Freeze-Drying Process Optimisation for a Small Molecule - Pharmaceutical Technology

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Freeze-Drying Process Optimisation for a Small Molecule


Pharmaceutical Technology Europe
Volume 24, Issue 6


Table II
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.


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