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 the sodium salt (NS). However, 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, 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 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.