INTRODUCTION TO PRIMARY DRYING IN LYOPHILIZATION

Hi pharma folks,

Lets proceed towards our topic of perception……PRIMARY DRYING in Lyophilization.

Till now we have gone through the freezing step, where In the freezing stage, the solution or product to be processed is cooled down to a temperature where all the material is in a frozen state.

Once the formulation was frozen completely, then it further proceeds for drying. Actually any pharmaceutical formulation that has to be lyophilized, has to pass through two stages of drying namely primary drying and secondary drying.

The frozen water (if aqueous formulation) or solvent (If non aqueous formulation) is removed through the process called sublimation (A process in which the ice crystals / frozen solvent gets converted to vapour without passing through the phase of liquid). Once there is no ice is available to sublime (at the sublimation interface) then it is called end of primary drying step.

So, as a formulator, you may have some questions…

• ·         What is the temperature to be chosen for primary drying?
• ·         For how much time it must be carried out?
• ·         How do we know that this is the time to stop the primary drying step?
• ·         What are all the equipment/instrument we should have for determination of primary drying end point?
• ·         What to do if we don’t have any equipment/instrument for determination of primary drying end point?
• ·         Does pressure have role in primary drying? If so, what is the set point?
• ·         What are the other factors affecting the primary drying process?

So, lets imagine, we have a frozen formulation and a lyophilizer with us. Now first I must know the answer for basic needs to proceed for primary drying that I can control. They must be set as a recipe in the lyophilizer right at the beginning itself.

• ·         Shelf set temperature
• ·         Chamber vacuum
• ·         Condenser temperature
• ·         Duration of primary drying

If we know the answers for setting above parameters, then the job is almost done.

Shelf set temperature:

The temperature is required for Sublimation, as it requires heat energy to drive the phase change process from solid to gas.

Before setting the shelf temperature, let’s have an idea about the shelf. 

Shelf in any lyophilizer act as a heat exchanger, removing energy from the product during freezing, and supplying energy to the product during the primary and secondary drying segments of the freeze-drying cycle. 

This energy exchange is traditionally done by circulating a fluid through the shelves at a desired temperature. 

Usually in many lyophilizers, shelves will be connected to the silicone oil system through either fixed or flexible hoses. 

The temperature is set in an external heat exchange system consisting of cooling heat exchangers and an electrical heater. 

The fluid circulated is normally silicone oil. 

This will be pumped around the circuit at a low pressure in a sealed circuit by means of a pump.

A commercial lyophilizer shelf was shown below. 

So, to maintain the product at a desired temperature, set the shelf temperature as closer as possible to the required product temperature. 

But keep in mind that, required product temperature is always 2-3 °C colder than the critical temperature or collapse temperature. 

(Remember that, Each product has a unique critical temperature. It is necessary to keep the product temperature safely below this critical temperature during primary drying to avoid collapse. we will have a broader look at it in later posts).

For example, If my product critical temperature (Collapse temperature) is -22°C. so, I should maintain my product at around -22°C. It means, the desired product temperature should be 2-3° colder than -22°C to prevent the product from collapse. Hence, I may chose to dry my product at a shelf temperature set at -24°C to -26°C.

Note: Sometimes, the product can be dried at a shelf temperature equal to collapse temperature also.

Chamber pressure:

Primary drying is carried out at low pressure to improve the rate of ice sublimation. 

The chamber pressure impacts both heat and mass transfer and is an important parameter for freeze-drying process design.

Hence, during primary drying, the chamber pressure is well below the vapor pressure of ice, and ice is transferred from the product to the condenser by sublimation and crystallization onto the cold coils/plates (<−50°C) in the condenser. 

The sublimation rate is proportional to pressure difference between the vapor pressure of ice and the partial pressure of water in the chamber, this difference being the driving force for ice sublimation. The partial pressure of water in the chamber is essentially the same as chamber pressure during primary drying.

A recommended approach is to first set the chamber pressure using the vapor pressure of ice table.  

A general guideline is to choose a system pressure that is 20% to 30% of the vapor pressure of ice at the target product temperature. 

When the vacuum level set point is deeper than the vapor pressure of ice at the current product temperature, sublimation can take place. 

Typically, vacuum levels for freeze drying are between 50mTorr and 300mTorr with 100mTorr to 200mTorr being the most common range.

For an example, our desired product temperature for primary drying is -24°C. then, the vapour pressure of Ice at -24°C is 524.30 mTorr or 0.7 mBar. 

Hence, as a rule of thumb, I will choose a chamber pressure as mentioned below.

Product Temperature	Vapor pressure of ice at temperature	20% of Vapor pressure of ice at temperature	30% of Vapor pressure of ice at temperature
-24°C	524.3  mTorr	104.9 mTorr	157.3 mTorr
Chosen chamber vacuum: 105 mTorr

Condenser temperature:

The condenser is also called as a cold trap. 

It is designed to trap the solvent, which is usually water, during the drying process. 

The process condenser will consist of coils or sometimes plates which are refrigerated to allow temperature. 

These refrigerated coils or plates may be in a vessel separate to the chamber, or they could be located within the same chamber as the shelves.

     

            

The condenser temperature required is dictated by the freezing point and collapse temperature of the product. 

The refrigeration system must be able to maintain the temperature of the condenser substantially below the temperature of the product.

Thus, the condenser temperature is always less than the shelf temperature / product temperature.

As rule of thumb, during drying the condenser temperature shall be set below -50°C.

Duration of primary drying:

Usually when we have to detect the end point of primary drying (using various techniques/devices to determine the Barometric Endpoint Determination).

If we don’t have any external devices/instruments to help in this regard, then the end of primary drying is identified by the product temperature reaching the set shelf temperature.

The temperature or literally energy we are providing to the product during primary drying for sublimation is taken up by ice. 

So, this loss of temperature to sublimation ensures that always colder product than shelf set temperature during the primary drying.

Once all the ice is sublimed and there is no ice left, then the temperature reaches directly to product and that results in increase inn product temperature. 

This increase in temperature continues till the maintenance of equilibrium of  shelf and product temperatures.

Another way to determine the end point of primary drying is by pressure rise. 

The pressure is lyophilizers at laboratory scale is by Vacuum Gauges  (Pirani & Capacitance Manometer).

Capacitance Manometers  (Give true vacuum readings and are not erroneously influenced by water vapor).

Pirani Gauges (Give artificially high readings proportional to the amount of water vapor present in the lyophilizer chamber).

With decrease in water vapour in the chamber, pirani gauge shows decrease in chamber pressure. At one point, both pirani and capacitance manometers will show same pressure (a single line in the lyo graph).

So once we got confirmation about any of the indicators (temperature /pressure) regarding the end of primary drying then it is the time to proceed for the secondary drying.

That's it for the day folks...

will go a bit deeper into the aspects of primary drying in further posts...

till then take care, by bye....

Yours. 

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