Screening enantioseparation

Fig. 4-2. Screen of REGISTER (data registration tool for enantioseparations).

A strategy for the enantioseparation of basic compounds was described by SokolieP and Koller [35] and is displayed in Figure 3.7. All steps from method development till validation are included in the flow chart. Perhaps a disadvantage in this approach is that sequential screening and optimization steps are used (i.e., every factor is optimized individually). The use of the developed scheme was demonstrated for one compound, for which the method was developed, optimized, and validated. The generic applicability of this approach was not considered and is unknown. 

Chip-based enantioseparations using an electrophoresis principle were presented by Gao et al. [59]. They used mono-, two-, and four-channel chips to develop chiral separations of fluorescein isothiocyanate (FlTC)-labeled basic compounds. To obtain the chiral separations, seven neutral CD were screened (i.e., a-CD, fi-CD, y-CD, HP-a-CD, HP-y-CD, and DM-fi-CD). Using the monochannel chip, the seven selectors were screened sequentially. Using the two-channel chip, between-channel repeatability could be demonstrated using the same separation conditions. Using two different selectors in the channels, the analysis time for the screening of the seven CD can be reduced to half, compared to the time needed in the monochannel... 

Welsh, C. J., Bhat, G., Protopopova, M. N. Selection of an optimised adsorbent for preparative chromatographic enantioseparations by microscale screening of a second-generation chiral stationary phase library. J. Com. Chem., 1999,... 

Figure 3.15 Rational screening process for enantioseparation by applying targeted selector design.

Although it is suitable, NMR spectroscopy is not recommended to be used just for screening of chiral selectors due to following reasons (a) the NMR spectroscopic experiment is commonly more time consuming and expensive compared to CE (b) enantioselective CICS observed in NMR spectroscopy do not a priori translate to an enantioseparation in CE. The possible reasons for this discrepancy between the two techniques have been discussed earlier [139, 141]. 

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... 

Among brush-type CSPs for HPLC, the Whelk-0(R) CSP, first designed for naproxen enantioseparation, has shown an outstanding applicability for a broad diversity of racemic compounds [72]. Nowadays it has become one of the CSPs of reference included in most screening processes addressed to the search of adequate conditions for enantioselective separation in drug discovery [73, 74]. A CS containing the Whelk-0( skeleton, and a lipophilic chain aimed to enhance solubility... 

The apphcation of screening tests in solution constitutes a quicker and cheaper alternative when facing enantioseparation for a new compound. Although these tests allow for addressing the attention to particular CSs, they do not save having to test the chosen CSP and to determine the adequate chromatographic conditions for analysis. Among other possible limitations, the latter may explain the exceptional use of this approach. 

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