Liquid-Phase Peptide Synthesis: Where LPPS Can Outperform SPPS | Alan Scientific

Solid-phase peptide synthesis transformed peptide chemistry because it solved one of its most repetitive problems: intermediate separation. The growing peptide remains attached to an insoluble resin while excess amino acids, coupling reagents and deprotection products are removed by filtration and washing.

That architecture remains exceptionally powerful for research-scale peptide synthesis. It is rapid, automatable and tolerant of sequence diversity, which is why solid-phase peptide synthesis remains the dominant platform for custom peptide production.

The situation changes as peptide manufacturing moves toward longer sequences, lipidated peptides, cyclic peptides and larger commercial volumes. At that point, peptide-bond formation itself is often no longer the dominant process problem. Solvent consumption, reagent excess, purification and isolation increasingly determine manufacturing efficiency.

This is where modern liquid-phase peptide synthesis, or LPPS, becomes interesting again.

Alan Scientific's view is that the current LPPS revival should not be understood as a competition between “old liquid-phase chemistry” and SPPS. The more useful interpretation is that LPPS attempts to redesign how the growing peptide is separated after each reaction.

LPPS Is Really a Separation Technology

Classical solution-phase peptide synthesis has always been capable of producing peptides. Its fundamental limitation is that every growing intermediate must somehow be separated from reagents and by-products before the next reaction.

Modern LPPS changes this by attaching the peptide to a soluble support or molecular tag.

The tagged peptide remains soluble during coupling, allowing the reaction to occur under homogeneous solution conditions. After reaction, the solvent environment is changed so that the peptide-tag conjugate can be selectively precipitated, partitioned, retained or otherwise separated.

The 2022 Chemical Reviews analysis of LPPS describes systems based on PEG supports, membrane-enhanced peptide synthesis, fluorous technology, ionic liquids, PolyCarbon, hydrophobic polymers and group-assisted purification. The common principle is that peptide elongation occurs in solution while the tag provides a physical property that simplifies isolation.

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Figure 1. SPPS and modern LPPS solve the same separation problem through different physical strategies. SPPS immobilizes the peptide on a resin; modern LPPS keeps the peptide soluble during reaction and changes its physical behavior during isolation.

That distinction is important because the chemistry used to make the peptide bond may be relatively conventional. The innovation lies in making the growing peptide behave differently from the excess reagents surrounding it.

In other words, modern LPPS is as much separation engineering as peptide chemistry.

Why the Industry Is Looking Again at Liquid Phase

The strongest argument for revisiting peptide manufacturing architecture comes from process mass data.

In 2024, the ACS Green Chemistry Institute Pharmaceutical Roundtable published manufacturing data covering 40 synthetic peptide processes from 14 pharmaceutical companies. The average process mass intensity for SPPS was approximately 13,000 kg of input material per kilogram of peptide product. Commercial and Phase 3 processes were reported at an average PMI of approximately 13,603.

The magnitude of the solvent contribution is equally important.

Across the synthesis operations included in the dataset, DMF represented 89.2% of normalized solvent consumption. In purification, water represented 77.3%, while acetonitrile contributed another 18.4%.

This changes how sustainable peptide synthesis should be discussed.

Replacing one coupling reagent with a greener alternative may be useful, but it does not address a process in which the majority of material moving through the plant is solvent.

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Figure 2. Normalized solvent composition reported in the ACS GCIPR peptide manufacturing dataset. DMF dominates the synthesis stage, while water and acetonitrile dominate purification.

This is also why statements such as “LPPS is greener because it does not use resin” are too simplistic.

A soluble-tag process may reduce resin washing but introduce precipitation solvent, anti-solvent, tag synthesis, filtration, redissolution and tag recovery. A process should therefore be evaluated by total material required to produce peptide meeting specification, not merely by whether resin is present.

That distinction is one of the most important principles in current peptide-process development.

Tirzepatide Shows Why LPPS Is Becoming Relevant Again

The significance of recent LPPS work becomes clearer when the technology moves beyond short model peptides.

