Recent developments in preparative-scale supercritical fluid- and liquid chromatography for chiral separations

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Highlights

  • Overview of evolutions in preparative-scale SFC and LC for enantioseparations.

  • Recent developments in instrumentation and methods for chiral compounds.

  • Preparative enantioseparation of pharmaceuticals, natural products and pesticides.

Abstract

This review covers preparative-scale chromatography for enantioseparations in both supercritical fluid and liquid chromatography published between 2016 and 2020. When pertinent, some fundamental publications from outside this time window are cited. The recent developments in instrumentation, novelties in method development and chiral stationary- and mobile phases are placed in context, while throughput, scale-up and sample issues are presented for supercritical fluid chromatography, and large-batch techniques together with computer-assisted method development, are described for liquid chromatography. Preparative-scale applications are reported for natural products, pharmaceutical compounds and pesticides, as well some other small molecules. Finally, a section is devoted to reports comparing supercritical fluid- and liquid chromatography and the strategies of various commercial users are briefly described. The goal of this review is to present current practices in the field of medium to large-scale chiral separations and offer indications as to how the best approach may be chosen for a given application.

Introduction

Why did evolution favor l-amino acids and D-sugars as the homochiral building blocks of proteins and nucleic acids in all living species? While its origins remain obscure, chirality exerts a profound influence on biology and defines many of the key mechanisms of life. Chiral molecules consist of at least two forms which cannot be superimposed on their mirror image, known as enantiomers or optical isomers, and different enantiomers can have very different pharmacological effects. The global market for chiral chemicals was valued at USD 39.79 billion in 2015 and is projected to expand at a compound annual growth rate of 13.67% to be USD 96.89 billion by 2023. Within this market are flavors and fragrances, agrochemicals such as herbicides, pesticides, plant growth regulators and fungicides (30% of registered pesticides are chiral compounds [1]), and lastly pharmaceuticals within which chiral compounds accounted for 72.5% of the global market in 2015. Among the top-selling drugs on the market, most of the pharmaceutical blockbusters are pure stereoisomers, clearly showing that methods which separate enantiomers are needed for biological testing [2].

Among the different methods developed for enantioseparation, chromatographic resolution of the racemic mixture is the most widely used technology (for more on the available methods, the reader is referred to a comprehensive review from 2018 detailing both analytical- and preparative-scale enantioseparation by chromatography and related methods [3]). Two approaches can be pursued: the first, “indirect” one forms true diasteroisomers, through derivatization of the compound using a chiral agent (CDA), which can then be subsequently separated in an achiral environment; the second, “direct” one, forms transient diastereoisomers between the solute and either a chiral stationary phase (CSP) or a chiral additive to the mobile phase (CAMP). While the CAMP method is classically employed in capillary electrophoresis (CE), this direct approach is not very popular in either supercritical fluid chromatography (SFC) or high-performance liquid chromatography (HPLC), mainly because it is only suitable for analytical-scale and not preparative-scale separations. However CE presents many advantages over chromatography, primarily derived from the small dimensions of the silica capillary. These include high flexibility and separation power, short migration times, low consumption of analyte and chemicals, and a wealth of available chiral selector types, while the use of capillaries results in very high plate numbers. The first CE chiral separation was reported in 1985 by Gassman et al. [4] on the resolution of amino acids using a ligand-exchange separation mechanism. Three years later, Snopek et al. achieved the separation of pseudoephedrine enantiomers using β-cyclodextrin and heptakis (2,6-di-O-methyl)-β-cyclodextrin as additives to the leading electrolyte in isotachophoresis [5]. Recently, the major contributions to chiral resolution by CE have been reported by the groups such of Fanali, Chankvetadze, Fillet and Scriba, among others [[6], [7], [8], [9]].

While HPLC with single and multi-column processes has been used for many years [[10], [11], [12]], SFC is starting to carve out a niche [13] thanks, in particular, to the work of Berger and colleagues in the mid-1990s [14], and has found its main field of application in chiral separation at the preparative scale [15,16].

This review will report the recent developments in preparative-scale chromatographic separations, covering preparative SFC and HPLC publications over the last five years and highlighting the emerging trends at the dawn of the 2020s. Readers will find a summary table (named Table 4) at the end of the manuscript summarizing the publications cited herein and one at the end of each of the three applications sections (Section 4) summarizing the methods used.

Section snippets

Supercritical fluid chromatography

The first application of a supercritical fluid as a mobile phase for chromatography was reported by Klesper et al. [17] in 1962. However, because of poor availability of accurate and reliable commercial devices, use of supercritical fluid chromatography was confined for many years to academic research [18] with home-made devices. It was not until the early 1990s that a first generation of SFC devices was commercialized by several suppliers such as Gilson or Hewlett-Packard (HP) then by Berger,

Chiral stationary phases and mobiles phases

The choice of a preparative chiral stationary phase (CSP), in both SFC and HPLC, is based upon several criteria: the CSP must be universal to separate different types of compounds with a high resolution; the utilization of the CSP in preparative chromatography requires a high loading capacity; and finally, it is best to select robust CSPs to handle many purifications – indeed, the only thing all CSPs have in common is their high cost, making it expensive to change them often. A few evolutions

Recent applications at the preparative-scale from 2016 to 2020

The present article covers the published works from 2016 to 2020, but the reader may refer to a review by Speybrouck and Lipka for studies published before 2016 [16].

Conclusion

The new developments and applications in preparative chiral SFC and chiral HPLC have been reviewed in the previous sections and the pros and cons of each method have been summarized in Fig. 1. We have described how the advances in preparative SFC and HPLC are being led by the appearance on the market of new CSPs, able to be used with more nonpolar solvents like DCM while at the same time exhibiting improved robustness and loadability. Innovative injection techniques and intelligent recycling

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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