Studying the thermal history and relaxation of solid amorphous drug product matrices by calorimetry is a well-known approach, particularly in the context of correlating the matrix parameters with the long-term stability of freeze-dried protein drug products. Such calorimetric investigations are even more relevant today, as the application of new process techniques in freeze-drying (which strongly influence the thermal history of the products) has recently gained more interest. To revive the application of calorimetric methods, the widely scattered knowledge on this matter is condensed into a review and completed with new experimental data. The calorimetric methods are applied to recent techniques in lyophilization, such as controlled nucleation and aggressive/collapse drying. Phenomena such as pre-Tg events in differential scanning calorimetry and aging shoulders in isothermal microcalorimetry are critically reviewed and supplemented with data of freeze-dried products that have not been characterized with these methods before.
Keywords: collapse; controlled nucleation; differential scanning calorimetry (DSC); freeze-drying; isothermal microcalorimetry (IMC); lyophilization; molecular mobility; relaxation.