Advances in Drying by Sublimation Blood Plasma, Penicillin, Foods EARL W. FLOSDORF
F. 3. Stokes Machine Company, Philadelphia, Pennsylvania DRYING BY SUBLIMATION
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N high-vacuum drying by sublimation, the product first is frozen. A region of low vapor tension is established in the vacuum system to cause rapid sublimation and the rapidity of evaporation results in sufficientcooling to keep the product frozen until dried. In rapid industrial processing this way, the major problem is one of introduction of heat into the frozen product with sufficient rapidity to maintain rapid evaporation and to prevent the temperature from going so low that the rate of drying would be retarded. OBJECTIVES OF SUBLIMATION
Various effects result from drying while frozen which give the method valuable applications and uses. First, the temperature is below that a t which many labile substances undergo chemical change. This applies to labile components in blood, to viruses and most forms of microorganisms, and to other biologicals and pharmaceuticals. Second, because of the low temperature, the loss of volatile constituents is minimal. This is particularly important in application to many foods like orange juice and pineapple juice. Third, since the product is frozen, there is no bubbling or foaming, which, in the case of drying some substances, would result in changes due to surface action such as the surface denaturation of proteins which occurs in drying their solutions even a t low liquid-temperatures under vacuum. Fourth, in most cases, the solute remains evenly dispersed and distributed without undergoing concentration, as frozen solvent sublimes, and the remaining dry residue emerges as a highly porous solid framework. It occupies essentially the same total space as the original solution did and the final residue is not the fine powder with which the chemist is mostly familiar. It consists of a friable, interlocking, and spongelike structure. As a result, solubility is extremely rapid and complete. For example, gelatin dried from a solution which had to be prepared in the &st place by boiling becomes instantly soluble in cold water. Fifth, since the molecules of solute are virtually "locked" in position in this way, the tendency for coagulation of even lyophobic sols is minimal. Even though the lipoidal constituents of dry blood plasma do not reconstitute perfectly after drying and do produce a slight degree of turbidity, there is far from complete coalescence. The particles are small enough to be safe for intravenous injection and do not cause capillary embolism. Sixth, during drying the surface of the evaporating
frozen ice layer gradually recedes to leave more and more of the highly porous residue of solute exposed. As a result, "case-hardening" never occurs. A far lower content of moisture may be obtained in the final product without use of excessively high final temperature. For this reason of lower moisture content, a greater degree of stability results than is the case after any other method of drying. Seventh, bacteriological growth and enzymatic changes cannot take place under the frozen conditions of drying. This is important for foods as well as medical products used in parented injection. The final fully dried product likewise resists bacterial growth and enzymatic action. Eighth, because of the high vacuum used, in contrast with the degree of vacuum used in ordinary low-temperature liquid evaporation, the amount of oxygen present is so extremely small that even the most readily oxidizable constitueuts are protected. It is for these reasons that a method which only 10 years ago was developed from a laboratory curiosity into a workable procedure has becdme a commonly used process for drying in the biological and pharmaceutical industry. The detailed history of the development has heeu recorded with full bibliography given (I, 4). Our main contributions (4) by 1935 for commercial operation included the establishment of proper surface relationships of frozen product for fast and complete drying with exposure to heat, from the atmosphere, and equipment for medical products consisting of Dry Ice condenser with manifold for sterile processing in final market containers. Later other advances were made in equipment and manner of processing. I t has been only within the last 10 or 15 years that i t has been recognized that by establishing proper conditions of vacuum for removal of water vapor and by rapid application of heat to the frozen product, rather than keeping it in an icebox, this process could be made industrially workable, and with improved products resulting. The final dried product is raised to a temperature well above OaC. and often as high as 60" or 70°C., in order to reduce the final content of moisture to a minimum. BASIC PRINCIPLES
Two Stages of Drying and the Probia of Heating There are two stages in drying by sublimation. In the first, ice is evaporated from a frozen mass. In the second, moisture is removed from the final dry solid to lower the residual content to a minimal level. Dur-
ing the first stage, depending on the particular product, some 98 to 99 per cent of all water is removed. In the second, the residual moisture content is reduced to 0.5 per cent of the final product or less, which represents final removal of 99.95 per cent of the original content of water (assuming 10 per cent solids originally). In the first stage, temperatures are well below O°C. Actual temperature varies with the product, as will be discussed later. Upon passing from the first stage to the second the temperature gradually rises and finally reaches that of the room or higher, depending upon whatever final ambient temperature is used. Basically, during the first stage of drying a maximal rate of evaporation of the frozen product must be obtained. To achieve this, heat must be introduced into the frozen product as rapidly as possible without causing it to soften or melt. At the same time a maximal rate of flow away from the evaporating surface must be established. To accomplish this rapid flow adequate passageways must he provided for vapor, and this must then be condensed or evacuated efficiently. Highly efficient condensers of adequate capacity for rapid removal of water vapor in the vacuum system may he used. Also, high-capacity steam ejectors for direct pumping or evacuation of vapor are available. Therefore, the controlling factor for rapid evaporation becomes the rate of supply of heat to the frozen product. In this there are certain basic limitations. Heat must not be carried to the walls of the container which holds the product faster than the heat can be conducted through the frozen mass to a free surface where it is utilized to induce evaporation. Otherwise melting adjacent to the container wall will occur. Heat can be carried down directly to the evaporating surface itself in order to avoid conductance through ice, but even here there is a limitation. As soon as sublimation has proceeded to an appreciable extent the ice layer has receded from the level of the original surface, so that the evaporating surface has become confined within the interstices of the outer framework of porous dry solid. The heat must then he carried across this porous structure, but the temperature of this dry portion of the product must not he brought above the level where it will be harmed. All of this means that the ultimate speed of drying is determined and limited by the speed a t which the heat of sublimation can be camed to the ice surface, and this limitation is one of conduction through poor conductors. When heat is applied rapidly to a product during sublimation, measurement of the temperatnre a t dierent levels throughout the frozen layer reveals that there is a considerable thermal gradient from the outside surface up through the ice to the evaporating surface. The only remaining unexploited means that can be foreseen at present for further acceleration of drying lies in development of a means for rapid generation of heat a t the evaporating and receding ice surface only. In the final stage of drving the rate of s n.. ~ ~ l v i heat ng is not so critical. This is because the actual weight of
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