The art of lyophilisation

The art of lyophilisation

Natrajan Iyer, Pallavi Hanwante

Lyophilisation is a process in which liquid material is slowly frozen in a vacuum, thereby removing water by maintaining the water vapour pressure. This technology appears to be very simple, but when the techniques are practiced and developed, the processes are deceptively complex, therefore, lyophilisation is treated as an art rather than science.

Refrigeration system for lyophilisation

Lyophilisation consists of three separate unique and interdependent processes—freezing, primary drying (sublimation), and secondary drying (desorption).

The freezing step utilises maximum power. Lyophiliser manufacturers in India are few, which is why most of the time they are imported from Europe or China, and the problem with imports is that sometimes the specifications do not meet with the requirements of Indian climatic conditions, due to which the system does not operate properly, leading to more number of breakdowns in the refrigeration system. The principle function of lyophilisation is to slow down the kinetic clock while freezing.

In figure 2 the indirect cooling takes place in the shelf and direct cooling takes place in the ice condenser.

The whole system in the figure can be taken as a low temperature reservoir in the figure below.

In figure 3, the condenser named in the lyophilisation equipment is a misnormer because this part of the equipment contains the coil, which maintains the lowest temperature in lyophilisation during the freezing cycle, thereby, propagating water vapour from product to coil due to the difference in temperature, and converting the vapour phase into solid phase (ice).

The thermal energy moves from left to right through five loops of heat transfer to lyophilisation (see figure 4).

The refrigeration system used in lyophilisation—the vapour compression refrigeration (VCR)—uses mechanical and electrical energy.

The compression refrigeration cycles take advantage of the fact that highly compressed fluids at a certain temperature tend to get colder when they are allowed to expand. If the pressure change is high enough, then the compressed gas will be hotter than the source of cooling (outside air, for instance) and the expanded gas will be cooler than the desired cold temperature. In this case, fluid is used to cool a low temperature environment and reject the heat to a high temperature environment.

Vapour compression refrigeration cycle has two advantages-first one being that a the large amount of thermal energy is required to change liquid to vapour, and therefore, a lot of heat can be removed from the shelf and the ice condenser. Secondly, the isothermal nature of vapourisation allows extraction of heat without rising the temperature of the working fluid to the temperature of whatever is cold i.e. heat transfer rate remains high.

As explained in figure 5, low pressure liquid refrigerant transfers the heat directly in case of ice condenser and indirectly through heat transfer medium silicon oil in case of shelf. During this process, it changes its state from liquid to gas as the exit of the ice condenser and silicon oil tank is slightly superheated.The superheated vapour enters the compressor where its pressure is raised and the temperature is also increased because the portion of the energy put into the compression process is transferred to the refrigerant. The high pressure superheated gas passes from compressor to the condenser and the initial part of the cooling process de-superheats the gas before it is turned back into liquid. The cooling for this process is usually achieved by using air or water. The high pressure sub cooled liquid passes through an expansion device, which reduces its pressure, and controls the flow into the evaporator. The condenser is capable of rejecting the combine heat input of the evaporator and compressor.

The high pressure superheated gas will be converted into liquid at a particular temperature known as saturated temperature. In countries where there is not much of a seasonal variation the atmospheric temperature variation is also minimum when we import lyophilisation equipment from these countries and try to operate them in India. This may not work upto our satisfaction because in our country the summer is as high as 40° C at some of the places and winter is as low as 8-10° C. The difference between these temperatures is almost 30° C. The selection of the condenser and the compressor has to be done properly to be fully efficient. If this is not done during the peak of summer, the lyophilisation equipment goes on high pressure, trips, leading to leakages. Normally, in such situations the condenser can be cleaned, having no impact on the operation. So while making the user required specification, the operational parameters, and the condition of the place the equipment is imported from need to be mentioned. It is generally preferred that condenser should be bought from the same manufacturers as that of compressors.

A variety of refrigerants are used in vapour compression systems which require the cooling temperature largely depending on the choice of fluid. Nowadays CFC free refrigerants are used. The specific power consumption KW/TR is a useful indicator of the refrigeration system’s performance. By measuring refrigeration duty performed in TR and the KW input, KW/TR is used as an energy performance indicator while making the specification for a lyophiliser. By comparing KW/TR for two different systems, the one with a narrow gap should be chosen.

The theoretical coefficient of performance (Carnot), (COP Carnot, a standard measure of refrigeration efficiency of an ideal refrigeration system) depends on two key system temperatures—evaporator and condenser temperature.

COPCarnot=Condenser Temperature-C. T- E T

Where as, C T is condenser temperature and E T is evaporator temperature

The theoretical equation is only a ratio of temperature and does not take into account the type of compressor being used. Hence, the practical equation for coefficient of performance is COP=Cooling Effect (KW) .

Power input to Compressor (KW)

This is also an important parameter in selecting the refrigeration system for lyophilisers. The power consumption is maximum during refrigeration in the lyophilisation process. To reduce the power consumption and to keep all the other parameter constant, COP of one needs to be greater than the other, making the system efficient.

Vacuum requirement in lyophilisation

To create vacuum in system a pump is required to remove mass or gas from the system. The more mass is removed; lower is the pressure that exists inside the system. Various vacuum levels are defined depending on the ultimate absolute pressure, in Torr or mm/Hg. The pressure is directly proportional to boiling point i.e as the pressure reduces, the boiling point also reduces. In lyophilisation, we freeze and sublimate the product which is thermally sensitive and unstable in solution.

The vacuum is divided as:

  • Coarse vacuum 10-760 Torr

  • Medium Vacuum 0.001-10 Torr

  • Fine vacuum 10-3 – 10-7 Torr

  • Ultra High vacuum