Increasing Lyophilization Productivity, Flexibility, and Reliability Using Liquid Nitrogen Refrigeration–Part 1 - - BioPharm International


Increasing Lyophilization Productivity, Flexibility, and Reliability Using Liquid Nitrogen Refrigeration–Part 1

BioPharm International
Volume 20, Issue 11

Low Temperature HTF

The thermophysical properties of the HTF circulating in the freeze-dryer have a significant impact on the unit's performance. Many of these properties are highly temperature-dependent. For example, the viscosity of the HTF can significantly increase as the temperature declines and approaches first the HTF pour point and then the freezing point. Although high pump-around rates ensure low temperature differences between the shelf inlet and outlet temperatures of the HTF, they may also lead to significant frictional parasitic heat generation. Hence, care must be taken in choosing the proper HTF. Table 1 summarizes key properties of some popular HTFs.

Mechanical Refrigeration Systems

In mechanical systems, compressors driven by significant electric power provide the active cooling. In general, ultralow-temperature mechanical systems that match the refrigeration demand at the necessary operating temperatures are increasingly complex and less flexible. They involve multistage or multirefrigerant cascade compression systems.12 The complex refrigeration package includes compressors, heat exchangers, expansion devices, evaporators, and extensive controls. Necessary auxiliary systems include a cooling water loop, oil lubrication system, and an extra power infrastructure (including an extra supply and backup system) to support the significant power draw of the compressors. The rotating compression equipment involved can be screw or reciprocating types, with a trend towards costlier screw compressors because of their better reliability.7,10,12 The cooling duty is provided by appropriately chosen refrigerants, such as R-23, R-404a, R-507, and R-508b (an azeotropic mixture of R-23 and R-116).12 The refrigerants are first vapor compressed, condensed, adiabatically expanded, and evaporated 1) in a heat exchanger to cool the HTF, and 2) directly in the condenser to freeze out the solvent ice. These refrigerants are typically single or multiple component mixtures of hydrofluorocarbons (HFCs), which are often toxic or flammable.

Cryogenic Refrigeration Systems

Cryogenic cooling systems recover the stored cold from liquid nitrogen in specially engineered cryogenic heat exchangers. The necessary auxiliary systems include a liquid nitrogen storage tank, a set of cryogenic valves, and piping from the tank to the refrigeration skid. All of these components are highly insulated to minimize cryogen losses, e.g., by vacuum jacketing or superinsulation. The cryogenic LN2/GN2 cools the HTF in an initial cooling circuit. Typically, a second LN2/GN2 cooling circuit cools the condenser by direct expansion in the coils or plates. A more advanced cryogenic refrigeration system is noq available that uses a single nonfreezing cryogenic heat exchanger to simultaneously cool both the shelves and the condenser at different temperature set-points using two HTF loops.


As demand for parenteral and biologically-derived products expands, companies are increasingly using lyophilization to protect and stabilize their sensitive pharmaceutical and biologic products. Freeze-dryer performance is key to achieving the required activity, stability, quality, and shelf-life for the finished products. As products are becoming more complex, cryogenic nitrogen refrigeration is gaining favor over mechanical refrigeration because of its inherent reliability and responsiveness to meet stringent and flexible cooling profiles while achieving ultra-low shelf and condenser temperatures. This will be further discussed in Part 2 of this article, to be published in the December 2007 issue.

Balazs Hunek, PhD, is a senior manager of technology, 630.320.4242,
Alan Cheng, PhD, is a senior development associate, R&D, and John Capettini is a manager of global applications market development, all at Praxair, Inc.


1. Rey L. Introduction: the saga of freeze-drying. Pharma Techn 2004;Mar 5.

2. Thomas P. The needle gets another shot. 2006. Available from

3. Przic DS, Ruzic DS, Nenad NL, Petrovic SD. Lyophilization—the process and industrial use. Chem Ind 2004;58(12):552.

4. Shanley A. PAT advances freeze dryer control. Available from:

5. US Food and Drug Administration. Guide to inspections of lyophilization of parenterals. Available from:

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