Sucrose collapse temperatures

The frequency at the minimum of this curve is called TOF by the authors. TOF varies with the temperature as shown in Fig. 1.55.6. The extrapolated intersection of the two linear portions identifies the collapse temperature. The predicted Tc by TOF for 10 % sucrose, 10 % trehalose, 10 % sorbitol and 11 % Azactam solution deviates from observations by a freeze-drying microscope (Table 1, from [1.126]) to slightly lower temperatures, the differences are -3 °C, -1.4 °C, 2.2 °C and 0.7 °C. 

Fig. 3.2. Collapse temperature of a sucrose solution as a function of the added citrate solution (%) (Fig. 3 from [3.6]).

Of course, the above considerations are valid only if the presence of fert-butyl alcohol does not lower the collapse temperature of the formulation. For sucrose-based formulations, Kasraian and DeLuca (1995a) showed that the addition of tert-butyl alcohol does not alter the collapse temperature however, there are cases where the presence of an organic solvent together with water can reduce the collapse temperature of the formulation. As an example, Liu et al. (2005) showed that the collapse temperature of sulfobutylether-7-P-cyclodextrin formulation was reduced by 2 °C when a 5% (w/w) fert-butyl alcohol aqueous solution was used. 

AKZO Pharma Division of Organon International B.V. also reported how TBA concentrations affect the stability of freeze-dried sucrose formulations. Adding 5 percent TBA to a 180mg/ml sucrose solution resulted in a pharmaceutically acceptable, stable freeze-dried cake with no collapse. Therefore, while TBA addition did not change the collapse temperature of the sucrose solution, it increased the rate of sublimation. The increase thereby prevented the product from ever rising to the collapse temperature. 

One other point of interest of thermal analysis in freeze drying is the use in examining phase concentration. Frequently, inert sugars or polyhydric alcohols such as mannitol or sucrose are included in solutions to be freeze dried. Roos [157] reviewed the frozen state transitions in relation to freeze-drying. It is these conditions that should be used to derive a proper freeze-drying condition. Freeze-dried products should be porous and easy to hydrate. However if collapse occurs during dehydration a product may exhibit poor dehydration properties. Collapse occurs if the temperature of ice is higher than the collapse temperature, of a material. 

A simple relationship was not found between shrinkage and glass - rubber transitions of both peach and apricot tissue (Campolongo, 2002 Riva et al., 2001, 2002). Even when sorbitol use increased AT (= T — 7g ) values, both the color and the structure showed the highest stability. The fact that sorbitol performed better than sucrose indicates that the chemical nature of the infused solute is more important than its glass transition temperature in preventing structural collapse, in accordance with the results reported by del Valle et al. (1998). 

De Luca [3.5] recommends, furthermore, the addition of e.g. tert-butyl alcohol (TBA), to increase the transport of water vapor out of the product and to avoid collapse in sucrose, lactose and sorbitol solutions. Thereby, higher temperatures during drying (e.g. for hemoglobin in sucrose solution) can be applied. 

It is also essential to consider the glass transition temperature of the freeze-dried product, particularly with a view to predicting physical and chemical storage stability. The relationship between the physical stability of freeze-dried formulations and Tg must be considered not only in terms of recrystallization but also of product collapse. For example, te Booy et al. (119) showed that storage of sucrose-containing freeze-dried formulations above Tg may result in product shrinkage, collapse, or excipient recrystallization. 

There are, however, other ways in which conventional drying could, in principle, be performed at temperatures above Tg, without deleterious results. If a solution could be treated so that one or several components can undergo crystallisation, then the crystals formed would serve as a substitute for the subliming ice crystals and could mechanically protect the porous, amorphous matrix against structural collapse. The efficacy of this type of formulation for freeze-drying purposes has been demonstrated for the system water-sucrose-NaCl. " Its practical applications may, however, be limited to products where the bioactive component is not chemically degraded in the freeze-concentrate at temperatures above Tg. 

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