Freeze Drying 101

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Freeze Drying 101
Some helpful freeze drying basics
by Larry Ulfik
VirTis
After you finish our Lyophilization 101 notes, you may want to attend our Fundamentals of Lyophilization Seminar. Full details are available by clicking this link (a new window will open).
Lyophilization, commonly referred to as freeze drying, is the process of removing water from a product by sublimation and desorption. This process is performed in lyophilization equipment which consists of a drying chamber with temperature controlled shelves, a condenser to trap water removed from the product, a cooling system to supply refrigerant to the shelves and condenser, and a vacuum system to reduce the pressure in the chamber and condenser to facilitate the drying process.
Lyophilizers can be supplied in a wide variety of sizes and configuratins and can be equipped with options that allow system controls to range from fully manual to completely automated. For pharmaceutical compounds that undergo hydraulic degradation, lyophilization offers a means of improving their stability and shelf life. Many parenteral medications such as vaccines, proteins, peptides, and antibiotics have been successfully lyophilized. New biotechnology products will also increase the demand for freeze drying equipment and processes.
Early attempts at lyophilization were largely empirical in nature because the process variables were not thoroughly understood. However, much of the "black magic" of freeze drying has been replaced through basic research over the last twenty years. Lyophilization equipment and control mechanisms continue to evolve, based on scientific evaluation of thermal, physical and chemical data derived from freeze drying cycles and products.
Lyophilization cycles consist of three phases: Freezing, primary drying, and secondary drying. Conditions in the dryer are varied through the cycle to insure that the resulting product has the desired physical and chemical properties, and that the required stability is achieved.
During the freezing phase, the goal is to freeze the mobile water of the product. Significant supercooling may be encountered, so the product temperature mayhave to be much lower than the actual freezing point of the solution before freezing occurs. The rate of cooling will influence the structure of the frozen matrix. If the water freezes quickly, the ice crystals will be small. This may cause a finer pore structure in the product with higher resistance to flow of water vapor and longer primary drying time. If freezing is slower, ice crystals will grow from the coolingt surface and may be larger. The resultant product may have coarser pore structure and perhaps a shorter primary drying time.
The method of cooling will also effect the structure and appearance of the matrix and final product. If the solution is frozen in vials on the cooled shelf, ice will grow from the bottom ofthe vial toward the top, while immersion in a cooling fluid will cause crystal growth from the bottom and sides ofthe vial. Because some materials form glassy layers, cooling conditions must be controlled to avoid the formation of the dense "skin" on the surface of the frozen product that may impede the escape of water vapor during subsequent drying phases.
A term that is frequently encountered in discussions about freeze drying is eutectic point. On a phase diagram, this is the temperature and composition coordinate below which only the solid phase exists.
It should be understood that, depending on the composition of the solution, there may be mroe than one eutectic point for a product or none at all. During the freezing phase, the product must be cooled to a temperature below its lowest eutectic point. This tmeperature may then be maintained throughout the primary drying phase.
It should be noted that products will not necessarily have a eutectic point. For products with components tht do not crystalize during freezing, drying should be performed at temperatures below the glass transition temperature of the amorphous phase (multicomponent mixture). The glass transition temperature will be determined by the composition of the amorphous phase in the frozen product, which, in turn, is dictated by the product formulation and the freezing procedure employed. Mannitol and some other compounds can exist as an amorphous phase or exhibit a crystalline phase depending upon its thermal history.
In the primary drying phase, the chamber pressure is reduced, and heat is applied to the product to cause the frozen mobile water too sublime. The water vapor is collected on the surface of a condenser. The condenser must have sufficient surface area and cooling capacity to hold all of the sublimed water from the batch at a temperature lower than the product temperature. If the temperature of the ice on the condenser is warmer than the product, water vapor will tend to move toward the product, and drying will stop.
It is important to control the drying rate and the heating rate during this phase. If the drying proceeds too rapidly, the dried product can be blown out of the container by excaping water vapor. If the product is heated too rapidly, it will melt or collapse. This will cause degradation of the product, and will certainly change the physical characteristics of the dried material, making it visually unappealing and harder to reconstitute. While frozen mobile water is present, the product must be held below the eutectic temperature or glass transition temperature.
The components shown in Table A below cause products to have the indicated collapse temperatures.
As water sublimes, the product cools. Therefore, throughtout this phase, the product will remain colder than the shelf temperature which is supplying the heat of sublimation. Athe end of primary drying, the product temperature will rise asymptotically toward the shelf temperature. This and several other methods may also be used to detect the endpoint of primary drying.
Many modern drying cycles use chamber pressure control to control drying rate. At very low pressure, the main form of heat transfer is conduction from the shelf through the bottom of the product container. Since glass is an insulator, this process is not very efficient, and drying can be slow. To improve the heat transfer mechanism, inert gas such as nitrogen may be introduced into the drying chamber at a controlled rate. The rpesence of these gas molecules facilitates heating of the walls of the container in addition to conduction through the bottom of the container, thereby increasing the amount of heat being supplied to the product per unit time. This will enhance the drying rate, reduce the cycle time, and reduce energy and labor costs associated with a lengthy process.
However, if the pressure in the chamber exceeds the ice vapor pressure of the product, water may not be able tosublime. All of the energy from the heat source will be used to increase the product temperature until melting occurs. Therefore, the accuracy and precision ofthe pressure control system are critical to successful lyophilization.
Since there in no mobile water in the product at the end of primary drying, the shelf temperature may be increased without causing melting. Therefore, temperature is increased to desorb bound water such as water of crystallization until the residual water content falls to the range required for optimum product stability. This phase is referred to as secondary drying, and is usually performed at the maximum vacuum the dryer can achieve, although there are products that benefit from increased pressures, too. Be careful not to increase product temperatures too fast so as not to exceed the glass transition of some prodeucts. Products contain 10% or less water can still collapse if the tg1 is exceeded.
tg1: glass transition temperature
The length of the secondary drying phase will be determined by the product. Many products such as proteins and peptides require water to maintain secondary and tertiary structure. If this water is removed, the material may be denatured and lose some or all of its activity. In this case, water content must be carefully controlled. In addition, excessive heat may cause the dry cake to char or shrink.
Lyophilization equipment has improved over the years, and, with the advent of automated, sophisticated control mechanisms, has become much easier to use. The comoplexity of the controls, however, has made validation efforts more complicated and usually quite time consuming.
In addition to cooling, heating, and vacuum control functions already discussed, many freeze dryers will also incorporate clean in place (CIP), sterilize in place (SIP), computerized cycle control, and cycle monitoring functions. The reliable reproducible performance of all these functions must be validated rigorously to insure consistent product quality.
Citations for various compounds and mixtures are for general reference; data ignore important interactions, so use with this understanding.
However, if the pressure in the chamber exceeds the ice vapor pressure of the product, water may not be able tosublime. All of the energy from the heat source will be used to increase the product temperature until melting occurs. Therefore, the accuracy and precision ofthe pressure control system are critical to successful lyophilization.
Since there in no mobile water in the product at the end of primary drying, the shelf temperature may be increased without causing melting. Therefore, temperature is increased to desorb bound water such as water of crystallization until the residual water content falls to the range required for optimum product stability. This phase is referred to as secondary drying, and is usually performed at the maximum vacuum the dryer can achieve, although there are products that benefit from increased pressures, too. Be careful not to increase product temperatures too fast so as not to exceed the glass transition of some