Solubility Enhancement of the Nonsteroidal Anti-inflammatory Drug of Pelubiprofen Salts

Pelubiprofen (PBF) is an anti-inflammatory drug that effectively relieves pain in rheumatoid patients compared to other BCS class II nonsteroidal anti-inflammatory drugs (NSAIDs). In the present work, three new PBF salts were synthesized using three GRAS coformers, piperazine (PIP), cyclohexylamine (CyHA), and isopropylamine (IsoPA). PBF salt formation was confirmed by using diffractive, spectroscopic, and thermal methods. The crystal structures of the salts were determined through single-crystal X-ray diffraction, and the proton transfer from PBF to coformers was identified using NMR spectroscopy, which revealed the presence of carboxylate-ammonium (⁺N-H···O^-) heterosynthons in the salt adducts. These salts (PBF-PIP, PBF-CyHA, and PIP-IsoPA) dramatically enhanced the PBF solubility and dissolution rate in aqueous and phosphate buffer media. Among the salts, PBF-IsoPA exhibited 60- and 1300-fold solubility enhancements in phosphate buffer and water media, respectively, compared to PBF. This dramatic solubility increase was due to intermolecular interactions, low melting point, and low hydrophobicity. Our model study suggested boosting the absorption efficacy of the PBF drug, which can be an alternative for the commercialized formulations after toxicity analysis.