Physical and Chemical Stability

Proteins, peptides, and other polymeric macromolecules display varying degrees of chemical and physical stability. The degree of stability of these macromolecules influence the way they are manufactured, distributed, and administered. Chemical stability refers to how readily the molecule can undergo chemical reactions that modify specific amino-acid residues, the building blocks of the proteins and pep-tides. Chemical instability mechanisms of proteins and peptides include hydrolysis, deamidation, racemization, betaelimination, disulfide exchange, and oxidation. Physical stability refers to how readily the molecule loses its tertiary and/or sec-

PROTEIN PHARMACEUTICALS

PROTEIN PHARMACEUTICALS

CHEMICAL INSTABILITY

- deamidation

- racemization

- racemization

- oxidation

- beta elimination

- disulfide exchange

PHYSICAL INSTABILITY

- denaturation

- aggregation

- precipitation

- adsorption

Figure 5.10. Possible mechanisms of chemical and physical instability that influence biological activities of protein pharmaceuticals. (Adapted from Manning et al. [18])

ondary structure (denaturation or unfolding), aggregates with itself, and precipitates from solution. In some cases these events lead to adsorption of proteins to storage containers and reduce the concentration of protein drug in solution, thereby the dose delivered to a patient. Both physical and chemical instability leads to loss of biological activity and, in some cases, to toxicity.

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