Changes of Structure in Freezing or Frozen Products

Independent of the growth of ice crystals (Section 1.1.2), which can be observed down to —100 °C, and possible recrystallization (Section 1.1.3), this section describes only such developments or changes of structures that can be influenced by additives. The addition of CPAs to albumins, cells or bacteria influences the nucleation of ice - or at least its growth - in such a way that their natural structures are retained as much as possible. On the other hand, additives are introduced to crystallize dissolve substances. If this method does not help, e.g. with antibiotics, the solution increasingly concentrates until a highly viscous, amorphous substance is included between ice crystals. This condition has disadvantages  

The phase transition from amorphous to crystalline can sometimes be promoted by thermal treatment (annealing) (TT) [1.45], It is recommended first to search for CPAs and process conditions which would lead to crystallization. The evaluation can be carried out using methods such as described in Section 1.1.5 (see also Yarwood and Phillips [1.46]). If this is not successful, the time and temperature for TT should be chosen in such a way that the tolerances for time and temperature are not too narrow, e.g. -24.0 0.5 °C and 18 1 min are difficult to operate, while -30 1.5 °C and 40 2 min might be easier to control. 

A suitable freezing rate, start-up concentration and an amount of product per vial (e.g. for Na-ethacrynate) can be selected that result in a stable, crystalline phase. However, the addition of CPAs may provide another means of achieving crystallization, as seen for several pharmaceutical products [1.47]. 

De Luca et al. [1.48] showed that the addition of 5% tert-butyl alcohol (tBA) to aqueous sucrose and lactose solutions (up to 40%) resulted in a frozen matrix, which could be easily freeze-dried. They demonstrated by DSC that the melting point rose distinctly (with 60% solution to -10 °C), but the endotherm of melting returned to 25%, indicating that not much water had frozen. In solutions with 5% tBA the exotherm of crystallization became more visible and the melting of tBA could be recognized. 

After the ice has been sublimed, the adsorbed water is desorbed from the solid. This process is governed by laws different from those of the main drying. This step is called secondary or desorption drying. During the secondary drying (SD) the ener- 

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The drying at a lower Tsh did not change the desorption behavior. In the product there exists a combination of two or more structures. Slow freezing produces in a 10% mannitol solution a mixture of a- and p-polymorphs, and fast freezing the 8 form (Kim et al. [1.173] see also [1.149]). If the mannitol solution is frozen in LN2 at a rate... 

This quick evaporation will produce foam or bubbles in the product. This is unacceptable in most cases, since the original structure is changed and that part of the product which is vacuum dried will have different qualities than the freeze-dried part. Often the product frozen in this way can not be freeze-dried at all. 

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