A novel naproxen potassium dihydrate: single-crystal structure and solid-state characterization of the dihydrate and its anhydrous form with improved dissolution properties

Abstract

Naproxen (NAP) is a widely used nonsteroidal anti-inflammatory drug indicated in the treatment of muscle pain, dysmenorrhea, and arthritis. Due to its limited solubility, it is generally administered as a sodium salt (NS). However, the NS is contraindicated in patients with heart failure, as it may increase blood pressure and predispose to cardiovascular events. As a promising alternative, this work reports the preparation of naproxen potassium dihydrate (NP-DH) via a simple and reproducible solvent evaporation method. The crystal structure of NP-DH was elucidated by single-crystal X-ray diffraction, providing structural insight into the hydrated pharmaceutical salt. Upon controlled drying, NP-DH yielded an anhydrous form (NP-ANH), with the dehydration process evidenced by thermal analysis. Both crystalline phases were thoroughly characterized by powder X-ray diffraction, solid-state nuclear magnetic resonance, and mid and near-infrared spectroscopies. Improved biopharmaceutical properties were demonstrated for NP-ANH through intrinsic dissolution rate studies, revealing a significant increase in solubility when compared with NS. NP-DH exhibited a similar performance to NS, while still representing a suitable alternative. Finally, the novel salts were formulated into tablets and evaluated against NAP and NS through dissolution performance tests. NP-DH and NP-ANH emerged as promising alternatives for naproxen administration, particularly in patients requiring sodium restriction.