In 2025, Pang and colleagues reported hydrophobic-tag-assisted LPPS for tirzepatide, a 39-residue modified peptide. The growing peptide was connected to a soluble hydrophobic tag whose distinctive solubility enabled solution-phase reaction followed by separation of the tagged product.

The researchers also used a Cbz/Fmoc dual-protection strategy to construct the modified lysine side chain. Importantly, the authors reported reduced wastage of amino acids and solvents relative to the heavily SPPS-dependent strategy they were addressing.

The significance is not simply that tirzepatide can be synthesized by another method.

Tirzepatide represents exactly the type of molecule for which peptide manufacturing is becoming more challenging: relatively long, highly engineered and containing a substantial side-chain modification.

A successful LPPS strategy for such a molecule suggests that soluble-support chemistry is beginning to move from methodological demonstrations toward process-relevant peptide structures.

The 2026 Surfactin Result Extends the Argument Further

An even more recent example involves the cyclic lipopeptide n-C14-surfactin.

A 2026 study reported hydrophobic-tag-assisted LPPS combined with an optimized sequential coupling and deprotection process. The synthesis delivered 17.5 g of purified n-C14-surfactin, with an overall yield of 72% across 13 steps.

The result matters because cyclic lipopeptides combine several manufacturing challenges at once: peptide elongation, strong hydrophobicity, lipid incorporation and macrocyclization.

The study therefore extends the LPPS discussion beyond linear peptides.

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Figure 3. Recent LPPS development is moving from platform chemistry toward longer modified peptides and process-relevant cyclic structures. The 2025 tirzepatide study and 2026 decagram-scale surfactin synthesis illustrate this transition.

This progression is more important than any single reported yield.

The field is gradually testing whether soluble-support peptide chemistry can tolerate the structural complexity that increasingly defines modern therapeutic peptides.

LPPS Does Not Eliminate the Hard Part; It Moves It

There is nevertheless a fundamental limitation that should not be overlooked.

In SPPS, a major process variable is resin behavior. Resin swelling, diffusion, aggregation and accessibility of the growing peptide can determine coupling performance.

In LPPS, the corresponding process variable becomes solubility behavior.

An effective soluble tag must satisfy two conflicting requirements. During reaction, the peptide-tag conjugate must remain sufficiently soluble for efficient homogeneous chemistry. During isolation, the same material must become sufficiently different from the surrounding reagents to permit selective recovery.

This challenge becomes progressively harder because the peptide does not remain chemically constant.

A five-residue tagged peptide and a thirty-residue tagged peptide may have completely different polarity, aggregation tendency, aromatic content and solvent compatibility.

This leads to a central Alan Scientific interpretation:

The limiting technology in future LPPS may not be peptide-bond formation. It may be predictive control of peptide-tag solubility and separation behavior.

That creates an interesting connection with computational peptide design. In the future, process development may increasingly model not only peptide biological properties but also aggregation, solvent compatibility and synthetic accessibility.

This would make LPPS a natural target for data-driven process optimization rather than simply another manual synthesis platform.

The Best Future Process Is Probably Hybrid

The peptide industry is unlikely to choose one universal winner between SPPS and LPPS.

SPPS has major advantages when sequence diversity is high, quantities are relatively small and rapid synthesis is more important than optimizing every kilogram of solvent.

LPPS becomes more attractive as a peptide moves toward repeated manufacturing, higher material demand, expensive protected amino acids, difficult modifications or process economics in which resin and solvent consumption become substantial.

The two approaches therefore occupy different parts of the development landscape.

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Figure 4. LPPS is not automatically preferable for longer peptides. Its value increases when repeated manufacturing, material efficiency, selective intermediate isolation and total purification burden become dominant process variables.

Alan Scientific therefore expects future peptide manufacturing to become increasingly hybrid.

One part of a molecule may be prepared by SPPS because automation and sequence flexibility are valuable. Another fragment may be produced in solution because scale and reagent efficiency matter more. Fragment coupling, soluble tags, enzymatic transformations, selective precipitation and chromatography can then be combined according to the specific molecule.

This is already conceptually consistent with recent complex glycopeptide work, where hydrophobic-tag-assisted liquid-phase synthesis has been integrated with enzymatic glycosylation to prepare structurally defined glycopeptides, including a 31-residue glycosylated GLP-1 derivative.

