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Analytical and prep...
Analytical and preparative separation of phosphorothioated oligonucleotides : Columns and ion-pair reagents
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- Enmark, Martin, 1984- (författare)
- Uppsala universitet,Karlstads universitet,Institutionen för ingenjörs- och kemivetenskaper (from 2013),Uppsala University,Farmakognosi,Karlstad Univ, Dept Engn & Chem Sci, S-65188 Karlstad, Sweden
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- Bagge, Joakim (författare)
- Karlstads universitet,Institutionen för ingenjörs- och kemivetenskaper (from 2013),Karlstad Univ, Dept Engn & Chem Sci, S-65188 Karlstad, Sweden
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- Samuelsson, Jörgen, 1971- (författare)
- Karlstads universitet,Institutionen för ingenjörs- och kemivetenskaper (from 2013),Karlstad Univ, Dept Engn & Chem Sci, S-65188 Karlstad, Sweden
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- Thunberg, Linda (författare)
- AstraZeneca, BioPharmaceut R&D, Pharmaceut Sci, Early Chem Dev, S-43183 Mölndal, Sweden
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- Ornskov, Eivor (författare)
- AstraZeneca, BioPharmaceut R&D, Pharmaceut Sci, Adv Drug Delivery, S-43183 Mölndal, Sweden
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- Leek, Hanna (författare)
- AstraZeneca, BioPharmaceut R&D, Pharmaceut Sci, Early Chem Dev, S-43183 Mölndal, Sweden
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- Lime, Fredrik (författare)
- Nouryon, Separat Prod, S-44580 Bohus, Sweden
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- Fornstedt, Torgny, 1957- (författare)
- Karlstads universitet,Institutionen för ingenjörs- och kemivetenskaper (from 2013),Karlstad Univ, Dept Engn & Chem Sci, S-65188 Karlstad, Sweden
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(creator_code:org_t)
- 2019-12-09
- 2020
- Engelska.
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Ingår i: Analytical and Bioanalytical Chemistry. - : Springer. - 1618-2642 .- 1618-2650. ; 412:2, s. 299-309
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Abstract
Ämnesord
Stäng
- Oligonucleotide drugs represent an emerging area in the pharmaceutical industry. Solid-phase synthesis generates many structurally closely related impurities, making efficient separation systems for purification and analysis a key challenge during pharmaceutical drug development. To increase the fundamental understanding of the important preparative separation step, mass-overloaded injections of a fully phosphorothioated 16mer, i.e., deoxythymidine oligonucleotide, were performed on a C18 and a phenyl column. The narrowest elution profiles were obtained using the phenyl column, and the 16mer could be collected with high purity and yield on both columns. The most likely contribution to the successful purification was the quantifiable displacement of the early-eluting shortmers on both columns. In addition, the phenyl column displayed better separation of later-eluting impurities, such as the 17mer impurity. The mass-overloaded injections resulted in classical Langmuirian elution profiles on all columns, provided the concentration of the ion-pairing reagent in the eluent was sufficiently high. Two additional column chemistries, C4 and C8, were also investigated in terms of their selectivity and elution profile characteristics for the separation of 520mers fully phosphorothioated deoxythymidine oligonucleotides. When using triethylamine as ion-pairing reagent to separate phosphorothioated oligonucleotides, we observed peak broadening caused by the partial separation of diastereomers, predominantly seen on the C4 and C18 columns. When using the ion-pair reagent tributylamine, to suppress diastereomer separation, the greatest selectivity was found using the phenyl column followed by C18. The present results will be useful when designing and optimizing efficient preparative separations of synthetic oligonucleotides.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
- NATURVETENSKAP -- Kemi -- Analytisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Analytical Chemistry (hsv//eng)
Nyckelord
- Ion-pair RPLC
- Therapeutic oligonucleotides
- Phosphorothioate
- Diastereomers
- Overloaded peaks
- Preparative separations
- Kemi
- Chemistry
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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