Why the dry state is so much better
Peptides degrade by four principal chemical routes, and three of them need water as a reactant or a mobility medium.
- ·Hydrolysis. Peptide bond cleavage, requiring water. Effectively stopped in a dry solid.
- ·Deamidation. Conversion of asparagine and glutamine side chains to the corresponding acids, proceeding through a cyclic imide intermediate. Strongly water- and pH-dependent, and among the best-characterized solid-state degradation routes.[2]
- ·Oxidation. Methionine, cysteine and tryptophan side chains oxidising on exposure to air and light. This is the one route that proceeds meaningfully in the dry state, which is why lyophilized vials are sealed under partial vacuum or inert gas.
- ·Aggregation. Physical rather than chemical: chains associating into species that will not redissolve. Driven by concentration, agitation and freeze-thaw cycling.
- ·A fifth route worth naming for lyophilized material specifically: residual moisture in the cake enables amide-linked adduct formation with excipients, which is why moisture control in the dry state matters more than it intuitively should.[1]
