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.