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Application Note: Thermal Stability of Proteins

Protein formulations exist in a thermodynamic metastable state. One consequence of protein formulation metastability is their sensitivity to temperature changes (Frokjaer and Otzen, 2005). Proteins are incredibly heat sensitive. At temperatures not much higher than body temperature (greater than 40°C) proteins can denature. Protein denaturation is the complete loss of higher order (quaternary, tertiary, and secondary) structure in the protein leaving only the primary structure, the amino acid sequence, intact. This fragility is not limited to high temperatures, but also low temperatures (Bhatnagar et al, 2007). Excipients like surfactants, sugars, and salts can be incorporated into formulations to improve protein stability under thermal stress.

Other excipients are added to improve their stability and functionality at moderate temperatures. Free amino acids like histidine and arginine are commonly added to protein formulations to reduce viscosity by screening protein-protein interactions (Dear et al, 2019). However, what is not known is how these excipients perform under high temperature. Understanding the differences between excipients and the knowing the environment your fluids will experience, will help guide and improve formulation development.

In this application note we will examine viscosity changes of two model proteins, bovine serum albumin (BSA) and bovine gamma globulin (BγG), as they are heated and cooled. We observe that proteins in formulations enriched in salt are more resistant to thermal denaturation than proteins in formulations containing amino acid excipients. These results demonstrate that excipients have strengths and weaknesses depending on their environment. Saline excipients increase viscosity compared to amino acid excipients but demonstrate greater performance under thermal stress in comparison.





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