Effect of Glass Transition Temperature on the Stability of Lyophilized Formulations Containing a Chimeric Therapeutic Monoclonal Antibody |
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Authors: | Duddu Sarma P. Dal Monte Paul R. |
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Affiliation: | (1) Department of Pharmaceutical Technologies, SmithKline Beecham Pharmaceuticals, Pennsylvania, 19406 |
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Abstract: | Purpose. The purpose of this study is to highlight the importance of knowing the glass transition temperature, Tg, of a lyophilized amorphous solid composed primarily of a sugar and a protein in the interpretation of accelerated stability data.Methods. Glass transition temperatures were measured using DSC and dielectric relaxation spectroscopy. Aggregation of protein in the solid state was monitored using size-exclusion chromatography.Results. Sucrose formulation (Tg ~ 59°C) when stored at 60°C was found to undergo significant aggregation, while the trehalose formulation (Tg ~ 80°C) was stable at 60°C. The instability observed with sucrose formulation at 60°C can be attributed to its Tg (~59°C) being close to the testing temperature. Increase in the protein/sugar ratio was found to increase the Tgs of the formulations containing sucrose or trehalose, but to different degrees.Conclusions. Since the formulations exist in glassy state during their shelf-life, accelerated stability data generated in the glassy state (40°C) is perhaps a better predictor of the relative stability of formulations than the data generated at a higher temperature (60°C) where one formulation is in the glassy state while the other is near or above its Tg. |
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Keywords: | glass transition temperature Tg lyophilization solid-state stability proteins monoclonal antibody aggregation |
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