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Impact of controlled nucleation temperature in freeze drying

Article courtesy of SP Scientific

The ability to control nucleation in freeze drying is now possible by using ControLyo Nucleation on Demand Technology originally developed by Praxair1. 

Figure 1 shows the impact of controlled nucleation on the primary drying phase of freeze drying.  A high degree of super-cooling leads to small ice crystals, which in turn results in product morphology of small pores during and after sublimation. These small pores create a high resistance (Rp) to mass flow (water vapour leaving product via sublimation). Because of the high resistance, primary freeze drying is relatively slow2,3. When nucleation is forced at higher temperatures, larger ice crystals are formed, which result in larger pore structure. This morphology of larger pores allows for lower resistance to mass flow and faster primary drying time. 

In the first series of experiments, the impact of nucleation temperature on product resistance was explored using a 5% sucrose solution. In two cycles, nucleation was not controlled and SMART cycles were run. Subsequently, we nucleated the same solution at -2oC, -3oC and -5oC and SMART was utilised to determine and complete the cycles. 

Figure 2 shows product resistance (Rp) plotted against dry layer thickness (Ldry - also calculated by SMART) for each of the experimental runs. Two points are worth noting in the graph:

  1. The reproducibility of the data as evidenced by the overlap of the two separate runs nucleated at-3oC .
  2. The ability to discern differences in resistance with only a 1oC change in nucleation temperature. 

As mentioned above, product resistance is one of the most important critical product parameters in freeze drying4.  Cake shrinkage, collapse and cracking, even subtle changes in the cake inner morphology (micro-collapse) can be examined by the product resistance data5. The complementary use of product interface temperature (Tp-mtm) and product resistance (Rp) provides a direct link between temperature during primary drying and product quality.  This is clearly illustrated in the example in Figure 36.

In this example, three (3) separate runs were performed in the Lyostar 3 freeze dryer, without controlling nucleation. At the end of the runs, Rp was plotted against Ldry. The run with the green triangles and the run with the open blue squares  are classic resistance plots that one would expect to see. The run with the open red circles reveals an anomaly that occurs about half way through the primary drying.  The resistance of the product drops significantly for a short time period and then continues its normal course, similar to the others.  During this short time interval, the pressure in the chamber increased. As a result, product temperature at the ice-sublimation interface increased, as well, and resulted in structural loss (collapse) in this particular region of the cake. Once the pressure control was regained, the product temperature decreased to below the collapse temperature and the cycle was completed. When the freeze dried cake was examined, the increase in temperature and subsequent collapse that occurred during the pressure loss can be seen as a layer of decreased structural integrity in the cake. 

This example offers opportunity to use product resistance as a process analytical technology (PAT) tool to perform “In-Process” analytical analysis.  If Rp vs. Ldry was reported and visible in real time, the anomaly that occurred would have been seen during the run, and would have predicted that the cake would likely have morphological anomalies.

Credit: Mark Shon

References:

1. Sever, R.R., (2010). ControLyo Nucleation On-Demand Technology. SP Scientific Lyolearn Webinar. http://www.spscientific.com/LyoTech-Center/LyoLearn-Webinars-Archive.aspx

2. Pikal, M. (2011).  Quality by Design and Scale-Up Issues in Freeze Drying: The role of controlled ice nucleation.  SP Scientific Lyolearn Webinar.  http://www.spscientific.com/LyoTech-Center/LyoLearn-Webinars-Archive.aspx

3. Searls, J.A., Carpenter, T., Randolph, T.W. (2001). The Ice Nucleation Temperature Determines the Primary Drying Rate of Lyophilization for Samples Frozen on a Temperature Controlled Shelf.  J. Pharm. Sci., 90:860-871.

4. Gieseler, M. (2011). The Relevance of Product Resistance on Primary Drying.  SP Scientific Technical Briefs.  http://www.spscientific.com/Lyotech-Center/Lyolearn-Tech-Brief.aspx

5. Gieseler, H., Kramer, T., and Pikal, M.J. (2007). Use of Manometric Temperature Measurement (MTM) and SMART Freeze Dryer Technology for the development of an optimized Freeze-Drying cycle. J. Pharm. Sci., 96:3402-3418.

6. Gieseler, H. (2011). Unpublished Results.

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