Preparative chromatographic resolution of enantiomers using polar organic solvents with polysaccharide chiral stationary phases

Miller, Larry; Orihuela, Carlos J.; Fronek, Randy; Murphy, James L.

doi:10.1016/s0021-9673(99)00743-8

Cited by 45 publications

(21 citation statements)

References 11 publications

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“…Table 2 shows that ketoprofen enantiomers have increasing solubilities for 20% ethanol, pure ethanol and pure methanol. These results also confirm that racemic drugs have considerably higher solubilities in alcoholic solvents than in the traditional mobile phases used in analytical chiral separation, consisting in an alcohol-hydrocarbon combination, with high hydrocarbon content [6]. This conclusion is underlined with the experimental results obtained for the dependency of the racemic ketoprofen solubility on the alcoholic content of an ethanol/n-hexanebased solvent, shown in Fig.…”

Section: Solubility Measurementssupporting

confidence: 83%

Preparative separation of ketoprofen enantiomers: Choice of mobile phase composition and measurement of competitive adsorption isotherms

Ribeiro

Graça

Pais

et al. 2008

Separation and Purification Technology

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The present work intends to investigate how mobile phase composition influences the adsorption behavior of ketoprofen enantiomers (a nonsteroidal anti-inflammatory drug) on an amylose-based chiral stationary phase (Chiralpak AD). Three mobile phase compositions were studied: the usual 20% ethanol/80% n-hexane mixture and two pure mobile phases; methanol and ethanol. Pulse and breakthrough experiments under preparative conditions were carried out in order to measure and test adsorption isotherms. The results obtained show that, for preparative separations, pure ethanol is a better mobile phase than the usual 20% ethanol/80% n-hexane mixture: it allows higher solubility of the racemate, lower retention times, and also a higher selectivity at high enantiomer concentrations. These are aspects of crucial importance when the final goal is to achieve high productivity preparative separations, as it is shown for the simulated moving bed (SMB) operation.

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Section: Solubility Measurementssupporting

confidence: 83%

Preparative separation of ketoprofen enantiomers: Choice of mobile phase composition and measurement of competitive adsorption isotherms

Ribeiro

Graça

Pais

et al. 2008

Separation and Purification Technology

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“…The lack of a step change in selectivity indicates a consistent recognition mechanism for most compounds in both the hexane-based and polar organic modes of separation. These results are consistent with those reported by Miller et al 9 The results of titrating from normal phase to polar organic conditions suggested that addition of moderate amounts of alkane to neat alcohol may affect retention.…”

Section: Alcohol-based Mobile Phasessupporting

confidence: 93%

“…6,7 Using polar organic mobile phases offers several advantages for preparative applications of chiral chromatography, including enhanced solubility and simplicity of operation and solvent recovery. 9 This has led to routine screening of these mobile phases at Chiral Technologies, Inc. for submitted preparative projects. While individual sample results are proprietary and must remain confidential, 25 -30% of submitted samples can be resolved with polar organic mobile phases.…”

mentioning

confidence: 99%

Chiral separations on polysaccharide stationary phases using polar organic mobile phases

Lynam¹,

Stringham²

2005

Chirality

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About 30% of a chemically diverse set of compounds were found to separate on four polysaccharide chiral stationary phases using polar organic mobile phases. No structural features appeared to correlate to successful separations. Titrations between normal and polar organic mobile phases suggested that separation mechanisms do not differ between these mobile phases. Attempts made to control retention met with varying degrees of success. Addition of hexane to alcohols had minor effects on retention although this was occasionally beneficial. Addition of water to alcohols increased retention. Addition of water to acetonitrile decreased retention. Addition of alcohol to acetonitrile also proved beneficial to the separation of some compounds. Loading studies performed to mimic preparative separations indicated that the benefits of polar organic mobile phases are largely due to increased solubility.

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“…The two columns were also examined in the ''strong polar mode'' using 100% polar solvents. 11 Using these approaches, we identified 100% MeOH on Chiralpak AD and 1:1 (v/v) EtOH/heptane on Chiralcel OJ as suitable preparative methods for carrying out the separation of rac-2.…”

Section: Resultsmentioning

confidence: 99%

Strategic use of preparative chiral chromatography for the synthesis of a preclinical pharmaceutical candidate

et al. 2007

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The modern use of preparative chromatography in pharmaceutical development is illustrated by the case of a recent preclinical candidate from these laboratories. The synthesis of the candidate employed a coupling of two enantiopure intermediates, each of which could be resolved using preparative chiral chromatography. SFC screening was employed to identify the enantioselective stationary phases, and semipreparative SFC methods derived from this screening were used to produce gram amounts of enantiopure intermediate for initial studies. However, initial larger scale resolution required the translation of the SFC methods to HPLC conditions. Preparative chiral HPLC on a 30-cm i.d. column was then used to produce enantiopure intermediates which were coupled to give 170 g of the preclinical candidate. Subsequent preparation of the candidate at larger scale for later-stage clinical evaluation employed an improved synthesis in which one component was constructed by asymmetric synthesis. Resolution of the other component, now a more advanced intermediate, was carried out using newly obtained large-scale SFC equipment. Some discussion is presented on the varying strategies whereby preparative chiral chromatography can be used to support either short-term or long-term synthetic goals in preclinical pharmaceutical development.

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Preparative chromatographic resolution of enantiomers using polar organic solvents with polysaccharide chiral stationary phases

Cited by 45 publications

References 11 publications

Preparative separation of ketoprofen enantiomers: Choice of mobile phase composition and measurement of competitive adsorption isotherms

Preparative separation of ketoprofen enantiomers: Choice of mobile phase composition and measurement of competitive adsorption isotherms

Chiral separations on polysaccharide stationary phases using polar organic mobile phases

Strategic use of preparative chiral chromatography for the synthesis of a preclinical pharmaceutical candidate

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