ABSTRACT
Historically, preparative supercritical fluid chromatography (SFC) was first envisaged by Klesper et al. in 1962 in their pioneering paper [1].However, it did not fully materialize until 1982, when Perrut developed and patented [2] a prototypical preparative SFC chromatographic process, together with an eluent recycling capability for the purification of achiral petrochemicals and fatty acid intermediates (used for cardiovascular drugs). Perrut and coworkers later disclosed the feasibility applications of their integrated SFC process in several ensuing patent applications [3-6] and conference presentations [7-9]. Their innovative work was reviewed in 1990 [10] together with a utility comparison with other known chromatographic techniques (GC, HPLC, and TLC) and had set
the stage for subsequent applications of preparative SFC in industrial separation processes [11-13]. In the two years spanning from 1998 to 1999 when multiple commercial preparative SFC instruments [1416] were available from various suppliers (Prochrom, Gilson, Berger, Jasco, and Thar), there were approximately 45 publications [17-21] relating to preparative SFC, most of which were primarily focused on the setup of industrial processes, trial-and-error equipment customizations and/or feasibility studies of various self-integrating SFC instrumentation units directly adapted from LC systems. Such studies, summarized in a few well-documented reviews [22-26], included separations of both achiral and chiral petrochemicals, natural products, pharmaceuticals, and agrochemicals on various scales, ranging from milligram in discovery laboratories to the kilogram scale in industrial processes. Since the year 2000, with the surge of chiral drugs and the high demand for racemic separations in the pharmaceutical industry [27], packed column preparative SFC has gained wider utility, splitting into two distinct application frontiers: chiral SFC and achiral SFC. The former uses chiral stationary phases (CSPs) as packed column materials to resolve enantiomeric eluents that have identical chemical and physical properties in an achiral environment. The use of the SFC technique for chiral separations began several years after that of HPLC, which dates back to 1981 with the introduction of CSP chromatography [28]. However, the advantages for the use of supercritical fluids over liquid eluents for chiral drug separations were emerging. Low viscosity and high diffusivity of supercritical fluids allow for higher flow rates, lengthier columns, the inclusion of multiple columns, and higher sample loading capacities than other chromatographic techniques, including LC, GC, and CE [29]. Efficient separations and fast column re-equilibration are common in SFC where racemates that are inadequately resolved in normal-phase and reversed-phase HPLC can be separated. Moreover, most chiral SFC processes technically have only two fractions to be collected, which fits well with the initial preparative SFC hardware settings that are limited to collecting a maximum of six to eight fractions in a closed bed format [14-16]. The stacked injection technique with isocratic elution of the mobile phase, once used in SFC for the achiral separation of cis/trans isomers of phytol [12], an ingredient in the perfume industry (Fig. 5.1), presently is the most common practice for the purification of large amounts of racemic materials. Chiral
SFC has rapidly replaced LC in the past decade and now is the norm for chiral separation in both discovery laboratories and industrial manufacturing settings [30]. Commercial instrumentation suppliers for chiral SFC applications have helped to revitalize the technique by supplying a spectrum of instruments ranging from semi-preparative scale to the kilogram production scale.
