Freeze drying formulation

Number of formulations studied Number of formulations freeze dried %... 

Freeze-Dried Products. Freeze drying was first carried out in 1890 by Altman but became well known through the industrial development of the process. The process is used in the food industry, e.g., for the production of instant coffee, tea, and other products. In the field of pharmaceutical technology, it was for a long time restricted to only few formulations for injection containing the active ingredient in the freeze-dried state in an ampoule to be dissolved just before application. With the increasing interest in protein and peptide formulations, freeze-dried products became more important. These are discussed under section Microparticles for Injection. ... 

G Needham. Formulation and processing factor affecting residual solvent levels in TBA/water formulations. Freeze-Drying of Pharmaceuticals and Biologicals, Breckenridge, CO, August 1-4, 2001. 

Formulation Sterile filtration/ dispensing Freeze drying... 

The development of freeze-drying for the production of blood derivatives was pioneered during World War II (96,97). It is used for the stabilization of coagulation factor (98,99) and intravenous immunoglobulin (IgG iv) products, and also for the removal of ethanol from intramuscular immunoglobulin (IgG im) solutions prior to their final formulation (Fig. 2). 

The resuspended and formulated Fraction II precipitate normally contains some aggregated IgG and trace substances that can cause hypotensive reactions in patients, such as the enzyme prekail ikrein activator (186). These features restrict this type of product to intramuscular adininistration. Further processing is required if products suitable for intravenous adininistration are required. Processes used for this purpose include treatment at pH 4 with the enzyme pepsin [9001-75-6] being added if necessary (131,184), or further purification by ion-exchange chromatography (44). These and other methods have been fiiUy reviewed (45,185,187,188). Intravenous immunoglobulin products are usually suppHed in the freeze-dried state but a product stable in the solution state is also available (189). 

J. C. May and F. Brown, eds., "Biological Product Freeze-Drying and Formulation," Derelop. Biol Stand. 74 (1992). 

Because most food matrices are water soluble, many efforts were directed to the formulation of lipophilic pigments (mainly carotenoids) into water-soluble formulations (powders or gels). For hydrophilic pigments like flavonoids, polar dried microcapsules are the most popular ways to stabilize their functionality. Extracts rich in P-carotene were encapsulated using three different encapsulation techniques (spray drying, drum drying, and freeze drying)." ... 

In the first example, procaine penicillin, an aqueous vehicle containing the soluble components (such as lecithin, sodium citrate, povidone, and polyoxyethylene sorbitan monooleate) is filtered through a 0.22 pm membrane filter, heat sterilized, and transferred into a presterilized mixing-filling tank. The sterile antibiotic powder, which has previously been produced by freeze-drying, sterile crystallization, or spray-drying, is aseptically added to the sterile solution while mixing. After all tests have been completed on the bulk formulation, it is aseptically filled. 

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]. 

In addition to the effects of formulation factors on freeze-drying behavior, it is important for the pharmaceutical scientist to understand basic principles of heat and mass transfer in freeze-drying [29,30]. Because of the high heat input required for sublimation (670 cal/g), transfer of heat from the heated shelf to the sublimation front is often the rate-limiting step in the coupled heat... 

Most proteins are not sufficiently stable in aqueous solution to allow formulation as a sterile solution. Instead, the protein is freeze-dried and reconstituted before use. Development of a freeze-dried protein formulation often requires special attention to the details of the freezing process (potential pH shifts and ionic strength increase with freezing) as well as to potential loss of activity with drying. Formulation additives, such as sugars and polyhydroxy compounds, are often useful as cryoprotectants and lyoprotectants. Residual moisture may also be critical to the stability of the dried preparation [33],... 

B. Lueckel, B. Helk, D. Bodmer, and H. Leuenberger, Effect of formulation and process variables on the aggregation of freeze dried interleukin-6 (IL-6) after lyophilization and storage, Pharm. Dev. Technol., 3, 337 (1998). 

M. L. Roy, M. J. Pikal, E. C. Rickard, and A. Maloney, The effects of formulation and moisture on the stability of a freeze-dried monoclonal antibody-vinca conjugate A test of the WLF glass transition theory Dev. Biol. Standards, 74, 323 (1991). 

M. Pikal, Freeze drying of proteins Process, formulation, and stability, in Formulation and Delivery of Proteins and Peptides (J. Cleland and R. Langer, eds.), ACS Symposium Series 567, 1993, pp. 120-133. 

MJ Pikal. Freeze-drying of proteins, Part II Formulation selection. BioPharm 3(9) 26-30, 1990. 

Figure 2 The rate of water loss and residual water content during freeze drying. Moxa-lactam disodium formulated with 12% mannitol in aqueous solution at 30% solids 10 mL tubing vials with a solution fill depth of 1 cm. The chamber pressure was 0.05 torr (6.6 Pa). (From Ref. 2.)...

Final product formulation Product filling, freeze drying (if required) and sealing -> Labelling and packaging... 

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