Aggregation of a lyophilized pharmaceutical protein, recombinant human albumin: effect of moisture and stabilization by excipients.
In the presence of water vapor at 37 degrees C, lyophilized recombinant human albumin (rHA) undergoes intermolecular thiol-disulfide interchange, eventually forming high-molecular-weight, water-insoluble aggregates. The relationship between the extent of aggregation and the water content of the lyophilized protein was bell-shaped, with maximum aggregation (over 80% after one day) at approximately 50 g water per 100 g dry protein, corresponding to incubation at 96% relative humidity. Nineteen different excipients were co-lyophilized with rHA to test their ability to inhibit aggregation under these conditions. These compounds included low- and high-molecular-weight sugars, as well as various organic acids (amino, hydroxy, and aliphatic), and the simple inorganic salt sodium chloride. Seven of them afforded complete stabilization of rHA against moisture-induced aggregation. The stabilizing potency of the excipients correlated with their water-sorbing capability, presumably due to increasing the moisture level in the vicinity of rHA.
Costantino
H R
HR
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139, USA.
Langer
R
R
Klibanov
A M
AM
D000418:Albumins / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005079:Excipients; D005612:Freeze Drying; D006801:Humans; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D012995:Solubility; D014867:Water / Q000737:chemistry
D000418:Albumins; D005079:Excipients; D011994:Recombinant Proteins; D014867:Water