Primary shelf temperature

Figure 7 The effect of chamber pressure on the rate of primary drying, (a) 0.18 M methylprednisolone sodium succinate 2 mL in molded vials (2.54 cm2), shelf temperature +45°C. (Smoothed data from Ref. 6.) (b) Dobutamine hydrochloride and mannitol (4% w/w in water), 12 mL in tubing vials (5.7 cm2) and shelf surface temperature +10°C. (MJ Pikal. Unpublished data.) (Modified from Ref. 1.)... 

Gieseler et al. utilized tunable diode laser absorption spectroscopy to detect water vapor concentrations, gas velocities and mass flow during freeze-drying of pure water at different pressure and shelf temperature settings and of a 5%w/w mannitol solution. The analyzer was interfaced to the spool that connected the dryer chamber to the condenser. The reported method was advantageous in that primary and secondary drying end-point control based upon mass flow rate was independent of freeze-dryer size and configuration. ... 

Thermal analysis data also dictate the maximum product temperature allowable during primary drying. Shelf temperatures and chamber pressures are then selected to assure that the product remains below this critical threshold temperature during primary drying. Secondary drying conditions necessary to achieve the desired residual moisture content are also identified. Determination of these processing parameters requires numerous process studies and corresponding stability studies to define optimal conditions. 

As compared with a higher pressure and lower shelf temperature outlined in Table 7, drying rates with the reversed conditions of lower pressure and higher shelf temperature would be expected to be slower than the conditions at target shelf temperature and chamber pressure. Compared with those conditions, freezing would be expected to require more time. Primary drying rates would also be reduced because heat transfer rates would be less, product temperatures lower, and residual moisture higher. 

Shelf Temperature and Pressure Versus Product Temperature During Primary Drying... 

During primary drying, the temperature of the product is dependent on shelf temperature and on chamber pressure. The higher the temperature of the shelf, the higher the temperature of the product will be. An increase in chamber pressure favors the thermal exchanges at the gas-product interface and the thermal conductivity from the shelf to the tray. More heat is transported to the product and this results in a rise of product temperature. 

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. 

An increase in shelf temperature will unambiguously accelerate the primary drying of the product, unless it is excessive and promotes a slowing down of water removal consecutive to collapse or melt-back. 

For several validations, we have implemented planned deviations of 10-15°C around the target temperature during primary drying and of 5-10°C for secondary drying. The products obtained from these extreme cycles complied with all specifications and the range of the temperature variations was satisfactory for most practical purposes. When the freeze-dried product can accommodate shelf temperature variations of 10°C or more, the lyophilization cycle can often be transposed without modifications to another lyophilizer. 

Figure 8 Thermal profiles of 28% CET aqueous solution during crystallization and subsequent freeze-drying process. (A) Normal unified plug (B) brilliantly dappled plug and (C) shrinking plug, a, b, c Same procedures are followed as in Figure 4 d primary drying e programmed shelf temperature.

Shelf temperature has the greatest influence on the processing rates and ultimate product temperatures at the completion of each process step. The achievable shelf temperature capability ranges from the coldest temperature for freezing to the warmest temperature for primary and secondary drying. High rates of... 

Typically, the drying process can be divided into primary and secondary phases. During the primary phase, the drug solution is filled into vials and then placed within a temperature-controlled drying chamber. There, the solution is frozen according to physiochemical principles as the shelf temperature is lowered to below freezing. The shelf temperature is... 

The chamber pressure during the sublimation step (i.e. the primary drying process) has been found to be related to the product and shelf-surface temperatures [8] however, determining the shelf temperature required is more difficult as it depends on the nature of the heat transfer fluid used to control the shelf temperature and also on the particular design of the freeze-dryer. 

The relative contributions of the differing heat transfer routes therefore vary with pressure and with vial characteristics. A rise in chamber pressure may lower the product temperature by increasing mass transfer (sublimation) relative to heat input this should be compensated by raising the shelf temperature or, preferably, by adjusting the primary drying time. 

It has already been mentioned that there exists no absolute dividing line between primary and secondary drying. However, for practical purposes of process control and economy, it is important to establish the point of completion of sublimation, i.e. the removal of all ice from the product. The interested reader is directed to the literature, where available techniques have been described and compared in detail.The most direct indicator of ice removal is the chart recorder output of the product temperature. As sublimation nears completion, the product temperature rises, dually to reach the shelf temperature. A practical problem lies in the difficulty of measuring the temperature of the dried cake in a reliable manner, and in the atypical drying behaviour of any vial that carries a temperature probe. 

Having estimated the optimum primary drying parameters, a pilot study should be performed. It is not good practice to carry out such a study either in an incompletely filled drier or by filling up shelves partly with empty vials. The reliability of pressure and temperature measurements should be checked at this stage. It has sometimes been found that the (apparent) product temperature exceeds the shelf temperature. Since this is an obvious physical impossibility, such an anomaly is due to faulty calibration of the thermocouple probe. 

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