Optimizing the Solid Phase Preparation for Oligonucleotide Synthesis
(2026) KASM05 20261Centre for Analysis and Synthesis
- Abstract
- Oligonucleotides are short fragments of RNA or DNA that can act as active pharmaceutical ingredients (API) in medicines used to target a wide range of diseases, with further applications continuously emerging. Solid Phase Oligonucleotide Synthesis (SPOS) remains the dominant platform for oligonucleotide production. However, SPOS is characterized by high reagent consumption and a poor sustainability profile. This study targets the solid phase preparation stage as a key opportunity for process optimization, focusing on coupling efficiency, capping performance, and solid support swelling behavior in different solvents across different loadings.
A solvent screening revealed potential substitutes that outperformed the current solvent in... (More) - Oligonucleotides are short fragments of RNA or DNA that can act as active pharmaceutical ingredients (API) in medicines used to target a wide range of diseases, with further applications continuously emerging. Solid Phase Oligonucleotide Synthesis (SPOS) remains the dominant platform for oligonucleotide production. However, SPOS is characterized by high reagent consumption and a poor sustainability profile. This study targets the solid phase preparation stage as a key opportunity for process optimization, focusing on coupling efficiency, capping performance, and solid support swelling behavior in different solvents across different loadings.
A solvent screening revealed potential substitutes that outperformed the current solvent in coupling efficiency, despite being lower in polarity. These results could be explained by enhanced solid support swelling and improved diffusional accessibility of reactive sites. Optimization of the capping step demonstrated that reagent volumes can be reduced from 2.00 to 0.66 solid phase volumes without significant loss of performance when using the current formulation, representing an increase of 80% in production capacity. Furthermore, elevated temperature was shown to enhance capping efficiency, enabling shorter reaction times and highlighting the importance of mass transfer and reaction kinetics. A swelling study across multiple solvents and loadings indicated that succinate linker loading has negligible influence on swelling within the investigated range, whereas the solid support composition plays a dominant role.
Collectively, these findings demonstrate that targeted optimization of solvent selection, capping reagent volumes, and process conditions significantly can improve the efficiency and sustainability of SPOS without compromising performance or requiring fundamental changes to established manufacturing workflows. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/student-papers/record/9230625
- author
- Linder, Elsa LU
- supervisor
- organization
- course
- KASM05 20261
- year
- 2026
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Oligonucleotides, solvent, Solid-phase synthesis, SPOS, Organic chemistry
- language
- English
- id
- 9230625
- date added to LUP
- 2026-06-04 09:29:40
- date last changed
- 2026-06-04 09:29:40
@misc{9230625,
abstract = {{Oligonucleotides are short fragments of RNA or DNA that can act as active pharmaceutical ingredients (API) in medicines used to target a wide range of diseases, with further applications continuously emerging. Solid Phase Oligonucleotide Synthesis (SPOS) remains the dominant platform for oligonucleotide production. However, SPOS is characterized by high reagent consumption and a poor sustainability profile. This study targets the solid phase preparation stage as a key opportunity for process optimization, focusing on coupling efficiency, capping performance, and solid support swelling behavior in different solvents across different loadings.
A solvent screening revealed potential substitutes that outperformed the current solvent in coupling efficiency, despite being lower in polarity. These results could be explained by enhanced solid support swelling and improved diffusional accessibility of reactive sites. Optimization of the capping step demonstrated that reagent volumes can be reduced from 2.00 to 0.66 solid phase volumes without significant loss of performance when using the current formulation, representing an increase of 80% in production capacity. Furthermore, elevated temperature was shown to enhance capping efficiency, enabling shorter reaction times and highlighting the importance of mass transfer and reaction kinetics. A swelling study across multiple solvents and loadings indicated that succinate linker loading has negligible influence on swelling within the investigated range, whereas the solid support composition plays a dominant role.
Collectively, these findings demonstrate that targeted optimization of solvent selection, capping reagent volumes, and process conditions significantly can improve the efficiency and sustainability of SPOS without compromising performance or requiring fundamental changes to established manufacturing workflows.}},
author = {{Linder, Elsa}},
language = {{eng}},
note = {{Student Paper}},
title = {{Optimizing the Solid Phase Preparation for Oligonucleotide Synthesis}},
year = {{2026}},
}