Peptide impurity synthesis
Peptides are reaction products of dehydration condensation of amino acids. Peptides are easy to synthesize and sequence optimized, their medicinal value can be quickly determined. Due to peptide characteristics, the time required for peptides to go from clinical trials to approval by the US FDA is much shorter than that of small molecule drugs, the probability of peptide drugs passing clinical trials is twice as high as that of small molecule compounds.
Compared with small molecular compounds, peptides generally have a shorter half-life and are easily metabolized in the body; compared with macromolecular proteins or antibody drugs, peptides are more stable and require less dosage and higher unit activity; compared with macromolecular proteins, technology of peptide & peptide impurity synthesis is mature, easy to separate from impurities, and has higher purity.
In addition, recombinant protein cannot introduce unnatural amino acids, it is difficult to modify the end, the production cycle is long, cost is high. With the advancement of science and technology, the synthetic and commercial costs of peptides have dropped significantly. These advantages give peptides specific advantages in drug development.
The solid-phase synthesis of peptides has been widely used nowadays. In the process of peptide synthesis and storage, related structural impurities are easily formed, such as amino acid loss, amino acid insertion, deamination, degradation products, etc.
Many related structural impurities not only have no medicinal effect, but have certain toxic and side effects. Therefore, the European Pharmacopoeia requires qualitative analysis of related structural impurities with a content of more than 0.5%, quantitative analysis of related structural impurities with a content of more than 1%, and investigation of their toxic and side effects.
6 impurities that appear during the peptide synthesis & storage of peptides:
1. Amino acid deletion/ insertion
In solid-phase peptide synthesis, incomplete removal of amino acid protecting groups attached to the resin or the introduction of incompletely activated amino acids will reduce the efficiency of the condensation reaction, which will result in the loss of one or more amino acids in the entire peptide chain.
During transportation and storage, peptides will also produce a small amount of degradation products, missing one or more amino acids at the N or C-terminus, which can also be classified as amino acid-deleted impurities.
In solid-phase synthesis of peptides, an excess of amino-protected amino acids is often added to ensure maximum condensation efficiency. However, if the excess reactants are not completely washed away after the condensation reaction, additional amino acids will be inserted into the target peptide sequence.
2. Protective group residues
In solid-phase synthesis of peptides, sometimes the protecting group cannot be completely removed (amino group protection, side chain protection, etc.), which will cause the protecting group to remain in the target peptide.
3. Oxidation / reduction
Certain amino acid residues are prone to oxidation/reduction reactions during solid-phase peptide synthesis. Prolonged exposure to light or exposure to air during storage of histidine and lysine can lead to the formation of oxidative impurities. The side chain of tryptophan can be oxidized to generate impurities under acidic conditions, and can also undergo reduction reactions.
Amino acid racemization in peptides. Even a small amount of isomeric impurities, even a single amino acid isomerization, can greatly affect the overall biological function
5. Side chain / terminal modification impurities
Side chain impurities can be mainly divided into 2 categories: impurities introduced by side chain protecting groups and impurities introduced by amino acid side chain itself with reactivity. Such as the deamination of the side chains of two basic amino acids, asparagine and glutamine.
Chain-end impurities include two categories: one is the impurities produced by N-terminal acylation or C-terminal deamidation, such as N-terminal acetylation. Another class of impurities is those formed by reactive groups at the end of the chain.
6. Peptide aggregates
Peptide aggregation can be divided into two types, covalent and non-covalent, and the degree of its formation depends on various environmental factors. Covalent aggregates are usually formed by two monomers through amide bonds and disulfide bonds.
Non-covalent aggregates are the result of weak interactions such as hydrophobic interactions and electrostatic interactions. Usually there is an equilibrium switch between non-covalent aggregates and their monomers. During the purification and storage process of peptide drugs, a certain amount of polymeric impurities may be generated.
COA of Peptide Impurity Cases:
Fast Links of Peptide Impurities Synthesis:
>> Salmon Calcitonin Impurities
>> Desmopressin Impurities
>> Liraglutide Impurities
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