Pharmaceutical Freeze-Drying Systems

The drying of products as well as the freezing and subsequent storing at correspondingly low temperatures are well-known processes applied for the conservation of sensitive usually perishable products. These processes are mostly used in the production of foods. 

Freeze-drying is a combination of these two processes. With freeze-drying, storage at low temperatures is avoided and in addition, reactions which can still happen at low temperatures if water is present - even in the form of ice - cannot occur. Freeze-drying is the careful drying of a frozen product under vacuum through sublimation of the solvent at temperatures below the freezing point of the solvent. 

Freeze-drying is mainly used when water or occasionally other solvents must be removed from a temperature sensitive or structurally difficult product - usually of biological origin - without noticeable influence on the quality of the final product. After removal of the water or solvent, the dry product is then easy to store, ft becomes again a product that can be used simply by adding water or the corresponding solvent. 

The main areas in which freeze-drying is used can be found in the process technology applied in pharmacy, biology and medicine. A few examples of freeze-dried products are antibiotics, bacteria, sera, vaccines, diagnostic media, biotechnolog-ically produced products and foods. 

Vacuum Technology in the Chemical Industry, First Edition. Edited by Wolfgang Jorisch. 

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Craig, D.Q.M., Royall, P.G., Kett, V.L., and Hopton, M.L. 1999. The relevance of the amorphous state to pharmaceutical dosage forms Glassy drugs and freeze dried systems. Int. J. Pharm. 179,... 

Trehalose is a relatively new bulk sweetener with potential for use in soft drinks. It is a di-glucose sugar and it occurs in nature in shellfish and mushrooms, where it confers a degree of protection to plant and animal cells in conditions causing dehydration. This led to its use as a cryoprotectant in freeze-drying systems in the pharmaceutical industry. In food markets, its potential use is as a bulk sweetener. It is manufactured using the Hayashibara patented process using starch as a raw material. The process involves enzymatic conversion and crystallisation to the trehalose dehydrate crystal (LFRA, 2001). 

Freeze-drying systems used in the pharmaceutical industry must fulfil the following conditions ... 

In pharmaceutical systems, both heat and mass transfer are involved whenever a phase change occurs. Lyophilization (freeze-drying) depends on the solid-vapor phase transition of water induced by the addition of thermal energy to a frozen sample in a controlled manner. Lyophilization is described in detail in Chapter 16. Similarly, the adsorption of water vapor by pharmaceutical solids liberates the heat of condensation, as discussed in Chapter 17. 

Nail, S. L., Schwegmani, J. J., Kamp, V. analytical tools for characterization of frozen systems in the development of freeze-dried pharmaceuticals. Amer Pharm... 

Pikal, M.J. Heat and mass transfer in low pressure gases application to freeze-drying. In Transport Processes in Pharmaceutical Systems, pp. 611-686, edited by G.L. Amidon, P.I. Lee, E.M. Topp. Marcel Dekker, New York, 2000... 

Most protein stability studies have focused their interpretation on either a thermodynamic mechanism or a pure kinetic mechanism, and consequently there is some controversy and confusion over which mechanism is correct. Since the direction of a formulation development effort may depend on which theory is being followed, clarification of the roles of thermodynamic stabilization and kinetic stabilization in given stability problems would provide some practical benefit. This chapter is an attempt to provide such clarification. To this end, the major stresses, or destabilizing effects, that operate during the freeze-drying process are discussed, selected empirical observations regarding pharmaceutical stability in protein systems are presented, and the structure and dynamics in amorphous protein formulations are discussed. 

By the development of new galenic systems in the form of freeze-dried Biomatrices, new application possibilities could be developed for the freeze-drying process in the pharmaceutical field as well as in cosmetics. Constant innovations and process optimizations made it possible to produce these products on an industrial scale in constant top quality with a maximum degree of product safety. 

Most freeze-dried pharmaceuticals—and, of course, all injectable products—need to be sterile. Until now, the usual rule to achieve that goal has been to start with a sterile solution and, from there on, to carry out an entirely sterile process. Indeed, the time is over when the manufacturers could add a 1/10,000 merthiolate to get rid of an accidental contamination. Today all freeze-dryers have their cabinets opening within a sterile room while the machinery is sitting behind the wall in the engine room. Moreover, the drying chambers are all equipped with clean-in-place (CIP) systems and can be sterilized by pressure steam before each operation. Finally, those products that are prepared in vials are sealed directly within the chamber thanks to moving pressure plates that drive the stoppers tight into the neck of the vials. 

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