Why pressure gradients are the main drivers in improving sublimation rates

From ski slopes to marble race tracks, a good height gradient is an absolute must to generate speed. Your freeze dryer is no different, but it appreciates temperature and pressure gradients rather than height gradients. Contrary to common belief, very low-pressure values might be hurting the rate of the freeze-drying process, rather than improving it. Instead, use this post to learn how pressure gradients can increase lyophilization speed.

I was cleaning up the attic last weekend and I stumbled upon a childhood treasure, my marble run. Oh, I spent so many hours with the neighbourhood kids trying to build the fastest tracks. Of course, the steeper the slopes, the faster the marbles flew down. It was a real challenge trying to defy gravity and avoid boring races.

It’s not only children racing marbles that love nice slopes. Your freeze dryers also appreciate a good gradient, but with pressure rather than height.

One of the biggest misconceptions in laboratory freeze drying is that very low chamber pressure will speed up the sublimation process.

True, if the chamber, i.e. vapor pressure is too high, the product temperature will also rise, leading to unwanted consequences such as sample melting.

Naturally, one would then assume that very low pressure would result in very fast sublimation rates. This is categorically false due to one main reason.

The driving force in freeze-drying is the temperature difference and therefore the vapor pressure difference between the sublimation surface of the sample and the ice layer on the condenser. In principle, the bigger the difference, the faster the process.

As pressure directly influences sample temperature, lower pressures lead to lower sample temperatures. As the temperature of the sample decreases, so does the difference between sample temperature and condenser temperature. It is precisely this smaller temperature difference that causes the sublimation process to slow down. Reducing the pressure below the vapor pressure of the condenser could even lead to sublimation of the ice from the condenser towards the vacuum pump.

The direct effect of pressure on sample temperature can be demonstrated with the measured values of water temperature according to chamber pressure when no extra heat is added (table below). A temperature difference of 15 °C to 20 °C between sample and condenser is frequently recommended. Thus, for condenser temperatures of -55 °C, chamber pressure values lower than 0.40 mbar would be counterproductive. For condenser temperatures of -105°C, vapor pressure values lower than 2.6×10-4 mbar would likely slow the sublimation process rather than speed it up.

freeze drying, water, temperature, pressure, gradient

I do have something else to add. In the last freeze-drying post , I discussed how addition of heat can help speed up the lyophilization process. Indeed, to generate a proper gradient, heat from the environment or an external source needs to be added to the system to facilitate sublimation. If not enough heat is applied, the process can slow down or stop completely.

In a freeze-drying chamber, heat transfer by convection is possible due to the remaining air molecules in the space. At lower chamber pressures, fewer air molecules remain the in the chamber and the amount of heat transfer by convection decreases. This results in a slower freeze drying process.

To test how chamber pressure influences the rate of sublimation, we measured the sublimation of ice at two different chamber pressures, 1 and 0.2 mbar. After 7.5 hours of freeze drying, 28% of the ice was sublimated at 0.2 mbar and 32% of the ice was sublimated at 1 mbar pressure values. However, when the sample shelves were heated, the rate of sublimation dramatically increased at higher chamber pressures. In this case, after 7.5 hours of sublimation, 61% of the ice was sublimated with a chamber pressure of 0.2 mbar, whereas 75% of the ice was sublimated at 1 mbar.

The take home message is that using low chamber pressure settings with your freeze dryer does not always result in faster sublimation rates. Instead, bear in mind that

well-balanced parameters can significantly increase the sublimation rate.

Thus, it is recommended to optimize the pressure settings when designing a freeze-drying method, rather than simply applying low pressure settings.

Are there other ways to speed up the freeze drying process? You bet! I’ve already discussed how shell freezing can improve lyophilization speed and how heated shelves can increase freeze drying rates . No pressure, but make sure you stay tuned for more posts on how to optimize your freeze drying process.

Till next time,

The Signature of Bart Denoulet at Bart's Blog