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 recombinan t human albumin (rHA) undergoes intermolecular thiol-disulfide interch ange, eventually forming high-molecular-weight, water-insoluble aggreg ates. The relationship between the extent of aggregation and the water content of the lyophilized protein was bell-shaped, with maximum aggr egation (over 80% after one day) at approximately 50 g water per 100 g dry protein, corresponding to incubation at 96% relative humidity, Ni neteen different excipients were co-lyophilized,vith rHA to test their ability to inhibit aggregation under these conditions. These compound s included low- and high-molecular-weight sugars, as well as various o rganic acids (amino, hydroxy, and aliphatic), and the simple inorganic salt sodium chloride. Seven of them afforded complete stabilization o f rHA against moisture-induced aggregation, The stabilizing potency of the excipients correlated with their water-sorbing capability, presum ably due to increasing the moisture level in the vicinity of rHA.