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Deamidation of model beta-turn cyclic peptides in the solid state.
Stephanie L Krogmeier1, D Srinivasa Reddy, David Vander Velde
1Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue Lawrence, Kansas, USA.
Journal of Pharmaceutical Sciences
|November 1, 2005
Summary
Secondary structure significantly impacts peptide deamidation in solid-state formulations. However, matrix mobility, particularly in glassy solids, plays a more critical role in slowing degradation rates.
Area of Science:
- Pharmaceutical Sciences
- Solid-State Chemistry
- Biophysical Chemistry
Background:
- Peptide deamidation is a critical degradation pathway affecting drug stability.
- Understanding solid-state behavior is essential for lyophilized formulations.
- Secondary structure's role in solid-state peptide degradation remains under-investigated.
Purpose of the Study:
- To investigate the influence of secondary structure on peptide deamidation in lyophilized solids.
- To compare the degradation rates of structured cyclic beta-turn peptides versus unstructured linear analogs.
- To elucidate the impact of matrix mobility on solid-state peptide stability.
Main Methods:
- Utilized cyclic beta-turn peptides and linear analogs as model systems for Asn residues.
- Determined secondary structure in solution and solid-state using NMR, CD, and FTIR spectroscopy.
- Performed accelerated stability studies at 37°C in poly(vinyl pyrrolidone) (PVP)-based lyophilized solids.
- Investigated matrix mobility effects by varying moisture content and using plasticizers.
- Conducted molecular dynamics (MD) simulations to explore peptide conformations.
Main Results:
- Cyclic peptides adopted predominantly Type II beta-turns (approx. 80%), while linear analogs were mostly unstructured (30-35%).
- Cyclic peptides exhibited 1.2-8 times slower degradation than linear analogs across various conditions.
- Degradation rate constants decreased dramatically (four orders of magnitude) in glassy solid matrices.
- Matrix mobility was identified as a key factor influencing solid-state deamidation rates.
Conclusions:
- Secondary structure influences peptide deamidation, with structured peptides showing greater stability.
- Solid-state matrix mobility, especially in glassy states, is a dominant factor controlling peptide degradation.
- Lyophilization conditions and formulation properties significantly impact peptide stability in the solid state.