INSIGHT - Comments
Volume 4 No. 11 Can we really optimize a lyophilization or freeze-drying process?
Tom
Hi - how are things going, long time no see.
I have read the last issue of Insight with my usual avid interest and, unusually, I have failed to grasp it. One of us (probably me) is obviously having a bad hair day which is quite clever as we do not have a full head of hair between us.
Using equation 2 you derive equation 3 by stating that everything that is concerned with the product is fixed and therefore the vapour throughput is related to pressure. I have no problem with this, if something is denser (at higher pressure) and you pass the same volume then more mass will be transferred, providing that the condenser can scavenge the vapour quickly enough to maintain the pressure gradient \(although I suspect you would have problems with a oil pump).
However this is not the full story
The rate limiting step in freeze drying is the vapour clearance from the cake, this allows the local pressure at the ice interface to be low enough to be below the saturated vapour pressure at the temperature of the ice interface, otherwise sublimation cannot occur. If heat is supplied to the system the ice will increase in temperature until the system pressure is below the SVP at the new product temperature, at this point sublimation will begin and the temperature will stabilise (or try to) by subliminative cooling. Hopefully, melting or collapse does not occur on the way.
If the process were to be run at 300 mbar then the pressure above the interface has to be greater than this and in order to achieve any sublimation. In this case the product temperature would be too high. By definition anything above 6 mbar (equivalent to 0 deg C) would result in any aqueous system melting.
Therefore, irrespective of the freeze dryer design, my belief is that the laws of physics rule, as always, and you could not use this strategy to speed up drying.
Of course, I may have totally got hold of the wrong end of the stick and I would appreciate any comments
Take care
Kev M
Dr Kevin Murgatroyd
E-Mail: Kevin.Murgatroyd@bllpharma.com
November 2001
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Response by Dr. Jennings
Hi Kevin:
I am sorry for any confusion you may have had with this INSIGHT. When a reader experiences trouble with understanding then it is the fault of the writer not the reader. What is sometimes self-evident to the writer may not be self-evident to the reader and there could be “the rub”.
Let me see if I can shed some light on the subject by making some statements that I find to be self-evident.
1. The sublimation rate of ice, at a constant pressure at the interface, is directly related to the heat flux (q) shown in equation 1.
2. The pressure at the interface approached that of the drying chamber throughout the primary drying process.
3. Increasing “q” some 20 times, without increasing the shelf-surface temperature, will increase the sublimation rate some 20 times provided the pressure in the chamber remains the constant and the pressure at the interface is not increased significantly
4. Under these conditions, there will be no significant increase in the product temperature but only the time of drying will be altered. However, there would have to be a significant increase in the shelf-fluid temperature.
5. However, if the configuration of the dryer is a limiting factor, then using the above shelf-fluid temperature, an increase in the sublimation rate could result in an increase in chamber pressure which will then result in an increased product temperature and also an increase in the shelf-surface temperature. Thus the configuration of the dryer will define the limits of “q”.
I can see that the age old problem of clinging to the shelf-fluid temperature has come back to haunt us. Where I failed was not to emphasize the fact that in order to increase ‘q”, for a given set of product and shelf-surface temperatures, there would have to be an increase in the fluid temperature.
I hope that we are in agreement at this point and if so I would appreciate it if you allow me to publish your comment and my response next month for if you had trouble with the INSIGHT so did others.
Thank you forreading the INSIGHT and taking the time and trouble to write to me.
Wish you and yours a Happy Thanksgiving Day from us here in the States.
Tom
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Response by Dr Kevin Murgatroyd
I now see where you are going but I still have difficulties with any form of
practicality
Sure, if you can remove the vapour and as long as the heat flux supplied is balanced by the energy absorbed in sublimation then the interface will remain constant. As the heat input is proportional to the mass of water sublimed putting heat in faster would increase the sublimation rate and thus reduce primary drying time.
However, the rate limiting factor is not the ability of the freeze dryer to remove the vapour, if this was the issue you could just use steam ejectors, but the resistance of the dried cake above the freeze drying interface to the passage of vapour.
If you cannot transport the vapour through the dried cake then the local partial pressure of water vapour above the interface will rise, stop sublimation and you will then get a rise in temperature leading to melting or to collapse.
The issue is therefore not to alter the configuration of the drier but to alter the configuration of the product.
If you wish to use this correspondence in Insight please do, debate always makes things more interesting
Best regards
Kev M
Dr Kevin Murgatroyd
E-Mail: Kevin.Murgatroyd@bllpharma.com
November 2001
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Response by Dr. Jennings
Dear Kevin:
I am certainly a firm believer that dissidence does breed discovery.
What you say is true about the cake impeding the flow of water vapor will result in an increase in the product temperature because of an increase in the pressure at the sublimating interface. However, that is not the issue here.
The issue is that the design of most freeze dryers today consist of a separate drying chamber and condenser chamber, the conductance limiting factor will be the dimensions of the piping between the chambers.
Thus when the sublimation rate exceeds the gas conductance between the two chambers, the pressure in the drying chamber will increase in order to increase the throughput. The increase in the chamber pressure will then result in an increase in product temperature and shelf-surface temperature.
It should be self evident then that the options to continue to dry using the same drying parameters (chamber pressure, product temperature and shelf-surface temperature), at a substantial increase in the sublimation rate, will be either to change the configuration of the piping between the chambers or reduce the amount of product on the shelves. If we wish to continue with the same amount of product in the chamber then we must change the configuration of the piping between the chambers. How the water vapor load is removed or if the increased water vapor load exceeds the capacity of the condenser are issues not addressed in this INSIGHT.
Best regards.
Tom
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