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FDM measurements were repeated after one week of storage at room temperature to investigate potential instability of the solution
that may lead to changes in Tg. Regarding the standard deviations, no clear difference between immediate measurements and
experiments after one week of storage can be observed. It is important to note that at higher concentrations, the visual detection
of collapse becomes more difficult. Due to the increased density of the sample and, therefore, reduced translucence, variations
between replicate measurements increase.
Figure 2
Comparison of DSC and FDM data. Tg' and Tc are not identical as the measurement methodologies are different. Collapse describes a dynamic process because
sublimation actually takes place during a FDM experiment, and the observed structural changes occur in the already dried matrix.
In contrast, during the DSC measurement, the amorphous drug is in direct contact with ice without a drying process. Therefore,
the experimental conditions of a FDM measurement better simulate those of a real freeze-drying run, and the structural changes
can be visually observed. Moreover, Tg' values are commonly reported as midpoint while the collapse temperature mostly refers
to the onset of collapse. To roughly estimate a 50% structural loss in the dried matrix (midpoint) and to simplify comparison
to DSC data, Tc-50 was introduced as a calculated average of Toc and Tfc (8). Figure 2 illustrates the CFTs determined with both methods during the present study. As previously described in the literature (2,
8, 12), Tg' in the authors' study is lower than Toc, with greater difference at higher total solid content. For example, Toc of the 5% solution is about 2 °C higher, and at 30% total solid content, the difference amounts to approximately 4 °C compared
to the midpoint Tg'. Taking Tc-50 into account, the gap ranges from 2.6 °C (5% w/v) to about 5 °C at 30% w/v for the measurement series directly after preparation.
Regarding the fact that an increase of only 1 °C in product temperature during primary drying can reduce cycle time up to
13%, the application of Toc instead of Tg' clearly permits more space for cycle optimisation, especially at higher concentrations (13).
Conclusions
The results of this study show that even for the relatively simple solution of a pure small-molecule drug, the collapse temperature
determined by FDM can be considered as the practically more relevant CFT for process development and optimisation. The direct
observation of the collapse event and the width of the gap between Toc and Tfc can provide additional valuable information on the temperature tolerance of the sample. In the case of gentamicin sulphate,
the temperature difference is not as big as it has been reported for protein formulations, indicating low robustness of the
dried material in the microcollapse regime. Considering the great influence of small differences in product temperature on
primary drying time and product morphology, the use of freeze-dry microscopy is a substantial contribution to efficiency and
quality in the freeze-drying of small molecules.
Henning Gieseler, PhD, works in the Department of Pharmaceutics at the University of Erlangen, Erlangen, Germany 91058.
tel. +49 9131 85 29545, gieseler@freeze-drying.eu.
Articles by Henning Gieseler, PhD
