Concept of Freezing in lyophilization-II

Hello folks,

In the last session i.e., concept of freezing in lyophilization -I, we have came to know about the importance of freezing, phenomena of nucleation, reasons for inability to freeze/freeze dry.

Lets further understand what actually happens in freezing of bulk solutions when loaded into lyophilizer.

The freezing step during which the material is hardened by low temperatures. In the freezing phase of the process the product is often cooled to -40 °C or lower and held for a period of time until the system is completely solid, with all “freezable water” converted to ice.

For understanding purpose, let us consider bulk solution is an aqueous solution (Water containing solids dissolved in it). When the bulk solution temperature is cooled from ambient temperatures to sub zero temperatures, water freezes in the first step, the dissolved components in the formulation remain in the residual liquid, a phase termed the freeze-concentrate. At the point of maximal ice formation, the freeze concentrate solidifies between the ice crystals that make up the lattice. Under appropriate lyophilization conditions, the ice is removed by sublimation during primary drying, leaving the remaining freeze-concentrate in the same physical and chemical structure as when the ice was present. 

During this very critical period all fluids present become solid bodies, which may be,

• Crystalline solids
• Amorphous solids
• Mixture of both amorphous and crystalline solids (Partially amorphous /partially crystalline)

Most often, water gives rise to a complex ice network, but it might also be imbedded in glassy structures or remain more or less firmly bound within the interstitial structures. Solutes do concentrate and might finally crystallize out. At the same time, the volumetric expansion of the system might induce powerful mechanical stresses that combine with the osmotic shock given by the increasing concentration of interstitial fluids.

At the most fundamental level, to achieve a lyophile with acceptable macroscopic appearance, the primary objective for crystalline materials is not to exceed their eutectic temperature and that for amorphous materials is not to exceed their glass transition temperature or collapse temperature between the initial cooling phase and the end of the sublimation process.

For the crystalline solutes, the interstitial material consists of a mixture of eutectic ice and crystalline solute. when ice is removed by sublimation, a crystalline solid with very little water is left.

For amorphous system, the interstitial glassy material must be rigid enough to support its own weight after the ice is removed in order to keep the micro-structure established during freezing.

However, often a formulation will contain a mixture of crystallizing and amorphous components, in which case, the critical temperature may not be so obvious. One approach is to assume complete phase separation will occur, assess the individual components separately, then aim to cool the starting material to below the lowest of the critical temperatures and maintain it below this temperature until the end of the sublimation process.

Effect of freezing rate on lyophilization:

Do we think there is something on freeze drying due to freezing rate?? The answer is YES.

Generally, with slower rate of freezing, larger ice crystals form. With rapid freezing rate, smaller crystals.

Slow freezing can subject the bulk solutions for longer periods of time, permitting maximum crystal growth that leads to larger sized crystals.

An aqueous solution cooled at rapid cooing and slow cooing rates, the resulting ice crystals were examined microscopically and the results were provided below.

Which is better, rapid freezing or slower freezing?

The crystal size formed during freezing can significantly affect the dissolution rate of the dried material.

A fast ice growth also helps to prevent the denaturation of proteins (If present) which may result from prolonged exposure to strong concentrations of salts because of slow ice growth.

Rapid cooling results in small ice crystals, useful in preserving structures to be examined microscopically, but resulting in a product that is, more difficult to freeze dry.

Slower cooling results in large ice crystals and less restrictive channel in the matrix during the drying process.

The main pores in the solid residue after freeze drying are those left by the sublimation of pure ice and they form the principal channels for the escape of vapor.

During sublimation, very small ice crystals form smaller pores and pathways, which are more restrictive to vapour flow than those formed after slower freezing.

The appropriate cooling cycles must be determined in order to obtain an appropriate structure of the frozen mass, which is a function of the rate of freezing and the final freezing temperature.

Now you decide, whether you freeze your product at rapid rate or slower rate…….

In the next session will meet you again…

Teja ponduri signing off.....Bye, Bye…