Application of on-line Raman spectroscopy for characterizing relationships between drug hydration state and tablet physical stability.

Experiments were conducted to elucidate the relationship between risedronate sodium (RS) hydration state and the physical stability of tablets containing RS. The RS crystal lattice contains channels occupied by water, which is removed by drying processes at temperatures below the boiling point of water, causing a reversible contraction of the crystal lattice. In this study, risedronate sodium was wet granulated followed by fluid bed drying to final granulation moisture contents between 1 and 7%, and then compressed into tablets. During drying, the RS solid-state form was continuously monitored using on-line Raman spectroscopy. Raman spectra acquired in these experiments enabled direct monitoring of changes in the RS crystal lattice, due to dehydration, which provided key information relating RS solid-state form characteristics to final granulation moisture content. Final granulation moisture was found to have a significant effect on the change in RS hydration state measured by Raman spectroscopy. As the final granulation moisture decreased, the amount of RS dehydrated form increased. The largest Raman spectral changes were in the CH stretching region and the region including the 3-picoline ring and PO2- stretches. These changes are indicative of substantial changes in the RS solid-state structure. Final granulation moisture also had a significant effect on the change in tablet thickness over time. Lower final granulation moisture caused a greater increase in tablet thickness as the RS rehydrated. In addition, the change in RS hydration state during fluid bed drying, measured by on-line Raman, was correlated to the increase in tablet thickness and subsequent loss of tablet integrity. Raman spectroscopy allowed direct RS hydration state monitoring, rather than inference from a bulk moisture measurement. Development of a Process Analytical Technology (PAT), specifically Raman, to monitor RS solid-state during drying enabled establishment of relationships between fundamental hydration dynamics associated with RS and final product performance attributes.