofenic acid (TA) using X-ray powder diffraction.
• To analyze the molecular interactions that stabilize the TA crystal structure.
• To investigate the conformational flexibility and potential biological interactions of TA through computational modeling.

Main Methods:

• X-ray powder diffraction was employed to solve the crystal structure of TA.
• Hirshfeld surface analysis and energy framework analysis were used to study intermolecular interactions.
• First-principle modeling and potential energy scans were performed to explore molecular conformations and energy barriers.

Main Results:

• TA crystallizes in the P21/c space group, with both enantiomers present in the asymmetric unit, indicating a complex crystal structure.
• The crystal packing features alternating enantiomers linked by hydrogen bonds, forming chains and layers stabilized by π-stacking interactions.
• Computational analysis revealed multiple stable conformations for TA within a low energy range and modest energy barriers, suggesting significant molecular flexibility.

Conclusions:

• The unique crystal structure of TA, solved via powder diffraction, highlights its distinct packing arrangement.
• The identified intermolecular interactions, including hydrogen bonding and π-stacking, are key to TA's solid-state structure.
• The computational findings suggest that tiaprofenic acid exhibits flexible and dynamic behavior, potentially enabling various interactions with biological substrates in vivo.