What is freeze drying (or lyophilization)?
Freeze drying is cool – literally! It’s the only method of drying that doesn’t require raising the temperature of a sample and it works by using sublimation. And water only sublimes because it has a triple point. So if you want to understand how freeze drying works, Pharma Drama has you covered.
Welcome to Pharma Drama, the channel where we look at the science of healthcare and healthcare products. In this video I’m going to talk about a drying method that’s super-cool – freeze drying. So get yourself warm and let’s get into it.
If you’ve watched my other videos on drying and drying methods, and if you haven’t I highly recommend them – you’ll know that water is usually removed from materials by evaporation. Freeze drying, which if you are American you might know as lyophilisation, is interesting however, because it’s the only method of drying that doesn’t evaporate water. Rather, it removes water by sublimation. I guess, therefore, that I should start by explaining the difference between evaporation and sublimation.
Since most pharmaceutical materials are at room temperature, any water they contain should be in the liquid state. When we dry the material, water transfers to the surrounding air and hence becomes a vapour. When a material transfers from the liquid state to a vapour the process is called evaporation. I’m sure you’re familiar with evaporation – it happens when you sweat for instance. There is a special case, however, when a material can go directly from the solid state to a vapour, without becoming a liquid, and that is called sublimation. Sublimation is quite an unusual phenomenon and not many chemical compounds do it. The reason is because in order to sublime a compound has to have a special property called a triple point. Luckily, from the point of view of drying, water is one of those rare compounds that does have a triple point!
Which leads to the question ‘What is a triple point Simon?’ – and that of course is a good question. The answer can be found by considering phase diagrams. In my experience, people find phase diagrams rather complicated (or should I say boring…?) but they are easy to understand if you know what you are looking at. A phase diagram simply shows what phase (that is solid, liquid or gas) a material exists in as a function of temperature and pressure. So, if we consider water at atmospheric pressure then below zero degrees centigrade it exists as a solid (ice), between zero and one hundred degrees centigrade it exists as a liquid (water) and above one hundred degrees centigrade it exists as a gas (steam). I’m pretty sure you knew that already. What you may not know is that as we change pressure, the temperatures at which water converts between phases will change. I can still remember from physics class at school putting water under vacuum in a round-bottomed flask and then holding the flask in my hand – as water boils at a much lower temperature under vacuum you can make it boil from your body heat!
If we were to create a plot of the phases of water as a function of temperature and pressure we would get something that looks like this. It looks rather complicated but fear not! It’s actually quite simple. At atmospheric pressure (ten to the five Pascals) you can see water is a solid, then a liquid and finally a gas as we increase the temperature, exactly as we expected. As the pressure is reduced the melting point of water increases, and the boiling point reduces. This trend continues with reducing pressure until a special point is reached where the lines intersect – this value, called the triple point, occurs at a pressure of six hundred and ten Pascals and zero point zero zero seven five degrees centigrade. It’s called a triple point because water exists in all three phases of matter at the same time, if you can imagine that… (no, me neither).
The triple point itself is not so important though – rather, look at what happens to the phases of water at pressures below the triple point. At low temperatures water exists as solid ice, as we expect, but as we heat it up there is only one change in phase – from a solid to a gas. In other words, there is no liquid phase at all. This is why materials that have a triple point are able to sublime; at pressures below their triple point, they never exist in a liquid phase and so are always able to change phase from a solid directly to a gas. I should say here that there are not many useful solvents that have a triple point like this. Water obviously, and very handily, is one and tertiary butanol is another. But that’s about it!
That’s all well and good, but how does this translate to a method of drying, I also hear you ask? After all, that’s the point of this video. And I can answer that with this diagram. It shows four points, marked one to four, that indicate how we dry a material in a freeze-drier. We load the material to be dried into the freeze drier at room temperature and pressure, indicated by point number one on the diagram. Then, keeping the pressure constant, the temperature of the material is reduced, such that the water becomes ice. This is represented by the change from point one to point two, and is why the technique is called freeze-drying! Next the drier places the frozen material under vacuum, moving the sample from point two to point three. It is absolutely critical that the pressure is reduced to less than six hundred and ten Pascals – can you see why? It’s because we can then heat the sample back to room temperature and as we do so the water will transform from a solid to a gas. This is shown by the line from point three to point four. If the pressure is not reduced to below six hundred and ten Pascals, then water will not sublime. You will see that we have then dried the sample but at no point have we increased the temperature above room temperature! Pretty clever stuff I think you’ll agree. For completeness, I will say that it is possible to heat the sample above its starting temperature if you want to, and this is sometimes done to dry materials fully.
Since freeze-drying is the only drying method that does not involve heating the sample it is perfectly suited to drying materials that are sensitive to heat, such as vaccines, which are often RNA, and biological drugs, which are proteins. Because samples that are dried with freeze-drying start as solutions, there is a lot of water to freeze. When the water sublimes, it leaves behind many void spaces, and so freeze-dried materials tend to be highly porous and have a very high surface area. To give you an example, on the screen is an image of a freeze-dried material, taken with a scanning electron microscope. I think you can see how porous the material is. This is very beneficial, because surface area is a key factor in how fast a material will dissolve. The higher the surface area the faster the rate of dissolution. So freeze-drying a material is a good way of making a fast-dissolving material.
Moreover, because the initial freezing step can be quite rapid, freeze-dried material are often amorphous (that is, the molecules are randomly ordered). Again, amorphous materials are very fast dissolving, because there is no crystal lattice energy to overcome. So freeze drying typically results in an amorphous material with a huge surface area, and so they are very fast dissolving.
These benefits are used specifically in two types of formulation; powders for injection and oro-dispersible tablets. A powder for injection sounds odd – no one would want to inject a powder and for good reason! Small particles in the blood would block capillaries, and that would be very bad. So powders for injection need to be dissolved first and this is done by adding a solution that is isotonic (or the same composition) with blood. It’s usually nought point nine percent saline solution. It is absolutely essential that the powder dissolves instantly and completely in the saline solution and the fact it is freeze-dried is what ensures this.
Oro-dispersing tablets are very different. They are tablets that are designed to be taken without water – you place one on your tongue and the moisture in your mouth makes them dissolve. And why do they dissolve so quickly? Because they are freeze-dried! So they are porous and amorphous. If you’ve ever held one of these tablets you will see that they are very light and easy to crush, precisely because they are porous.
So there we are. Freeze drying removes water from a sample (usually a solution or suspension) by sublimation and it is only possible to do this because water has a triple point. At pressures below the triple point water does not exist as a liquid. So if we freeze a sample and then hold it under vacuum, we can sublime any water off by heating it back to room temperature. In so doing, we usually make a highly porous material that is amorphous and so is very fast dissolving. We use these benefits to make products that need to be fast dissolving, such as powders for injection and oro-dispersible tablets, or to dry samples that are likely to be degraded by heat, such as biological drugs or vaccines. We can remove any solvent that has a triple point in this way, but the only other pharmaceutically useful solvent that can be removed by freeze drying is tertiary butanol.
Hopefully you found that very cool. If you did, please hit the like button and consider subscribing – it really helps the channel. Otherwise, thank you so much for watching, and I’ll see you again soon.
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