Thermophysical properties of pharmaceutically compatible buffers at sub-zero temperatures: implications for freeze-drying.

PURPOSE: To evaluate crystallization behavior and collapse temperature (Tg') of buffers in the frozen state, in view of its importance in the development of lyophilized formulations.
METHODS: Sodium tartrate, sodium malate, potassium citrate, and sodium citrate buffers were prepared with a pH range within their individual buffering capacities. Crystallization and the Tg' were detected during heating of the frozen solutions using standard DSC and modulated DSC.
RESULTS: Citrate and malate did not exhibit crystallization, while succinate and tartrate crystallized during heating of the frozen solutions. The citrate buffer had a higher Tg' than malate and tartrate buffers at the same pH. Tg' vs. pH graphs for citrate and malate buffers studied had a similar shape, with a maximum in Tg' at pH ranging from 3 to 4. The Tg' maximum was explained as a result of a competition between two opposing trends: an increase in the viscosity of the amorphous phase because of an increase in electrostatic interaction, and a decrease in the Tg' because of an increase in a water concentration of the freeze-concentrated solution.
CONCLUSION: Citrate buffer was identified as the preferred buffer for lyophilized pharmaceuticals because of its higher Tg' and a lower crystallization tendency.