What is Lyophilization?
General Principles of Freeze Drying (The Lyophilization Process)
Introduction
Application and Uses
Freeze drying, or lyophilization as it is referred to in the pharmaceutical and diagnostic industries, is a dehydration technique which enables liquid or slurry products which have previously been frozen to be dried under a vacuum. The applications of freeze drying are numerous, but it is generally employed when the requirements demand:
- Preservation of temperature sensitive products, particularly those of biological origin, such as enzymes, blood plasma, vaccines, etc.
- To achieve a chemical balance, such as for biological reagents
- To provide a practical solution for certain delivery problems, for example, the packaging of constituents that cannot be mixed in the liquid state, but which are solidified in successive stages and then freeze dried
- To implement an important stage of a product (such as concentration)
- To improve storage life and improved marketing of the end product
- To resolve certain filling problems. It may be difficult, for instance, to divide several milligrams of powder into precise vial dosages, due to the difficulty of measuring tiny amounts, homogeneity, granulation, static electricity etc. The distribution of the product from the liquid state eliminates such production problems.
- Product temperature sensitivity and its relation to taste
Description of the Operation
Generally, the Freeze Drying or Lyophilization cycle is divided into three phases:
An initial freezing process, carried out in such a way that:
- The product exhibits the desired crystalline structure
- The product is frozen below its eutectic temperature
A primary drying (sublimation) phase during which:
- The partial pressure of the vapor surrounding the product must be lower than the pressure of the vapor from the ice, at the same temperature
- The energy supplied in the form of heat must remain lower than the product's eutectic temperature (the highest allowable product temperature during the conditions of sublimation)
A secondary drying aimed at eliminating the final traces of water which remain due to absorption, and where:
- The partial pressure of the vapor rising from the product will be at its lowest levels.
At the completion of the process, the treated product will have retained its form, volume and original structure - as well as all its physical, chemical and biological properties. It can then be stored (provided packaging is effective for reduction of moisture migration) for an almost indefinite period of time. As the product is porous, it can be re-dissolved by the simple addition of a proper solvent.
From this description of the process of freeze drying, three facts emerge:
- The sublimation characteristics of the product are greatly dependent on the frozen structure.
- This structure cannot be altered during the process.
- Product temperature plays an active role in all three phases, and in execution it is upon this that the choice of other parameters (vacuum, heat rate etc) are based.
Theoretical Basis of Freeze Drying
The theoretical principle of freeze drying is clearly defined in the diagram ‘Pressure Temperature’ (Fig A)..
In order to avoid the liquid phase, it is absolutely essential to lower the partial pressure of water, below the triple point pressure. A freeze drying cycle is shown in this diagram, which has been designed to conform to a typical example (described below):
- Freezing of a product from 20° C to -20 C° at atmospheric pressure
- FSublimation of the product at -20° C
- FTransfer of evolved vapor to the condenser at low temperature
- FVacuum release
- FDefrost
Freeze drying is a complex operation and all facets cannot be addressed in this explanation. Instead, certain aspects will be highlighted which play a part in the development of a freeze drying operation:
- Freezing
- Drying
- Vacuum influence
- The liquid shelf on which the product is placed
- Essential control aspects during freeze drying
Freezing
Upon completion of product freezing, the product will have acquired a frozen structure, which cannot be changed during freeze drying. Sublimation and the qualities of the finished product are greatly dependent on this crystal structure. In fact, it is considered the most crucial stage of the freeze drying process.
Speed of Freezing
On the pilot level, fast or very fast freezing is relatively easy to achieve. However, for industrial production settings, freezing at the same rates is unrealistic because of the problems of product preparation (filling, loading time) and larger systems costs will dictate compromises in the same process. From Fig 1 we observe:
As soon as the product reaches 0° C (Point A on the curve of Fig 1), some of the particles transform to ice. This is the nucleation process. Generally, biological products contain between 80% and 95% water.
Observe that the temperature of the product stabilizes after time period at about 0° C.
At Point B, the ice crystals previously formed have expanded, and consist practically of pure water.
At Point C, the crystals have grown larger, and now occupy 80% to 90% of the initial volume of the solution. The crystallization of the free water is nearly complete. These crystals seem to be contained in an interstitial state, still liquid, but which constitutes the principal active element of the solution.
At Point D, the interstitial component itself has reached freezing temperature, and the amorphous appearance is even more apparent, and a barely visible ‘skin’ has formed on the surface. This structure is ideal for sublimation.
We now have a paradoxical situation: a slow cooling which can lead to a rapid coagulation of the constituent water. In many cases, freezing induced by these conditions may be necessary to achieve successful freeze drying of a sensitive product. |
