Lyophilization: A Primer - Pharmaceutical Technology

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Lyophilization: A Primer
Optimized freeze-drying cycles can offer scientific and business advantages.

Pharmaceutical Technology
Volume 37, Issue 5, pp. 42-45, 93


Fully characterizing each formulation provides the data necessary to ensure that the cycle designed is optimal for the product and the equipment. Without this information, there is no way to determine the basic process parameters or to scientifically verify the success of the resulting cycle.

Process conditions that are too aggressive will damage the product, decreasing stability and activity, and risking complete batch failure. Process conditions that are too conservative will add unnecessary energy costs, increase batch duration, and reduce turnaround time. A poorly designed cycle can experience some or all of these problems.

Collapse temperature. The most important characteristic of a material for freeze drying is its critical temperature. In simple crystalline materials this is the eutectic temperature (Teu), although more commonly the collapse temperature (Tc) is relevant. Tc is applicable to products which will form amorphous solids, such as pharmaceutical formulations.

Tc and Teu are typically ascertained using freeze-drying micro-scopy (FDM), a quick and well-understood process in which a small amount of product is frozen under a microscope. FDM can be carried out on quantities as small as 70 L (2). Such quick feedback makes it feasible to check the freeze-drying characteristics of each new product formulation, helping the formulation technologist understand the product's response to freeze drying. In the interests of achieving optimum efficiency, FDM can also be used to determine the relative rates of drying for different formulations, or for the same formulation at different temperatures.

In addition to the identification of critical temperature, FDM can also provide a visual indication of the potential for skin formation and the effects of annealing on the ice structure, solute crystallization, and critical temperature.

Frozen state mobility. It is common to think of freezing as a simple, discrete process whereby something is either a solid or a liquid. However, in complex formulations comprising many separate elements, solidification cannot be relied on as an indication of complete freezing and changes may still be taking place within the frozen structure.

A solid that has a non-crystalline (amorphous) structure is referred to as a glass and the point at which the product changes from a liquid to solid is known as the glass transition temperature (Tg). However, due to the complex nature of most pharmaceutical and biotechnological products, glass transition occurs over a range of temperatures. Changes in molecular mobility can occur even in product frozen below its collapse temperature, and these changes can have significant impact on the product's shelf life and long-term activity.

In the event that changes are taking place in the frozen state, it may be necessary to adjust the cycle or to adjust the formulation. However, in most cases the possibility of frozen state flexibility is ignored until problems with the dry product occur. To avoid late-stage redevelopment work, it is advisable to conduct the analysis early on in cycle development, ideally at the same time as FDM.

Typical frozen state analyses include differential scanning calorimetry (DSC) and joint differential thermal analysis (DTA)/impedance analysis.

DSC is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature. DSC is used to detect physical transformations such as phase transitions, endo- or exo-thermic events such as crystallization events, and glass transitions.

DTA is a technique similar to DSC. When used in conjunction with impedance analysis (ZSinΦ), a fixed frequency dielectric analysis, the molecular mobility of a frozen sample can be explored to a very high degree of accuracy.


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