A two-step continuous flow synthesis of multi-tail ionizable lipids.

Area of Science:

• Chemical Engineering
• Organic Chemistry
• Materials Science

Background:

• Lipid nanoparticles (LNPs) are essential for delivering RNA therapeutics.
• Current synthesis methods for ionizable lipids can be time-consuming and involve hazardous intermediates.
• Scalable and safe manufacturing processes are needed for LNP components.

Purpose of the Study:

• To develop a robust and safe continuous flow synthesis for multi-tail ionizable lipids.
• To optimize the epoxidation and polyalkylation steps for efficiency and safety.
• To demonstrate the scalability and throughput of the continuous flow process.

Main Methods:

• Continuous flow epoxidation of long-chain terminal alkenes using Oxone/acetone.
• Catalyst-free polyalkylation via high-temperature epoxide ring-opening in flow.
• In-line alkylation of crude epoxidation products.

Main Results:

• Nearly quantitative conversion in epoxidation, safely managing hazardous intermediates.
• Dramatic reduction in reaction time for polyalkylation (20 minutes residence time vs. days in batch).
• Production of representative ionizable lipids with a throughput >10 g/h in a lab setting.

Conclusions:

• Continuous flow synthesis provides a rapid, safe, and scalable method for producing ionizable lipids.
• The developed process overcomes limitations of traditional batch synthesis.
• This approach holds significant potential for industrial-scale manufacturing of LNP components for RNA therapeutics.