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Residual moisture content has a significant impact on the solid-state stability of biopharmaceutical products. Protein degradation due to residual moisture is minimal at or below the monolayer level of hydration owing to low availability of water and limited dynamic activity of the protein. However, residual moisture content beyond a monolayer generally results in increased rates of decomposition due to the enhanced conformational flexibility of the protein and the ability of the less tightly bound water to mobilize reactants. In addition to moisture content, the temperature and the composition of the lyophilized plug are important variables dictating the stability of proteins in the amorphous solid state. Water can act as a plasticizer to reduce the glass transition temperature, Tg, of the amorphous polymer, thus an increase in temperature or plasticizer level can result in a phase transition from a dynamically constrained state to a dynamically relaxed state. The selection of excipients can have a large impact on water-protein interactions as small ions and/or crystallization of excipients can redistribute water available to the protein. Owing to the key role that water content plays in the conformational and/or chemical state of the protein, an accurate and precise moisture determination is essential in resolving stability issues. A wide variety of techniques for the determination of moisture content have been utilized, with special attention being placed on sample handling to minimize atmospheric moisture contamination. |
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