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Freeze Drying with Liquid Nitrogen

There are two key considerations in providing refrigeration to a process:

1) The refrigeration temperature required

2) The maximum cooling power required


First, the refrigeration temperature required by the process determines the type of refrigeration system needed. Commercially available refrigeration technologies have different fundamental thermodynamic limitations in terms of operating temperature, cooling rate capability, efficiency, and cooling power. Second, the peak and turn-down capacities of the chosen type of system are determined by the refrigeration load profile over time.


Freeze-drying equipment typically relies on mechanical refrigeration systems, which use compressors and refrigerants as the cooling agent. However, the performance of these systems is limited by the coldest temperature they can achieve and the cooling rate. They also require periodic maintenance and the refrigerants present a threat to the environment and climate.


Cryogenic Systems


Since the early 1990s, cryogenically refrigerated freeze-dryers have been claiming an increasing market share. These reliable, flexible, and well-proven systems use liquid nitrogen (LN2) or cold gaseous nitrogen (GN2) to cool the components of the freeze-dryer.

Cryogenic systems, in contrast, provide practically constant cooling power throughout the temperature ranges of any lyophilization cycle. Some of the advantages of cryogenic systems are:


→ Increased cooling performance vs. conventional mechanical refrigeration systems:

– Faster cooling rates with near-linear cooling even at temperatures below -30°C

– Significantly lower shelf temperatures can be achieved (down to -65°C)

– Precise temperature control

→ Increased reliability and low maintenance due to simplicity of the design and absence of moving parts

→ Independent cooling of freeze-dryer shelves and ice condenser

→ Mid- and large-scale systems require significantly smaller equipment footprint

→ Very low noise levels

→ Environmentally friendly with zero emissions

→ Low capital investment required


Cryogenic systems are capable of providing a rapid, constant cooldown rate throughout the entire ultralow temperature range. Mechanical refrigeration systems, on the other hand, cannot maintain their initial cool-down rate. This is probably the reason why original equipment manufacturers (OEMs) of freeze-dryers relying on mechanical compression equipment typically specify the cool-down rate in terms of overall time to reach a certain temperature.


Compressors are ill-suited for short duration peak loads followed by extended operation at low load and ultralow temperatures. Under such conditions, compressors run inefficiently, using a lot of power while providing minimal cooling. They are designed to meet the short period peak load, yet are operated under suboptimal efficiency conditions for most of the lyophilization cycle time. Cryogenic systems, on the other hand, easily meet the variable refrigeration demands of lyophilization. Unlike mechanical systems, cryogenic systems operate with only small changes in thermal efficiency during the entire process cycle.


In summary, LN2 systems offer a wider processing window of operation leading to added flexibility and productivity benefits. They do not suffer from the fundamental thermodynamic limitations of mechanical refrigeration systems, such as deterioration of efficiency and cool down rate, or limits on operating temperatures. Lyophilization production managers often worry about the breakdown of the mechanical compressors on their freeze-dryers, which would lead to the loss of entire batches. A cryogenic refrigeration skid contains no moving parts unlike compressor-based mechanical refrigeration skids. Properly used and maintained, LN2/GN2-based refrigeration systems can run for decades with minimal maintenance requirements and a low chance of failure.


Original article: Increasing lyophilization productivity, flexibility and reliability, using liquid nitrogen refrigeration.

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