Solubility, Solubility Modeling, and Precipitation of Naproxen from Subcritical Water Solutions

In this paper, the solubility of naproxen in subcritical water (SBCW) between 130 and 170 degrees C is measured. The solubility of naproxen in SBCW was correlated to temperature using a Modified Universal Functional Activity Coefficient (M-UNIFAC) model. Errors in the model were minimized by optimizing the water-carboxylic acid interaction parameter, as other side groups were already optimized. The micronization of naproxen via processes that used the tunable solvent power of SBCW was conducted. Two precipitation techniques were developed. In the first technique, the temperature of a SBCW solution containing naproxen was rapidly quenched by injection into cold water solutions. The quenching media were either pure water or 1% w/v solution of lactose in water. Variations in SBCW-naproxen solution injection temperature and supersaturation ratios in pure water were examined. Product morphology was robust toward changes in operating conditions and consisted of flaky crystals with a particle size distribution ranging from 0.5 to 100 mu m. Under specific experimental conditions, naproxen crystals formed spherical agglomerates. Particles produced from lactose/water solutions were slightly smaller than those produced from pure water. In the second technique. precipitation was induced by vaporization of SBCW-naproxen solutions. The SBCW solutions were injected into a vessel that was connected to a vacuum pump. The process generated large naproxen microcrystals with broad particle size distributions.