taPrime Consulting Ltd

Freeze Drying is a science and not an art

State Diagram

Freeze drying is an established process in the biotechnology, pharmaceutical, diagnostics and food industries. Wherever a water based product has a short shelf life, even under refrigeration, freeze drying may be used to improve stability, and is a very effective method of producing a sterile solid product. The process has only 3 controllable variables:

  • Temperature
  • Time
  • Pressure

For every freeze dried product there are limits to these variables which mark out the edges of failure. These limits can be defined, in advance, from laboratory scale measurements.  In many ways the State Diagram maps the edges of failure.  The example shown, above right, is for a water/sucrose system.  With clearly defined edges of failure and only 3 process variables, Freeze Drying aligns easily with the concepts of Design Space mapping and Quality by Design.

Despite having only three controllable process variables, freeze drying can be problematic.  Problems often arise because freezing process does not follow text book chemistry - chemistry which applies to systems that are in thermodynamic equilibrium. Understanding the science behind non-equilibrium kinetically controlled processes is the key to rational process and product design - Quality by Design which leads us away from wasteful trial and error experimentation.  On freezing, a solution does not simply solidify but separates into ice and a concentrate. Unless the concentrate is physically and chemically stabilised, the process and the product are likely to encounter problems. Successful freeze drying requires the product to be frozen to a glassy state and maintained in that state throughout the drying cycle. Eutectic crystallisation is very much the exception and not the rule.

Tg' (Tg prime) is the key to success. It defines the temperature to which the formulation must be frozen, and in combination with the solids content, fill volume and vial geometry allows us to calculate the most appropriate pressure and time for primary drying (ice sublimation).

The (red) glass curve is important for controlling secondary drying (water desorption) and for understanding product stability.

Want to know more about the science of freeze drying?  Our taPrimer archive contains a series of short tutorial articles on the science behind freeze drying.

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