Freeze crystallization lyophilization

Drying is an operation in which volatile Hquids are separated by vaporization from soHds, slurries, and solutions to yield soHd products. In dehydration, vegetable and animal materials are dried to less than their natural moisture contents, or water of crystallization is removed from hydrates. In freeze drying (lyophilization), wet material is cooled to freeze the Hquid vaporization occurs by sublimation. Gas drying is the separation of condensable vapors from noncondensable gases by cooling, adsorption (qv), or absorption (qv) (see also Adsorption, gas separation). Evaporation (qv) differs from drying in that feed and product are both pumpable fluids. 

Polishing The last steps provide the product at the desired concentration, purity, and physical form. These steps may consist of sterile filtration, diafiltration, UF, crystallization, freeze drying, lyophilization, and spray drying. 

In Example 11-5, freeze crystallization of imipenem. which has lower stability in solution at room temperature, is presented. In this process, the product is rapidly frozen to an amorphous solid state to conserve its chemical purity. The temperature is then raised (still below the fieezing temperature at this stage), and the amoiphous solid converts to a crystalline solid over time. After the completion of the solid-state transition phase, the lyophilization drying cycle is initiated. 

Process development work at Ranbaxy began with the aim to develop a simple, practical, and efficient method for the preparation of crystalline imipenem monohydrate, which is thermally stable, has a uniform degree of crystallinity, and is of high purity. After extensive experimentation, a process was developed for the isolation of pure crystalline imipenem monohydrate from a solution containing imipenem. The process does not use capital-intensive techniques of lyophilization or freeze crystallization nor the time-consuming purification process of column chromatography using expensive hydro-phobic resins. 

The freeze drying of antibiotics and blood serum have largely represented the beginning of industrial lyophilization. Neumann [3.34] wrote in 1952 The (freeze drying) temperature for the older, not well purified Penicillin preparations had to be kept surprisingly low. It could not exceed -25 °C or -40 °C and later on Today Peniciilin is manufactured as crystals without the need of freeze drying . 

Nemati, F., Cave, G. N, Couvreur, P. Lyophilization of substances with low water permeability by a modification of crystallized structures during freezing. Assc. Pharm. Galenique Ind., Chatenay Malabry, 3, p. 487-493, 1992... 

Freeze drying or lyophilization is a drying process, in which the solvent and/or the medium of suspension is crystallized at low temperatures and thereafter sublimated from the solid state directly into the vapor phase. 

Another concern with freeze-drying LEH is the instability of liposome structure upon lyophilization. Vesicle formation occurs in the presence of bulk water and when water is removed, loss of structural integrity is inevitable. Fusion, crystal formation, and phase transition are observed, resulting... 

In an aqueous solution of DNA, the water outside of the solvation shell is referred to as bulk water. When DNA solutions are frozen, the bulk water crystallizes as a separate phase—ice. Ice does not form if the concentration of DNA is brought to a level where only the solvation shell remains, about 20-22 waters/nucleotide. If brought to this concentration slowly, a film is formed. Freezing a film does not create ice. Another type of sample is prepared by first lyophilizing DNA and then letting it sit at a preselected humidity that determines the level of hydration, typically 2.5 < F < 22. Subsequent freezing of these cotton-like samples does not yield ice. 

Lyoprotectants can affect enzyme stability in both stages of lyophilization the freezing and the drying stages. In the freezing stage of lyophilization, ice crystals form and have been shown to be a cause of enzyme denaturation. Studies have shown that when added as a lyoprotectant, the amorphous polyol mannitol stabi-... 

Buffers for lyophilized formulations need additional consideration. Some buffers like sodium phosphate can crystallize out of the protein amorphous phase during freezing resulting in rather large shifts in pH. Other common buffers such as acetate and imidazole should be avoided since they may sublime or evaporate during the lyophilization process, thereby shifting the pH of formulation during lyophilization or after reconstitution. 

The remedy to this situation is to perform a thermal treatment of the frozen solution. This treatment consists of a controlled rewarming of the solution until devitrification and recrystallization of the excipient occurs, followed by a last freezing step below the solidification temperature. A typical excipient justifiable of such a treatment on thermodynamic grounds is mannitol. In the absence of proteins that maintain the structural integrity of the pellet, mannitol solutions often yield cakes of poor appearance. The induction of mannitol crystallization by rewarming around -25°C evades this problem and allows one to obtain elegant pellets that are easy to lyophilize and do not shrink. 

It has been reported that replacing succinate buffer with glycolate buffer improved the stability of lyophilized y-interferon. In this work, it was found that the succinate buffer could crystallize in the frozen state, which limited its ability to maintain the appropriate pH, and therefore led to degradation. On the other hand, use of the glycolate buffer appeared to minimize the freeze-induced pH shifting, and the lyophilized product exhibited superior solid-state stability. 

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