Solid-Phase vs. Liquid-Phase Oligonucleotide Synthesis: Which is the Future?

Oligonucleotide synthesis has long relied on solid-phase synthesis, a well-established method that has been the industry standard for decades. However, as demand for oligonucleotides continues to rise—particularly in therapeutics and research—manufacturers are seeking more scalable, cost-effective, and sustainable solutions.

Enter liquid-phase synthesis, an emerging alternative that is showing promise for large-scale production. But how do these two methods compare, and is liquid-phase synthesis the future of oligonucleotide manufacturing? Let’s break it down.

 

1. Solid-Phase Oligonucleotide Synthesis: The Industry Standard

How It Works:

Solid-phase synthesis involves attaching nucleotides to a solid support (typically a resin bead) and building the oligonucleotide step by step through chemical reactions. Once the synthesis is complete, the final product is cleaved from the support, purified, and processed.

 

Strengths of Solid-Phase Synthesis:

✓ High efficiency for short oligonucleotides – Ideal for research and diagnostic applications.
✓ Established process – Widely used in the biotech industry, with well-developed protocols.

 

Limitations of Solid-Phase Synthesis:

✖️ Scalability issues – The process becomes inefficient and costly when producing large amounts.
✖️ High reagent consumption – Significant waste is generated, leading to higher Process Mass Intensity (PMI).
✖️ Limited sequence length – Producing longer, more complex oligonucleotides is challenging.

 

2. Liquid-Phase Oligonucleotide Synthesis: A Game-Changer?

How It Works:

Liquid-phase synthesis eliminates the need for a solid support. Instead, oligonucleotides are synthesised in solution, allowing for more flexibility in reaction conditions, purification, and product recovery.

 

Advantages of Liquid-Phase Synthesis:

✓ Better scalability – Easier to scale up for commercial production.
✓ Higher purity and yield – More controlled reactions lead to fewer side products.
✓ Lower reagent consumption – Reduces PMI, making the process more sustainable and cost-effective.
✓ Compatible with advanced purification methods – Technologies like Nanostar Sieving improve efficiency and product quality.

 

Challenges of Liquid-Phase Synthesis:

✖️ Requires specialised expertise – Unlike solid-phase synthesis, liquid-phase processes are still evolving.
✖️ Equipment investment – Companies need to invest in new technologies to transition from solid-phase methods.

 

3. The Future of Oligonucleotide Synthesis: Why Liquid-Phase is Gaining Ground

While solid-phase synthesis has served the industry well, it struggles to keep up with growing commercial demand. The biotech sector is moving toward larger-scale production, making efficiency, cost, and sustainability more important than ever.

This is where Exactmer’s innovations in liquid-phase synthesis, particularly Nanostar Sieving, are changing the game. By addressing scalability, purity, and sustainability, liquid-phase synthesis is positioning itself as the future of oligonucleotide manufacturing.

 

Key Takeaways:

✓ For small-scale research applications, solid-phase synthesis remains practical.
✓ For large-scale therapeutic and commercial oligonucleotide production, Liquid phase shows promise in offering improved efficiency.
✓ Innovations like Nanostar Sieving are making liquid-phase synthesis a viable, cost-effective alternative.

 

Final Thoughts

As demand for oligonucleotides continues to rise, the limitations of solid-phase synthesis are becoming increasingly apparent. Liquid-phase synthesis is emerging as the next step forward, offering a more scalable, cost-effective, and environmentally friendly approach.

At Exactmer, we are leading this transformation with our Nanostar Sieving and liquid-phase synthesis technologies, helping manufacturers achieve higher efficiency and lower PMI.

 

Want to learn more about how Exactmer’s innovations can optimise your oligonucleotide synthesis? Get in touch with us today.