Increasing Lyophilization Productivity, Flexibility, and Reliability Using Liquid Nitrogen Refrigeration–Part 2

Dec 01, 2007
Volume 20, Issue 12


In part 1 of this article, published in the November 2007 issue of BioPharm International, the lyophilization process, related equipment, and refrigeration requirements were discussed. This part 2 introduces key design considerations related to cryogenic refrigeration systems and provides guidance on relative cost factors for using cryogenic versus mechanical refrigeration in lyophilization operations. The article also discusses reliability and maintenance requirements; flexibility in terms of operating temperature range, cooling rate capability, and precision of temperature control; cost of ownership; footprint; and environmental impact.

Flexible, precise, and reliable cooling of the shelves and condenser in a lyophilizer is critical to effectively freeze-dry and protect a broad range of sensitive, high value pharmaceutical products. Conventional cooling methods, as introduced in part 1 of this article, include using either mechanical or cryogenic nitrogen-based refrigeration. Part 2 begins with an overview of the fundamental thermodynamic characteristics of cryogenic nitrogen and the factors influencing the maximum amount of refrigeration available from cryogenic systems. An optimal refrigeration design provides flexible, robust cooling at reduced cost of ownership versus mechanical alternatives.

We will now review the fundamental thermodynamic characteristics of cryogenic nitrogen, and the factors influencing the maximum amount of refrigeration available from the cryogenic fluid.


Liquid and Gaseous Nitrogen

Figure 1.
Pressure and temperature are two key intensive thermodynamic variables that determine the state of any saturated fluid and thus the refrigeration available from it. The saturation pressure of liquid nitrogen as a function of temperature is shown in Figure 1.

Maximum Refrigeration from Liquid Nitrogen

Figure 2.
Saturated liquid nitrogen stores refrigeration in the form of its latent heat of vaporization, i.e., the energy associated with the liquid changing state to gas without a temperature change. Boiling the liquid nitrogen (LN2) to gaseous nitrogen (GN2) provides the refrigeration in a cryogenic heat exchanger. Figure 2 illustrates the available latent heat as a function of operating pressure and temperature. The lower the pressure and temperature, the more refrigeration is available for recovery.

Maximum Refrigeration from Gaseous Nitrogen

Sensible heat is the energy associated with a change in the temperature of a substance. Depending on the cryogenic system design, the sensible heat from warming the gas may also be recovered in the same or another heat exchanger. The two key factors that determine the maximum amount of refrigeration recoverable per unit mass of cryogen are the heat capacity and the temperature rise of the fluid.

Maximum Refrigeration Recoverable from Liquid and Gaseous Nitrogen

Figure 3.
We can calculate the total recoverable refrigeration from cryogenic nitrogen by adding the two key components, i.e., the latent and sensible heat. Figure 3 shows an example of total available refrigeration as a function of gas exhaust temperature for near-atmospheric-pressure operation. The latent heat from vaporizing the liquid and the sensible heat from warming the gas each account for approximately 50% of the available refrigeration capacity under typical operating conditions. At higher pressures, the latent heat of vaporization decreases, as shown in Figure 2, thus reducing the total available refrigeration.

lorem ipsum