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How to prevent your cake from collapsing in Freeze Dried Products?

by biopharmaszymon in BTL News, BTL Right Sidebar Content, Uncategorized

Many drugs are unstable in solution and degrade rapidly over time, therefore they must be freeze dried to produce a suitable stable product which can be shipped and has an acceptable shelf-life for storage. The freeze dried product can be reconstituted to produce a solution containing the drug ready for administration. Different drugs can be stabilised by freeze drying (lyophilisation), these include small molecules but also biological treatments such as vaccines, proteins, enzymes, and other larger molecules.

Fig. 1 Freeze dried product – ‘cake’

Freeze drying API/ drug products comes with its own unique challenges and stability issues which need to be overcome. Many biological drug products require additional excipients to stabilise them during the freeze drying process and during storage.

These excipients typically stabilise the drug molecules by entrapping protein molecules in an amorphous matrix which reduces the mobility of the molecule slowing its degradation, and also by supporting the structure of the molecule when freeze dried by replacing the hydrogen bonds interactions of water, which maintain the structure of the molecule in solution, allowing its structure to be maintained once the water has been removed. The resulting product is commonly a freeze dried ‘cake’.


Freeze Drying

The freeze drying process to produce a ‘cake’ can be broken down into three main stages; freezing, primary drying and secondary drying.

Fig. 2 Freeze Drying stages

During freezing the drug and the excipients present are freeze concentrated while the water crystallises and phase separates.

The second stage is primary drying during which the pressure is reduced causing sublimation of the ice. To increase the rate of sublimation, the temperature can be increased allowing for more ice to be sublimated in a shorter period reducing the time required to freeze dry a product. However, if the temperature of the product is increased too much the ‘cake’ can undergo collapse.

The third stage is called secondary drying in which the temperature of the freeze dried cake is increase slowly to remove the residual water present in the amorphous phase created by the concentration of the excipients and drug molecules. If the temperature is raised too quickly the ‘cake’ again will collapse. During secondary drying the glass transitions temperature of the product changes as the water is removed.



Fig. 3 Cake total collapse

Collapse of cake during these stages occurs when the freeze concentrated material exceeds its collapse temperature. The collapse temperature is usually the same or higher than the glass transitions temperature of the freeze concentrate. This is the temperature at which the material passes its glass transitions temperature and the viscosity of the material starts to decrease until the material is unable to support its own weight and therefore collapses.

Exceeding the collapse temperature of the product can lead to longer drying times, increase molecular mobility resulting in increased degradation of the molecule, and the cakes physical structure collapsing which may not produce an atheistically pleasing product. The glass transition temperature and collapse temperature of the drug product can be determined by several analytical techniques below:

Differential Scanning Calorimetry (DSC)

 Freeze Drying Microscopy (FDM)


Determining the Critical Temperatures

Traditionally, Differential Scanning Calorimetry (DSC) is used to determine the maximum temperature a product can withstand during primary drying by detecting the glass transitions temperature, however, some products can be freeze dried above this temperature but below its collapse temperature which can be measured by a freeze drying microscope. The use of a Lyotherm instrument which measures exo- and endo- thermic events similar to DSC, as well as changes in molecular mobility, can also be utilised to determine the maximum temperature of viability.

Fig. 4 Bad vial vs good vial

Freeze Dry Microscopy (FDM) works by observing the structural behaviour of a sample whilst drying it under a light microscope. Whilst the purpose of freeze drying is to produce a final stable product, the purpose of FDM is quite the opposite; to cause the product to collapse and measure the moment that happens, in order to determine the critical event to avoid during the drying stages.

FDM has been traditionally used only for determining collapse temperatures, but the latest generation equipment can also identify crystallisation phenomena, the potential for skin/crust formation, and the effects of annealing on ice crystal growth and solute structure.


Freeze drying is a crucial process for a variety of industries, especially pharmaceutical and biotech as it extends the shelf-life of products and makes the material safer and more convenient for transportation. In order to achieve a successfully freeze dried product, the optimised formula which gives you the best results needs to be developed. As part of our laboratory services, Biopharma Group can provide you support throughout the formulation development process including your pre-formulation study. With our in-house equipment and expertize, Biopharma we can perform DSC analysis, freeze dry microscopy, frozen stage analysis MicroPress cake robustness analysis and much more.

Get in touch today to discuss your requirements or to discover more.

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