Formulation considerations for proteins susceptible to asparagine deamidation and aspartate isomerization

The asparagine (Asn) deamidation and aspartate (Asp) isomerization reactions are nonenzymatic intra-molecular reactions occurring in peptides and proteins that are a source of major stability concern in the formulation of these biomolecules. The mechanisms for the deamidation and isomerization react...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2006-11, Vol.95 (11), p.2321-2336
Main Authors: Wakankar, Aditya A., Borchardt, Ronald T.
Format: Article
Language:English
Subjects:
Amides - chemistry
Asparagine - chemistry
Aspartic Acid - chemistry
Biological and medical sciences
chemical stability
Chemistry, Pharmaceutical
deamidation
Drug Compounding
Excipients
formulation
General pharmacology
Hydrogen-Ion Concentration
Isomerism
Medical sciences
Particle Size
peptides
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Protein Structure, Secondary
Protein Structure, Tertiary
proteins
Proteins - administration & dosage
Proteins - chemistry
Temperature
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Summary:The asparagine (Asn) deamidation and aspartate (Asp) isomerization reactions are nonenzymatic intra-molecular reactions occurring in peptides and proteins that are a source of major stability concern in the formulation of these biomolecules. The mechanisms for the deamidation and isomerization reactions are similar since they both proceed through an intra-molecular cyclic imide (Asu) intermediate. The formation of the Asu intermediate, which involves the attack by nitrogen of the peptide backbone on the carbonyl carbon of the Asn or the Asp side chain, is the rate-limiting step in both the deamidation and the isomerization reactions at physiological pH. In this article, the influence of factors such as formulation conditions, protein primary sequence, and protein structure on the reactivity of Asn and Asp residues in proteins are reviewed. The importance of formulation conditions such as pH and solvent dielectric in influencing deamidation and isomerization reaction rates is addressed. Formulation strategies that could improve the stability of proteins to deamidation and isomerization reactions are described. The review is intended to provide information to formulation scientists, based on protein sequence and structure, to predict potential degradative sites on a protein molecule and to enable formulation scientists to set appropriate formulation conditions to minimize reactivity of Asn and Asp residues in protein therapeutics.
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.20740