Solvents are often used in the production of crystalline pharmaceutical species. During processing, these solvents can become incorporated in the lattice of the crystal in a specific stoichiometric ratio as solvates or hydrates (also known as pseudopolymorphs). The properties of these pseudopolymorphs differ from those of the unsolvated species, which should not be surprising because their compositions are different. Accordingly, transformations among pseudopolymorphic forms often produce variations in physical properties such as density, solubility, dissolution rate, and bioavailability that can create difficulties in downstream processing. Thus, predicting the occurrence or transition of crystal pseudopolymorphs is of importance in developing robust, large-scale crystallization processes in the pharmaceutical industry.

Sodium naproxen is a non-steroidal, anti-inflammatory drug which has been shown to exhibit four pseudopolymorphic forms (anhydrous, monohydrated, dihydrated, and tetrahydrated). The purpose of the present study is to examine the transition of pseudopolymorphic forms of sodium naproxen under mixed solvent (methanol/water and ethanol/water) systems with varying temperature. Using batch cooling crystallization, transitions can be seen clearly through a van't Hoff plot of solubility data. Currently, water activity is thought to play an important role in determining when transitions occur. This study explores the role of water activity in pseudopolymorphic transitions for these mixed solvent systems; specifically comparing the water activity at the various transitions of the pseudopolymorphs and how this change in the different alcohol/water systems.