Unfrozen Residual Water

After a multicomponent aqueous solution has been freeze-concentrated to the limit and the ice has been sublimed, any residual unfrozen water must be removed from the remaining solid solution by diffusion, desorption and evaporation (transfer to the condenser). This process is termed secondary drying . For an amorphous preparation, the amount of unfrozen water remaining after the removal of ice may be typically 20-30% w/w, but much higher values, even 50% w/w, have been found in some formulations. Attempts are on record to measure the amount of water that remains in the freeze-concentrated solution phase at 7, mainly by differential scanning calorimetry but such 

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Although the process of unfrozen water removal from the material, subsequent to ice sublimation, is commonly referred to as desorption , this is misleading. It has been shown that the residual water forms a mobile component of a solid solution, so that diffusion more correctly describes the mechanism of its removal. Compared to the diffusion rate of water from the bulk to the surface, its eventual desorption from the surface is rapid and can in practice almost be neglected. As will be shown later, secondary drying kinetics can be modelled adequately by standard treatments of diffusive processes. The effects of many variables on the kinetics of secondary drying may be found in Pikal et al ... 

Standard nanosilica A-380 (specific surface area 5bet=378 m /g) was heated at 673 K for several hours before the measurements to remove organic adsorbates and residual HCl. Polar and weakly nonpolar deuterated (D) solvents, CDjCN, ( 03)280, and CDCI3 (Aldrich, qualification for NMR spectroscopy at content of main isotope of 99.5%), soluble or practically insoluble in water, were used in the deuterium form to avoid their contribution to the H NMR signal intensity of unfrozen interfacial water at T<273 K. Bidistilled water was used here. 

FIGURE 7.32 H NMR spectra of unfrozen water in partially dehydrated bone marrow cells containing 20 wt% of residual water (a) initial and after addition of (b) 1 g/g and (c) 2 g/g of CDClj. (Adapted from Cryobiology, 59, Turov, V.V., Kerus, S.V., and Gun ko, V.M., Behaviour of water bound in bone marrow cells affected by organic solvents of different polarity, 102-112, 2009, Copyright 2009, with permission from Elsevier.)... 

It is harder to remove the unfrozen water trapped in an amorphous solid. So after primary drying, a secondary drying stage removes that water by increasing the temperature. The final temperature of this secondary process is the key factor in determining residual moisture in the dried cake. The pressure is kept the same for secondary and primary drying to avoid protein collapse. The ideal result is a porous cake with little residual moisture. Porosity is important in later reconstituting the product. 

Calculations of the size distribution of unfrozen water structures (Figure 1.264) show that the initial material is the most compacted (V is minimal. Table 1.36) but the pore size filled by this water is nearly maximal (peak maximum at / =22 nm). It is also possible that the initial material is characterized by smaller number of residual silanols than the diluted suspensions. 

Some of the more hydrophilie solvents such as ethanol and methanol retained significant amounts of associated water which only partially froze as the temperature decreased. Samples dried with organic solvents which do not completely freeze may produce a product which is heterogeneous with respect to residual solvent. Use of appreciable levels of solvents which do not freeze usually result in unacceptable cake appearance. However, in those products which produce a resistant surface skin during the drying process, a small level of unfrozen organic can cause discontinuities in the skin sufficiently to potentially facilitate the removal of the frozen water vapor [31],... 

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