Effects of Water and Polymer Content on Covalent Amide-Linked Adduct Formation in Peptide-Containing Amorphous Lyophiles

Water Clusters in Amorphous Pharmaceuticals

“…Moreover, water clustering was suggested as a possible explanation of the "leveling" effect. 87 In another study, rate of chemical degradation of IgG was shown to be similar in a relatively wide water content range from 0.2% to 5.2%. 88 This result would be qualitatively consistent with water cluster formation, although we should note that a different interpretation was proposed in the original paper.…”

“…One example of such leveling-off in the degradation rate with an increase in water content was reported in Ref. 87, where deamidation of a model tetrapeptide in amorphous polymeric matrixes was studied. The degradation rate increased with an increase in the water content from 6% to 8% (w/w), and then remained essentially constant while water content increased from 8% to 14% (w/w).…”

“…The degradation rate increased with an increase in the water content from 6% to 8% (w/w), and then remained essentially constant while water content increased from 8% to 14% (w/w). Moreover, water clustering was suggested as a possible explanation of the “leveling” effect . In another study, rate of chemical degradation of IgG was shown to be similar in a relatively wide water content range from 0.2% to 5.2% .…”

Effect of Water on the Chemical Stability of Amorphous Pharmaceuticals: 2. Deamidation of Peptides and Proteins

“…In addition to the formation of Asp and isoAsp via hydrolysis of the imide intermediate, a parallel reaction leading to the formation of the tetrapeptide/dipeptide adduct was observed for another peptide, asparaginyl tetra-peptide (GlyePheeL-AsneGly), in hypromellose matrix (DeHart and Anderson 53 ). Due to the bimolecular nature of the covalent adduct formation reaction, increasing the percentage of hypromellose (i.e., the reactant dilution) favors the formation of hydrolysis products over covalent amide-linked adducts.…”