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(513g) Investigating Fundamental Motions to Rapidly Predict Lyophilized Protein Stability

Badilla, K. - Presenter, University of South Alabama
Bommarius, A., Georgia Institute of Technology
Cicerone, M. T., National Institute of Standards and Technology
While it is common knowledge that lyophilization serves as a technique to stabilize protein-based drugs, the mechanism by which this occurs is not yet entirely known. Thermodynamics and reaction kinetics both play roles in the destabilization and eventual degradation of the proteins contained within the glass system, but the precursor to both degradation pathways is fundamental molecular-scale motion. Juxtaposed to the long-time studies that are currently used to quantify the stabilizing capabilities of their respective excipients, I will present how probing the fundamental motions can rapidly provide insight about protein stability for lyophilized systems.

It has been shown that there is a direct correlation between the degradation rate of proteins stored in the glass phase and molecular mobility of the systems in which the proteins are embedded1; this correlation holds true for a variety of proteins stored in multiple excipients and at multiple temperatures. This work was conducted using neutron scattering which is a technique less accessible to most researchers. However, alternative methods exist that allow for acquisition of similar data. The first method discussed in the present work is measurement of the optical Kerr effect (OKE) from which molecular reorientation times collected under the stress of an ultrashort laser pulse can be related to molecular mobility. It has been shown that measurement of the OKE provides signatures of the fundamental motions2, similar to observations from neutron scattering. The second method discussed in the present work is low-frequency Raman spectroscopy from which the energy difference of inelastically scattered light can be related to molecular mobility. Both these techniques are expected to provide insight on the stabilizing power of excipients in a much shorter window than current long-time studies because they measure the most fundamental motions of the system, which are sub-steps of the processes that cause protein degradation. These techniques can serve to drastically decrease the time spent optimizing formulations.

  1. Cicerone et al., Soft Matter, 8 (2012)
  2. Bender et al., Soft Matter, 16 (2020)