Sublimation science of Primary Drying in Pharmaceutical Lyophilization

In continuation from INTRODUCTION TO PRIMARY DRYING IN LYOPHILIZATION (https://pharmaperception.blogspot.com/2019/03/introduction-to-primary-drying-in.html)


Once freezing (and annealing if necessary) are complete, as we kick start the vacuum pump, ice sublimation begins, and the cycle moves into the primary drying phase. Primary drying will continue until all of the pure ice, surrounding the solute components of formulation is removed.

Hence, Primary drying is nothing but sublimation. Hence, it makes sense to understand Sublimation science to know about primary drying in lyophilization.

Sublimation is when a solid (ice) changes directly to a vapor without first going through a liquid (water) phase. Sublimation is the direct conversion of a solid to a gas or vapour. 

Sublimation in freeze drying process requires,
i) A Completely frozen / solid formulation
ii) Vacuum below triple point of water
iii) Sufficient heat to provide energy for sublimation


As lot of literature available on this topic, lets have a brief  look into it.

The above phase diagram is taken from SP scientific website and it figured out the behavior of substances under various circumstances. 

Initially, let us start with Liquid phase (Water) as the formulation we prepare will be in liquid (bulk solution). The temperature of bulk solution will be reduced to sub zero levels during freezing step. But keep in mind that, it will be performed at atmospheric pressure only. This results in freezing of water in the formulation. This is the conversion of liquid phase to solid phase.

Now, we have solid ice. Unless the freezing step, where pressure is not the major concern, sublimation requires vacuum depending on the vapor pressure of solvent. From the phase diagram provided above, once freezing occurs, by reducing the pressure to below atmospheric pressure, sublimation gets initiated. At a pressure of 4.58 torr / 0.006 Bar/ 0.006 Atmospheric pressure ice begin to convert as vapor. Remember, this happens at low pressure.

The next transition is condensation where vapor gets converted to liquid. The vapor collected during sublimation step (Primary drying) will go to condenser and converted to liquid (But as condenser is at the sub zero temperatures, the water immediately gets converted to ice which is later removed through defrosting). 

For much clarity, pls have a glance https://www.youtube.com/watch?v=HEzkHqWIiKM.

So far, we have seen the phase transitions in related to freeze drying. Now let us know more about sublimation behavior. 

Sublimation always starts at an open surface and then moves inwards into the sample. After some of the ice is sublimated, the sample exhibits two distinct regions, namely: the dry layer (from which ice crystals have sublimated) and the frozen layer (where ice crystals are still present). These two regions meet at the so-called “ice interface”, “Sublimation interface”, “freeze-drying interface” or, simply, “interface”. 

The sublimation step requires very careful control of two of the key variables of the freeze-drying process: temperature and pressure.

While sublimation can occur at atmospheric pressure, the process is rather slow because the gas molecules from the ice must find their way through the atmospheric gases that are bombarding the surface of the ice. This slow process by which the water molecules leave the ice surface is known as “diffusion”.

The rate of sublimation of ice from the frozen product depends on the difference in vapour pressure between the product and the ice collector. It can be increased by decreasing the pressure over the ice surface. This can be accomplished by placing the frozen material in an evacuated chamber, where molecules will migrate from the sample to an area of lower pressure. 

Although the extent to which the pressure is reduced increases with increasing vacuum in the chamber, there is relatively little change in sublimation rate of the water from the ice surface. Only when the pressure in the chamber becomes less than the pressure of the ice is there a marked increase sublimation rate. The vapor pressure of ice is dictated by the ice temperature.

That's it for the day folks...

In the next blog, we will meet with concept of determination of critical temperatures. 

Till then, TATA.....

Yours,

Teja Ponduri....................