Use of subambient differential scanning calorimetry to monitor the frozen-state behavior of blends of excipients for freeze-drying.

The purpose of this study was evaluation of mannitol and its blends with other excipients commonly used as freeze-drying cryoprotectants or bulking agents in simulated lyophilization conditions. Subambient differential scanning calorimetry (DSC) has been used as an analytical tool to evaluate the phenomena from both a qualitative and a quantitative point of view. The DSC scans were performed at rates comparable to those generally practicable in industrial lyophilizators. During a simulated freeze-drying process, three crystallization events have been observed on mannitol solutions: the first two on freezing, and the last one on heating. The phenomena are dependent on each other. The addition of other excipients can significantly influence this behavior by specifying the crystallization of mannitol in freezing or by inhibiting it fully. This means that the final physical state of the freeze-dried product (amorphous, crystalline, or partially amorphous/partially crystalline) can be tailored by accurately choosing not only the freeze-drying conditions but also the composition of the solution to be lyophilized. The results point out how the physical state of freeze-dried products can be controlled by an accurate choice of both excipients and their relative ratios, with the possibility of reducing the number of preformulation activities required to design the most appropriate formulation for each new drug candidate.