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Freeze-Dry Microscopy (FDM)

Freeze-Dry microscopy is an analytical tool that allows a highly accurate measurement of the critical temperature (i.e. the collapse temperature, Tc) of a given formulation in micro scale. Maximally 2 µl of the sample solution are placed on a glass slide which is then put on a silver block oven (Pic. 1). This silver block is the integral part of the freeze drying stage (Linkam Scientific Instruments). A special oil between the silver block and the very thin glass slide assures 1:1 heat transfer to the sample. A second glass slide is placed on top of the solution (Pic. 2). The stage is then sealed with a lid and the sample frozen. A control unit guarantees precise cooling by using liquid nitrogen and heating. After freezing the sample, the chamber is evacuated and the temperature of the oven elevated to enable defined sublimation. At this point one can observe the proceeding sublimation front microscopically. Dried structures have a dark appearance in contrast to frozen structures which show different colours in the used polarized light. We apply a digital camera and display the process itself as well as all important information in a computer system, Pic. 3. The measurement procedure simulates a freeze drying process in micro-scale. Once the collapse temperature is reached, the dried layer close to the sublimation interface starts to form bright spots which indicate structural alteration or loss of structure (Pic. 4). Further elevation the temperature results in a severe, more global loss of structure (Pic. 5). Note that this measurement technology takes advantage of a dynamic process and can not be directly compared to a DSC measurement (frozen solution in a sealed pan at atmospheric pressure). 

FDM Pic1
FDM Pic2

 

Pic. 1

 Pic. 2

                             

FDM Pic3

FDM Pic4

FDM Pic5

Pic. 3

Pic. 4

 Pic. 5

                                                                                                                                                 

It was observed that the measurement methodology (for many samples) has a great impact on the results obtained for Tc. In addition, some products even tolerate higher temperatures during laboratory scale freeze drying than Tc measurements by microscopy indicates (by the way this is the same situation for DSC measurements!). As we are on the way to optimize FDM, we see a great potential to (globally) establish FDM as a routine tool in formulation work once we understand how to accurately collect and interpret these data.

 

FDM Picture Gallery:

Get a more visual idea of collapse behavior by following the links below. FDM is indeed an art of its own. Note: the pictures are copyright protected!

                   

 

Our actual work includes:

  • optimization of the measurement methodology,
  • guidelines for FDM experiments with regard to formulation properties,
  • evaluation of the potential impact of total solid content on Tc and
  • translation of measured Tc to collapse behavior observed for typical loads in a freeze dryer.

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