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Peptide Synthesis: Solution Phase, Solid Phase or Hybrid?

Choosing the Right Synthesis Technique for Your Peptide API.

Peptide synthesis has roots dating back more than a century. Given its age, it may seem strange that peptide synthesis is currently undergoing a revolution…but it is. A new generation of therapeutics, diagnostics and research tools are emerging on the healthcare scene – a by-product of the industry’s turn towards biologics and a greater understanding of the benefits of peptides.

The Benefits of Peptide Therapeutics

Peptides offer some benefits not typically found in their larger or smaller siblings (proteins and small molecules). For example, they are highly-specific, and offer improved toxicological profiles. (Learn more about them in our previous post: Therapeutic Peptides – Has This Emerging Market Grown Up?)

Peptides – Different Production Methods

Peptides are produced using one of three synthesis methods: solution phase, solid phase or a hybrid approach. Each has its advantages and disadvantages.

  • Solution phase synthesis (commonly referred to as ‘liquid phase’) is regarded as the traditional approach to peptide production. Among its benefits, solution phase synthesis delivers better economies of scale – the technique is much more scalable, can produce large quantities of high-quality peptides, and at a lower cost point than solid phase or hybrid methods. Solution phase, however, is not well-suited to the production of larger peptides.
  • In solid phase synthesis, the peptide is constructed on resins (e.g., polystyrene, polyacrylamide, PEG).  The key advantage with solid phase is the ability to synthesize peptides which don’t lend themselves to bacterial expression using solution phase techniques. One of the major challenges facing solid phase synthesis, however, is yield – as the size of the peptide increases, yields typically decrease due to the challenge of removing closely related impurities from the product. And while some molecules don’t lend themselves to bacterial synthesis, others aren’t well-adapted to solid phase synthesis – either because of the inherent aggregation encountered during the assembly of longer peptides, or due to the chemicals used to remove them from the resin – which can damage the peptide. Production costs also tend to be substantially higher in solid phase synthesis.
  • The hybrid approach brings these two different methodologies together to produce peptides. For example, to construct a 40-amino acid peptide, small peptides of 5 to 8 amino acid segments would be produced using solid phase methods on resins, and then the segment condensations would occur in solution to construct the full peptide sequence.

Choosing the Right Production Method

The choice of which method to use is generally guided by a number of factors. A key factor is the desired chiral purity/integrity of the peptide. As a major supplier of commercial quantities of pseudoprolines, Neuland can exploit them for racemization-free condensations of segmentsterminating in a serine or threonine residue. This strategy allows us to maintain purity through the various segment synthesis steps – especially with longer (or more difficult to produce) peptides.

Other factors which drive the choice of synthesis method include:

  1. The number of amino acids in the peptide
  2. The scale of production (gram or sub-gram up through kilogram quantities)
  3. The timeframe required for the peptide

Peptides – Lowering the Production Cost
One aspect of peptide production that has historically proven a barrier to commercialization of peptide-based therapeutics is production cost. We’ve overcome this by developing proprietary preparative HPLC methods that allow purification at about 10% of the cost of our peers – bringing the use of peptides further into the mainstream of drug development.

What peptide synthesis methods does your company use? Share your experiences below.


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