Solid-phase oligonucleotide synthesis (SPOS) is a highly efficient and reproducible process, but it has significant environmental limitations, primarily due to the high consumption of organic solvents and the generation of chemical waste. In this context, process optimisation is a key strategy for moving towards more sustainable production models, in line with the principles of green chemistry.

One of the key areas for improvement lies in reducing the volume of solvents used during synthesis cycles. Acetonitrile, which is widely used due to its ability to dissolve phosphoramidites and ensure adequate reaction kinetics, accounts for a significant proportion of the process’s overall environmental impact.

Another critical aspect is improving coupling efficiency. In conventional protocols, excess phosphoramidites and activators are used to ensure high yields in each cycle, which increases the Process Mass Intensity (PMI). Optimising these reagents through the use of more selective activators or improved reaction conditions makes it possible to reduce such excesses, thereby decreasing both material consumption and the formation of by-products. This approach not only has a positive environmental impact, but also improves the economic efficiency of the process.

At the same time, the reduction of unnecessary stages or the integration of operations (process intensification) represents another way to achieve optimisation. The simplification of synthetic cycles, the elimination of washes redundant and the implementation of strategies for synthesis more compact strategies reduce the total number of operations and, consequently, the volume of solvents used. These improvements require a a35> thorough understanding of the kinetics and thermodynamics of the system, as well as a precise control of the reaction conditions.

As part of the project Syoligo, these optimisation strategies take on particular significance. The initiative promotes the development of therapeutic oligonucleotides through an approach that combines sustainability with scientific excellence. In this regard, improving synthesis processes is not limited to ensuring the quality of the final product, but also aims to reduce its environmental impact from the earliest stages of development. The adoption of more efficient methodologies, together with the continuous assessment of indicators such as the PMI or carbon footprint, enables progress towards more responsible production.

Furthermore, digitalisation and the use of advanced modelling tools facilitate real-time process optimisation. The application of new technologies makes it possible to identify optimal reaction conditions, minimise resource consumption and anticipate waste generation. These technologies, which are increasingly being integrated into environments, are essential for accelerating the transition towards more sustainable processes.

En conclusión, la optimización de procesos químicos en la síntesis de oligonucleótidos es un pilar esencial para reducir el consumo de solventes y la generación de residuos. A través de la mejora en la eficiencia de reacción, la reducción de etapas y la incorporación de tecnologías avanzadas, es posible avanzar hacia modelos de producción alineados con los principios de la química verde. Iniciativas como Syoligo reflect this commitment, placing sustainability at the heart of development of new therapies based on nucleic acids.

Resources:

Green innovations in oligopeptide to oligonucleotide sustainable synthesis (RSC, 2023)

Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing (ACS)

Trimming synthetic peptide and oligonucleotide waste-lines (Current Opinion, 2022)