Chiral screen

FIGURE 6 Overall road map of the chiral screening strategy for pharmaceutical compounds. Solid lines are for basic compounds, dashed lines for acidic compounds, and highly dashed lines are for neutral compounds. 

The chiral screen uses columns of 10 cm length, high flow rates, and fast gradients [3, 4, 13], An initial assessment with methanol as the modifier and the four columns is run serially, followed by screens using ethanol and isopropanol. One racemate can be analyzed in 80 min, making it possible to screen several samples overnight, to isolate rapidly small amounts on the analytical system and to scale up to the preprative system on the next day. The authors report a success rate of >90%. 

Figure 6.28 Bifunctional atropoisomeric thioureas and 58 lacking axial chirality screened in the cyanosilylation of benzaldehyde.

Luz de la Puente, M., White, C. T., Rivera-Sagredo, A., Reilly, J., Burton, K., Harvey G. Impact of normal-phase gradient elution in chiral chromatography a novel, robust, efficient and rapid chiral screening procedure, J. Chromatogr. A, 2003, 983, 101-114. 

Supported liquid membranes (SLMs) consisting of 5% tri-n-octylphosphine oxide (TOPO) dissolved in di-w-hexylether/n-undecane (1 1) have been used in the simultaneous extraction of a mixture of three stUbene compounds (dienestrol, diethylstilbestrol, and hexestrol) in cow s milk, urine, bovine kidney, and liver tissue matrices [183]. The efficiencies obtained after the enrichment of 1 ng/1 stilbenes in a variety of biological matrices of milk, urine, liver, kidney, and water were 60-70, 71-86, 69-80, 63-74, and 72-93%, respectively. A new method to contribute to the discrimination of polyphenols including resveratrol with synthetic pores was proposed [184]. The work [185] evaluated two types of commonly available chiral detectors for their possible use in chiral method development and screening polarimeters and CD detectors. Linearity, precision, and the limit of detection (LOD) of six compounds (trans-stilbene oxide, ethyl chrysanthemate, propranolol, 1-methyl-2-tetralone, naproxen, and methyl methionine) on four common detectors (three polarimeters and one CD detector) were experimentally determined and the limit of quantitation calculated from the experimental LOD. trans-Stilbene oxide worked well across all the detectors, showing good linearity, precision, and low detection limits. However, the other five compounds proved to be more discriminating and showed that the CD detector performed better as a detector for chiral screens than the polarimeters. 

Chiral gas chromatography (GC) is a useful tool when analyzing chiral raw materials and early intermediates because they are generally small molecules, have low molecular weights, are volatile, and typically do not have a chromophore for UV detection. As the majority of the pharmaceutical compounds available today are nonvolatile, the GC chiral screening is less developed than that of its liquid and supercritical fluid column counterparts. 

Whether for analytical or preparative application, finding a stationary phase that exhibits enantiomeric recognition for the molecule of interest is the point of emphasis for chiral screening. There are three modes employed in all LC and SFC chiral screens the presence of an umnodified, acidic-modified, and basic-... 

Reversed phase chiral separations are desired simply for efficiency in generating results from laboratories whose instrumentation is routinely configured to run in reversed and not normal phase modes.Normal phase conditions are less attractive to the analytical chemist for this reason and deter laboratory efficiency. Typical commercial chiral LC columns found on pharmaceutical reversed phase LC chiral method development screens are listed in Table 8. Table 11 shows suggested chromatographic conditions employed in reversed phase chiral screening. 

The column and phase selection for chiral GC is considerably less than that of liquid chromatography (see Table 6), which lends itself to simpler screening campaigns. Table 12 shows suggested chromatographic conditions employed in GC chiral screening. 

FIGURE 3 Unified chiral screening approach to chiral methods development. 

A knowledge-based chiral method development strategy can be very effective on chiral column selection. For example, a chiral screening method was used to monitor the enantiomeric purity of an atropisomeric dmg candidate. It returned the Chiralcel OD-RH column in reversed phase with a baseline enantioseparation of both atropi-somers (Fig. 12a). There was a need to redevelop the chiral method as the compound moved into development stages. Based on possible interaction sites around the chiral asymmetric axis of the compound (a primary amine for ionic and H-bonding interactions and an aromatic ring for k-k interaction), Chirobiotic V2 was tested since... 

Fig. 17 Chiral screening results of a 148-enantiomer sample set on polysaccharide CSPs (AD, amylose tris(3,5-dimethylphenylcarbamate) OD, cellulose tris(3,5-dimethylphenylcarbamate) OJ, cellulose tri(4-methylphenylester) AS, amylose tris[(5)-l-phenylethylcarbamate]). The graph is derived from data listed in [167]...

White C (2005) Integration of supercritical fluid chromatography into drag discovery as a routine support tool Part I. Fast chiral screening and puriftcation. J Chromatogr A 1074 163-173... 

De la Puente ML (2004) Highly sensitive and rapid normal-phase chiral screen using high-performance liquid chromatography-atmospheric pressure ionization tandem mass spectrometry (HPLC/MS). J Chromatogr A 1055 55-62... 

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