Calorimetry and complementary techniques to characterize frozen and freeze-dried systems

Lyophilization is a commonly used drying technique for thermolabile pharmaceuticals. Crystallization of formulation components may occur during various stages of the freeze-drying process. In frozen solutions, while crystallization of bulking agents is desirable, both from processing and product-elegance perspectives, buffer salt crystallization can cause a significant pH shift. Lyoprotectants (compounds that protect macromolecules, both during freeze-drying and subsequent storage) are effective only when retained amorphous. This review presents numerous applications of differential scanning calorimetry to characterize pharmaceutical systems in frozen state. These studies are aimed at defining the processing parameters and optimizing the freeze-drying cycle. Low temperature pH measurement and sub-ambient X-ray diffractometry served as excellent complementary tools in the characterization of frozen systems. The phase behavior of the systems during annealing (of frozen solutions), primary and secondary drying were monitored by X-ray diffractometry. Finally, the interplay of formulation composition and processing parameters on the development and optimization of freeze-drying cycles are reviewed.