Alternative pharmaceutical processes

The lyophilization of peptides and proteins, although very useful and common, suffers from several disadvantages. A protein can denature or aggregate during the freezing step, as already. Also, lyophilization needs substantial capital investment, high energy input, and long process times. A crucial factor that determines the shelf life of a product is its final physical state, irrespective of the method used to remove the water. This offers alternatives to lyophilization, such as controlled evaporative drying. As an endothermic process, such a technique will allow control of the temperature of drying. In contrast, freezing is an exothermic process; thus, latent heat of crystallization needs to be removed quickly to prevent ice from melting back into the product. Also, evaporation is faster, is more energy efficient, and requires less capital investment.66

Coprecipitation of enzymes with a water-soluble starch in an organic solvent has also been proposed as an alternative to freeze-drying. Using this technique, 100% of proteolytic enzyme activity was recovered for krill proteases. Coprecipitation with starch reduces the denaturation of the protein by physically entrapping the enzyme into a support matrix.67 A granulation technique, wet spherical agglomeration, has also been explored for peptides and proteins as a low-cost alternative to lyophilization. The procedure would involve suspending the protein in a suspension liquid and then agglomerating it by adding a small amount of a second immiscible liquid called bridging liquid. Bausch and Leuenberger68 have reported that, for water-soluble proteins such as bovine serum albumin or recombinant bovine a-inter-feron (IFN), n-hexane was an ideal suspension liquid. Agglomeration was achieved by adding an aqueous buffer as the bridging liquid. Before agglomeration, the protein was mixed with an excipient such as mannitol so that a fast-dissolving product was obtained. The procedure of agglomeration using n-hexane had no influence on the biological activity of a-IFN, and the residual organic solvent could be reduced to less than 0.01%.

Although these techniques may be of more academic interest, spray-drying or use of nonaqueous solvents offers a more feasible alternative to lyophilization and is discussed in greater detail. Some of the other processing techniques not discussed so far are also discussed in this section.

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