Solvates or hydrates (also known as pseudopolymorphs) crystallize in forms that differ from the unsolvated species, which should not be surprising because their stoichiometries are different. That is, they result from the incorporation of solvent bound in the lattice of the crystal in a specific stoichiometric ratio. Transformations among pseudopolymorphic forms often produce variations in physical properties such as density, solubility, dissolution rate, and bioavailability. These changes in physical form can interrupt downstream processing during manufacturing. Furthermore, the formation of pseudopolymorphs of pharmaceuticals can be of great importance because changes in the physical properties of the crystal can affect the safety and efficacy of a drug. Thus, predicting the occurrence 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 that has been shown to exhibit four pseudopolymorphic forms (anhydrous, monohydrated, dihydrated, and tetrahydrated). The purpose of the present study is to examine changes in the pseudopolymorphic states of sodium naproxen in mixed-solvent (e.g., methanol and water) systems with varying temperature. The work explores the transition from one pseudopolymorphic form to another using batch cooling crystallization, which can be seen clearly through a van't Hoff plot of solubility data. Specifically, the transition point between pseudopolymorphs occurs at decreasingly lower temperatures as the concentration of methanol is increased in the solvent. These data are being used to develop a capability that will allow prediction of the pseudopolymorphic state of sodium naproxen under a given set of conditions.