Crystallization of pseudopolymorphic forms of sodium naproxen in mixed solvent systems

Abstract

Several pseudopolymorphic forms of sodium naproxen were crystallized from methanol-water and ethanol-water solutions, including hydrated and alcohol-solvated forms. Results showed that the transitions of the pseudopolymorphic forms occur at temperatures that depend upon the solvent concentration. Results also revealed that water activity is a controlling factor for the transitions because regardless of which alcohol solvent mixture was used. The heats of solution for each pseudopolymorph were estimated by fitting the solubility data with the van't Hoff equation. The stability of hydrated forms over solvated forms at higher temperatures was proven for enantiotropic systems from a thermodynamic cycle. A 1:1 methanol-solvated form of sodium naproxen was discovered and fully characterized using a variety of analytical techniques. For further analysis, a single crystal was performed and revealed a two to three ratio solvate of sodium naproxen to methanol. The 1.5 solvate was shown to not be representative of the entire sample, but still provided insight into the bonding of the methanol solvent in sodium naproxen. Additionally, the ability of sodium naproxen to solvate with other alcohol solvents was explored, specifically looking at comparisons between pure ethanol, 1-propanol, 2-propanol, 1-butanol, and isobutanol solvents. It was shown that as the size of the alcohol increases and/or branching increases the ability to solvate decreases in relation to the molar amount of the alcohol present in the crystal structure. Additionally larger, branched alcohols required more energy to desolvate.