(302f) Determining Critical Water Activity Mediated Conversion of Anhydrate-Hydrate Solid Forms

The critical water activity value is a governing parameter to establish the phase diagram for anhydrate-hydrate solid form conversion. Understanding the solid phase diagram boundaries is imperative for controlling the crystallization of active pharmaceutical ingredients and developing a robust process. This value has been unable to be precisely measured in the literature due to influence of bound water post-equilibration and lack of accurate analytical methods. Historically, solid form equilibration in water activity studies have been performed over saturated salt solutions to control the system water activity. This process can occur over the timescale of months due to being limited by solid-vapor mass transfer. Contemporary slurry bridging methods offer improvement by solid-liquid equilibration in mediums with predetermined water activity values. However, it has not been possible to directly measure the final water activity value in reported slurry bridging studies with current technologies- namely electronic and chilled mirror hygrometers- due to either limitations in detection accuracy or incompatibility with organic solvents.

By using vapor phase frequency modulation spectroscopy, we have measured the solution water activity in organic solvent systems and accounted for the contribution that bound water has on the equilibration of a model compound, theophylline. A seeded slurry bridging approach was utilized to determine the exact water activity value and observe dual phase solid form coexistence. This approach allows for enhanced conversion kinetics and rapid in situ solid form assessment via raman spectroscopy without breaking the closed system equilibration. Employing these techniques enable a more accurate understanding of crystallization process conditions and allowance for these in situ analysis to streamline the experimental framework.