Chiral method development approach

Chiral method development is often referred to as one of the most difficult fields in terms of development time. Interaction with a chiral selector is required to achieve separation but the enantioselectivity of a given selector for a given chiral molecule is a priori unknown. For some compounds, it can take several days to find suitable separation conditions when using sequential approaches. Therefore, industry most often defines generic separation strategies, which are often kept internally or are... 

Another application of rapid chiral method development in SFC was presented by Villeneuve and Anderegg [50]. The same columns as in Reference 49 are used, combined with four organic modifiers, including methanol, methanol with 0.1% TEA, ethanol, and isopropanol. Using a six-way column switcher, the four columns can remain constantly inside the device. For some separations, 0.1% DEA or TEA was added. The separations were generated at a flow rate of 2 mL/min, 205 atm of pressure, and a temperature of 40°C. This approach seems applicable, based on the baseline separation that was obtained for the four analyzed compounds, but lacks detailed sequential steps. Therefore, no real strategy can be derived. 

Chiral CE can be widely applied in release and stability testing, the chiral purity of intermediates, and raw materials. Various generic method development approaches have been developed and published recently. " ... 

Figure 3 illustrates an orthogonal approach to chiral method development. This tactic resulted from the combined efforts and experience supplied by many pharmaceutical vendor and development laboratories. Each of the sections can... 

FIGURE 3 Unified chiral screening approach to chiral methods development. 

Wong, M. M., Holzheuer, W. B. and Webster, G. K. A Comparison of HPLC and SFC Chiral Method Development Screening Approaches for Compounds of Pharmaceutical Interest. Curr. Pharm. Anal 4 101, 2008. 

The comprehensive chiral HPLC method development approach designed for brivanib alaninate enantiomers and diastereoisomers separation included [150] the following ... 

AMn A, Antosz FJ, Ausec JL, Greve KF, Johnson RL, Mag-nusson L-E, Ramstad T, Secreast SL, Seihert DS, Webster GK. An orthogonal approach to chiral method development screening. Curr. Pharm. Anal. 2007 3 53-70. 

The most important and widely used approach to chiral sulfoxides is the method developed by Andersen (5) based on the reaction between the diastereomerically pure (or strongly enriched in one dia-stereomer) menthyl arenesulfinates and Grignard reagents. The first stereospecific synthesis of optically active (+H7 )-ethyl p-tolyl sulfoxide 22 was accomplished in 1962 by Andersen (75) from (-)-(iS)-menthyl p-toluenesulfmate 45 and ethylmagnesium iodide. 

Roos, N., Ganzler, K., Szeman, J., Fanali, S. Systematic approach to cost- and time-effective method development with a starter kit for chiral separations by capillary electrophoresis. J. Chromatogr. A 1997, 782, 257-269. 

The indirect approach has been widely applied since many functional groups can be derivatized with various chiral reagents and the covalent diastereoisomers can be separated with inexpensive non-chiral systems. Other advantages of the indirect approach are that method development is rather straightforward and that the detection sensitivity of the enantiomers can be improved by the selection of an appropriate CDR having a strong chromophor or fluorophor. 

The approach to method development is similar to the one described for HPLC and can be characterized as a rapid stationary phase screen using column and solvent switching with gradient elution followed by development of an isocratic preparative method. SFC has been successfully applied to the analytical and preparative separation of achiral and chiral compounds. 

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