The relevant question is therefore no longer simply:

Should this peptide be made by SPPS or LPPS?

A better question is:

Which manufacturing architecture produces the required peptide quality with the lowest total process burden?

Conclusion

Liquid-phase peptide synthesis is attracting renewed attention because peptide manufacturing itself is changing.

Longer therapeutic peptides, lipidation, macrocyclization and increasing production volumes expose limitations that are less important when synthesizing milligram quantities of short research peptides.

Modern LPPS addresses these challenges by treating the growing peptide's physical properties as part of the synthesis strategy. Solubility, selective precipitation, membrane retention and phase behavior become process tools rather than downstream inconveniences.

The 2024 industrial PMI dataset demonstrates why reducing solvent and purification burden matters. The 2025 tirzepatide study demonstrates that soluble-tag LPPS can be applied to a long, highly modified therapeutic peptide. The 2026 surfactin work extends the concept to decagram-scale cyclic lipopeptide synthesis.

References

1. Sharma A, Kumar A, de la Torre BG, Albericio F. Liquid-Phase Peptide Synthesis (LPPS): A Third Wave for the Preparation of Peptides. Chemical Reviews. 2022;122(16):13516–13546. doi:10.1021/acs.chemrev.2c00132.
   This review provides the core framework for modern LPPS, including soluble PEG supports, membrane-enhanced peptide synthesis, fluorous technologies, ionic-liquid systems, hydrophobic tags and group-assisted purification.

2. Kekessie I, Wegner K, Martinez I, Kopach ME, et al. Process Mass Intensity (PMI): A Holistic Analysis of Current Peptide Manufacturing Processes Informs Sustainability in Peptide Synthesis. Journal of Organic Chemistry. 2024;89(7):4261–4282. doi:10.1021/acs.joc.3c01494.
   The study compiled 40 peptide manufacturing processes from 14 pharmaceutical companies and reported an average SPPS PMI of approximately 13,000, providing the industrial data behind the sustainability discussion in this article.

3. Pang ZJ, Mao CY, Feng TT, Dong L. Hydrophobic Tag-Assisted Liquid-Phase Synthesis of Tirzepatide. Organic Letters. 2025;27(37):10442–10446. doi:10.1021/acs.orglett.5c03314.
   This work demonstrated hydrophobic-tag-assisted LPPS for tirzepatide and reported reduced amino-acid and solvent waste through the soluble-tag strategy.

4. Inagaki Y, Wakamori S, Katsuta R, Ishigami K. Efficient Synthesis of the Cyclic Lipopeptide n-C14-Surfactin Using Soluble Hydrophobic Tag-Assisted Liquid-Phase Peptide Synthesis. Tetrahedron Letters. 2026;176:155934. doi:10.1016/j.tetlet.2025.155934.
   The study reported decagram-scale preparation of n-C14-surfactin with 72% overall yield across 13 steps, demonstrating that tag-assisted LPPS can extend into cyclic lipopeptide synthesis and macrocyclization.

5. Ma W, Deng Y, Xu Z, Liu X, Chapla DG, Moremen KW, Wen L, Li T. Integrated Chemoenzymatic Approach to Streamline the Assembly of Complex Glycopeptides in the Liquid Phase. Journal of the American Chemical Society. 2022;144(20):9057–9065. doi:10.1021/jacs.2c01819.
   This study integrated hydrophobic-tag-supported liquid-phase synthesis with enzymatic glycosylation and demonstrated applications including 16 SARS-CoV-2 O-glycopeptides, four MUC1 glycopeptides and a 31-residue glycosylated GLP-1.

Alan Scientific's view is that LPPS is unlikely to replace SPPS. Its larger impact may be to push peptide manufacturing away from a single-platform mindset and toward integrated process design.

The next major improvement in peptide synthesis may therefore come not from another stronger coupling reagent, but from designing reaction, intermediate separation and final purification as one continuous manufacturing problem.

Researchers developing conventional or structurally complex peptide projects can explore Custom Peptide Synthesis, Amino Acids & Peptide Building Blocks and Peptide Purification & Quality Control.