Freeze maximum product temperature

Fig. 4.18 Example of the application of the feedbackcontrol strategy that uses the observer to estimate the maximum product temperature (the freeze-dried product is skimmed milk dv= 14.2 X 10 m, Lp = 8 X 10 m,...

When the temperature decreases, water becomes less soluble (see Figure 5.15) and deposits as fine droplets that begin to freeze as the temperature reaches 0°C. To prevent this occurrence, it is possible to use anti-freeze additives that absorb the water and lower the freezing point. These products, used at maximum levels of 1500 ppm, are ethers-alcohols for example, 2-methoxy... 

Sublimation of ice crystals to water vapor under a very high vacuum, about 67 Pa (0.5 mm Hg) or lower, removes the majority of the moisture from the granulated frozen extract particles. Heat input is controlled to assure a maximum product end point temperature below 49°C. Freeze drying takes significantly longer than spray drying and requires a greater capital investment. 

Therefore, freeze-drying should be carried out at the highest allowable product temperature that maintains the appropriate attributes of a freeze-dried product. This temperature depends on the nature of the formulation. Process development and validation requires characterizing the physical state of the solute, or solutes, that result from the freezing process and identifying a maximum allowable product temperature for the primary drying process [20,21]. 

Fig. 1.56.2. Course of a freeze-drying process. 1, Precooling of the shelves 2, freezing of the product 3, evacuation and main drying (MD) 4, secondary drying (SD) 5, changeover from MD to SD sh raised to maximum tolerable product temperature 6, Tjce measurements by BTM 7, temperature sensors RTD in the product 8, temperature sensors Th in the product 9, temperature of the shelves (T h) 10, ice condenser temperature ...

Fig. 1.80.1. Course of the freeze-drying after the product has been frozen at 0.6°C/min to-50°C. 2, Freezing 3, MD 4, SD 5, DR measurements to define the end of MD 6, some BTM 7-9, as in Figure 1.80.1 10, Tco 11, pch. At the beginning of DR measurements the pressure control in this example is deactivated. When the DR value has reached a predetermined number, (in this case) is increased to the maximum tolerable temperature. The optimum time frame for the change from MD to SD cannot be estimated from the 7"pr plot (Figure 6 from [1.63])...

Figure 1 Schematic evolution of the freeze-drying process. Temperatures (upper curve) and water content (lower curve) are indicated versus time. In the temperature diagram cs = maximum temperature of complete solidification 7 = minimum temperature of incipient melting = absolute limit for fast process = maximum allowed temperature for the dry product RMF, final requested residual moisture.

Although the measurement of product temperature with probes inserted nearly to the bottom of the vials or ampoules is often questioned for many reasons, we use this method routinely to evaluate the duration of primary drying and the maximum primary drying temperature as shown in Figure 1. During prevalidation trials, we have run a series of more or less extreme freeze-drying cycles for sucrose and lactose formulations. The pellets produced were examined for... 

The functional relationship between product temperature, on the one hand, and shelf temperature and chamber pressure, on the other hand, is affected by many factors including the size and design of the lyophilizer, the characteristics of the product, and the time evolved since the start of primary drying. With a sucrose formulation in vials, we have observed a maximum primary drying product temperature rise of -i-5°C when the shelf temperature was varied from -15 to -i-30°C, whereas a pressure variation from 30 to 250 microbars generated an increase of around -i-2.5°C. With a lactose formulation in ampoules lyophilized in a larger freeze-dryer equipped with a plate-type condenser, the effect of pressure was found to be predominant -i-6.5°C for a pressure move from 50 to 300 microbars, versus -t-l°C for a shelf temperature move from 0° to 25°C. 

Minimum pressure at the end of secondary drying Maximum temperature of the condenser Temperature range of the product at the end of freezing Maximum primary drying product temperature Product primary drying time... 

At the end of the sublimation drying, the product surface temperature reaches the maximum allowable product temperature, requiring that the temperature of the heating plates be lowered gradually, and the drying will change to desorption drying. The temperature will finally be kept constant at the level of the maximum allowable product temperature until the residual moisture has been reduced to 2 to 3 percent, which is a typical level for a freeze dried product. 

As regards the role played by excipients in determining the glass transitions of the freeze-concentrate and the final dried product, they may increase Tg, thus allowing the implementation of shorter cycles by raising the maximum safe temperature for ice sublimation. In addition, any excipient that increases Tg of the final dried product will thereby raise the product s maximum safe storage temperature. This is of particular importance for the production of shelf-stable products. Some excipients, particularly those of a PHC type, also stabilise proteins in... 

In a eutectic system, the whole composition or just the excipient may be subject to crystallisation, but this process takes time to reach completion. It may be much longer than the time taken to freeze the product to the desired temperature (Tg). After primary drying (ice sublimation), only solid solutes remain. The mixture may then be carefully warmed to its final storage temperature. The residual solid will not necessarily be anhydrous and may, for example, contain water of crystallisation. In addition, as the temperature is raised, the crystalline product may undergo solid-solid transitions, i.e. over a period of time, a different polymorph may become the preferred crystal habit. In a completely crystalline preparation, the maximum safe storage temperature will be governed by the component with the lowest melting point. 

The structural stability of a material relates to its ability to go through the freeze drying process without change in size, porous structure, and shape. The maximum allowable temperature in the frozen layer is determined by both structural stability and product stability (e.g., product bioactivity) factors that is, the maximum value of the tanperature in the frozen layer during the primary drying stage must be such that the drying process is conducted without loss of product property (e.g., bioactivity) and structural stability. 

The kinetics of oxidation of isotactic polypropylene was investigated in circulating apparatus with freeze-volatile products of oxidation at the temperature of liquid nitrogen. When the film thickness is less than 60 microns maximum rate of oxidation of the sample is proportional to its thickness. Consequently, at a thickness of less than 60 microns ( 1<60 mcm) kinetic regime is realized, i.e. diffusion of oxygen is a rapid process and does not affect the rate of oxidation. On the contrary, for 1 > 200 microns oxidation occurs in the diffusion regime and the maximum speed calculated for 1 cm the surface is practically independent of the thickness. 

Confirm DSC results with a freeze-drying microscope and determine the maximum allowable product temperature during the primary drying. 

In order to determine the freeze-drying parameters a number of critical parameters are required. The eutectic point of formulation components which crystallize on freezing and the glass transition of those which form an amorphous state should be determined in order to set the maximum safe product temperature for primary drying. This can be ascertained by one of a number of methods, as follows. 

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