Lyophilization freezing

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. 

Before the extraction procedure may commence, the sample must be prepared in such a way that it is in a condition for extraction of the analyte(s). For analyzing sulfonamide residues in liquid samples such as milk, a pretreatment dilution step with water prior to direct fluorometric detection may be required (207). Dilution of milk with aqueous buffer (208) or sodium chloride solution (209) prior to sample cleanup has also been reported. For the analysis of honey a simple dissolution of the sample in water (210, 211) or aqueous buffer (212) is generally required. Semisolid samples such as muscle, kidney, and liver, require, however, more intensive sample pretreatment. The analyte(s) must be exposed to extracting solvents to ensure maximum extraction. The most popular approach for tissue break-up is through use of a mincing and/or homogenizing apparatus. Lyophilization (freeze-drying) of swine kidney has been carried out prior to supercritical-fluid extraction of trimethoprim residues (213). 

Concentration. This group consists of those processes in which water is removed and the dissolved substances are left behind. Examples are freeze concentration, lyophilization (freeze-drying), vacuum distillation, and membrane processes such as reverse osmosis and ultrafiltration. A common disadvantage of these methods is that inorganic species are concentrated along with the organic constituents. 

Two general classes of methods can be functionally defined for preparing concentrates of organic substances. Concentration methods involve the removal of water (e.g., lyophilization, freeze concentration, vacuum distillation, reverse osmosis [RO], and ultrafiltration) and result in a more highly concentrated aqueous solution of organic contaminants. Isolation methods are those methods in which the organic substances are physically removed from the aqueous solution, for example, adsorption onto a solid substrate followed by desorption (I). 

Ultrafiltration (qv) (uf) is increasingly used to remove water, salts, and other low molecular-weight impurities (21) water may be added to wash out impurities, ie, diafiltration. Ultrafiltration is rarely used to fractionate the proteins because the capacity and yield are too low when significant protein separation is achieved. Various vacuum evaporators are used to remove water to 20—40% dry matter. Spray drying is used if a powdery intermediate product is desired. Lyophilization (freeze-drying) is only used for heat-sensitive and highly priced enzymes. 

Reducing sugars, 4-8%,7 are known to be present in cane juice they are D-glucose and D-fructose. The acetylation of lyophilized (freeze-dried) normal cane juice solids followed by chromatography on a magnesium acid silicate of these acetates led to the isolation and proper identification of the sugars as crystalline derivatives.8... 

Bakaltcheva, I., Reid, T. Lyopilization of blood cells. International Conference on Lyophilization-Freeze-Drying, Amsterdam, October 2002, International Society of Lyophilization-Freeze-Drying,... 

Remove the organic solvent by lyophilization/freeze-drying or centrifugation under vacuum. 

The practical solution to the protein stability dilemma is to remove the water. Lyophilization (freeze-drying) is most commonly used to prepare dehydrated proteins, which, theoretically, should have the desired long-term stability at ambient temperatures. However, as will be described in this review, recent infrared spectroscopic studies have documented that the acute freezing and dehydration stresses of lyophilization can induce protein unfolding [8-11]. Unfolding not only can lead to irreversible protein denaturation, even if the sample is rehydrated immediately, but can also reduce storage stability in the dried solid [12,13]. 

Adjustments in pH lo maintain water solubility cun sometimes lead lo chemical stability problems. An example is indomelhacin (HA acid pK ,4.S). which is unstable in alkaline media. Therefore. Ihc preferred oral liquid dosage form is a suspension buffered at pH 4 to 5. Because this is near the drug s pK . only. W f will be in the water-soluble form. There is a medical indication requiring intravenous administration of indomelhacin to premature infants. The intravenous dosage form is the lyophilized (freeze-dried) sodium salt, which is reconstituted just prior lo use. 

The lipid was hydrated to a concentration of 20-mg/ml. The formulation was to be lyophilized (freeze-dried) by snap freezing in liquid nitrogen and sublimation of the water, resulting in dry and stable lipid vesicles. 

By early 2004, 15 million doses of smallpox vaccine, Dryvax, were available in the United States. Dryvax, a Wyeth product, is a live virus preparation of vaccinia. The vaccine comes as a lyophilized (freeze-dried) powder in 100 dose vials containing the antibiotics polymyxin B, streptomycin, tetracycline, and neomycin. Fifty percent glycerin, containing a small amount of phenol as a preservative, serves as the diluent for reconstitution (25). Studies have shown that diluting the vaccine in a 1 5 ratio could expand the supply without reducing vaccine efficacy (25). In addition, 200 million antibiotic-free doses are in production. The CDC Web site has detailed directions on how to reconstitute and administer the vaccine at http //www.bt.cdc.gov/agent/smallpox/vaccination/ administration.asp. 

Enzyme activity is preserved by cold storage. Lyophilized (freeze-dried) proteins are stored in a freezer or refrigerator, while dilute solutions are stored at 2-5 °C. Concentrated suspensions of enzymes in ammonium sulfate are usually stable for long periods at 2-5 °C. 

Lyophilization (freeze drying) is used in laboratory medicine for the preparation of calibrators, control materials, reagents, and to a lesser extent individual specimens for analysis. Lyophilization first entails freezing a material at -40 °C or less and then subjecting it to a high vacuum. Very low temperatures cause the ice to sublime solid nonsub-limable material, initially locked in an ice matrix, remains behind in a dried state. 

Lyophilization (freeze drying) may be used to prepare a dosage form that is to be reconstituted for injection. The solution to be concentrated is distributed into small vials, and specialized equipment is employed to freeze the samples and remove the solvent. For other purposes lyophilization is impractical on scale. 

All of these questions can affect the optimal formulation of a drug. For example, an early formulation question is whether the product will be lyophilized (freeze-diied) or sold as a liquid. The advantages of a liquid include timesaving. 

Lyophilization Freezing Sublimation Freeze drying Full stoppering... 

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