Gradient enhanced-fluidity liquid hydrophilic interaction chromatography of ribonucleic acid nucleosides and nucleotides: A “green” technique

CONSPECTUS: Manufacturing process development of new drug substances in the pharmaceutical industry combines numerous chemical challenges beyond the efficient synthesis of complex molecules. Optimization of a synthetic route involves the screening of multiple reaction variables with a desired outcome that not only depends on an increased product yield but is also highly influenced by the removal efficacy of residual chemicals and reaction byproducts during the subsequent synthetic route. Consequently, organic chemists must survey a wide array of synthetic variables to develop a highly productive, green, and cost-effective manufacturing process. The time constraints of developing robust quantitative methods prior to each processing step can easily lead to sample analysis becoming a bottleneck in synthetic route development. In this regard, conventional "on demand" analytical method development and optimization approaches, traditionally used for guiding synthetic chemistry efforts, become unsustainable. This Account introduces recent efforts to address the aforementioned challenges through the development and implementation of generic or more universal chromatographic methods that can cover a broad spectrum of targeted compound classes. Such generic methods require significant resolving power to enable baseline resolution of multicomponent mixtures in a single experimental run without additional method customization but must be simple enough to allow for routine use by chemists, chemical engineers and other researchers with little experience in chromatographic method development. These powerful analytical methodologies are often employed to minimize the time spent developing new analytical assays, while also facilitating method transfer to manufacturing facilities and application in regulatory settings. Diverse examples of universal and fit-for-purpose analytical procedures are presented herein, illustrating the power of modern readily available analytical technology for streamlining the development of new drug substances in organic chemistry laboratories across both academic and industrial sectors. With recent advances in analytical instrumentation and column technologies, universal chromatographic methods are quickly becoming a proactive and effective strategy to accelerate the discovery and implementation of new synthetic methodologies, especially but not limited to laboratories where the synthetic process route is undergoing rapid change and optimization. Targets of these generic methods include analysis of organic solvents, acid and basic additives, nucleotide species, palladium scavengers, impurity mapping, enantiopurity, synthetic intermediates, active pharmaceutical ingredients and their counterions, dehalogenation byproducts, and mixtures of organohalogenated pharmaceuticals, among other chemicals used or formed in process chemistry reactions.

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Section: Generic Procedures For Analytical and Preparative Separation...mentioning

confidence: 99%

The Emergence of Universal Chromatographic Methods in the Research and Development of New Drug Substances

et al. 2019

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“…In HILIC separations, the addition of CO 2 to the conventional mobile phases makes the replacement of acetonitrile with methanol or ethanol possible, resulting in greener separations. This strategy has been recently applied for the analysis of nucleosides/ nucleotides, 253 amino acids, 254 drugs, and natural products. 254 The last strategy to minimize organic solvent consumption is to play with the column-related parameters.…”

Section: ■ Greening Lcmentioning

confidence: 99%

Recent Advances in Chromatography for Pharmaceutical Analysis

et al. 2018

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“…CO 2 reduces the viscosity of the ethanolic and methanolic mobile phases while retaining similar eluent strength and retention behavior than acetonitrile:water when used in HILIC mode. Consequently, it has been successfully applied to the fast separation of 16 RNA nucleosides/ nucleotides, 89 amino acids, 90 drugs and natural products. 91 McClain et al 92 suggest an attractive green chromatographic approach exploiting the advantages of LC and SFC in order to reduce the environmental footprint of flash chromatography, and then contributing to their sustainable applications.…”

Section: Acs Sustainable Chemistry and Engineeringmentioning

confidence: 99%

Sustainable and Eco-Friendly Alternatives for Liquid Chromatographic Analysis

Olives

González‐Ruiz

Martín

2017

ACS Sustainable Chem. Eng.

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This Perspectives article covers the most relevant current strategies aimed at reducing the environmental fingerprint caused by mobile phases in liquid chromatography. Modern stationary phases, such as columns packed with core− shell particles or stationary phases allowing high-temperature separations, are discussed. Mobile-phase additives creating secondary partitioning equilibria (micelle-forming reagents, cyclodextrins, or ionic liquids) and alternatives to acetonitrile as organic solvent are critically compared in terms of separation efficacy and wastes' toxicity. Advantages of CO 2 and superheated solvents are also considered to complete the picture of the most recent developments in the field.

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Gradient enhanced-fluidity liquid hydrophilic interaction chromatography of ribonucleic acid nucleosides and nucleotides: A “green” technique

Cited by 36 publications

References 28 publications

The Emergence of Universal Chromatographic Methods in the Research and Development of New Drug Substances

The Emergence of Universal Chromatographic Methods in the Research and Development of New Drug Substances

Recent Advances in Chromatography for Pharmaceutical Analysis

Sustainable and Eco-Friendly Alternatives for Liquid Chromatographic Analysis

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