Illkirch-Graffenstaden, France
Illkirch-Graffenstaden, France

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PubMed | Chiral Technologies Europe and Pvt Ltd
Type: Journal Article | Journal: Molecules (Basel, Switzerland) | Year: 2016

The chromatographic resolution of pregabalin enantiomers has been often achieved by derivatization of the molecule, in order to reach enough sensitivity at low concentrations of the minor enantiomer present in the active principle. In the present article, the development and optimization of two liquid chromatographic methods are presented for the direct resolution of pregabalin enantiomers on a chiral stationary phase (CSP) containing a zwitterionic selector derived from cinchona alkaloid and sulfonic acid (CHIRALPAK ZWIX). The key parameters for the separation as well as the compatibility of chromatographic conditions with different detection modes (ultraviolet and mass spectrometry) were investigated. The resulting methods were found to be selective, of high performance and low limits of detection (2 g/mL by UV and 1 ng/mL by MS, respectively) and quantification (6 g/mL by UV and 5 ng/mL by MS, respectively) for the minor enantiomer which is considered as a chiral impurity.


Zhang T.,Chiral Technologies Europe | Holder E.,Chiral Technologies Europe | Franco P.,Chiral Technologies Europe | Lindner W.,University of Vienna
Journal of Chromatography A | Year: 2014

CHIRALPAK ZWIX(+) and ZWIX(-) are cinchona alkaloid-derived zwitterionic chiral stationary phases (CSPs) containing a chiral sulfonic acid motif which serves as negatively charged interaction site. They are versatile for direct enantiomer resolution of amino acids and many other ampholytic compounds by HPLC. The synergistic double ion-pairing between the zwittrionic chiral selector and the ampholyte is the basis for interaction and chiral recognition mechanisms. ZWIX(+) and ZWIX(-) type CSPs or columns behave pseudo-enantiomerically and provide the feature of reversing enantiomer elution order by column switching. In the current study, extensive experimental work was carried out with the aim of developing schemes for an efficient generic screening and proposing straightforward approaches for method optimization on these ZWIX columns. Various chromatographic parameters were investigated using a large series of diverse amino acids and analogues for the purpose. The role of methanol (MeOH) as the protic solvent in the mobile phase is confirmed to be essential. The presence of water in a low percentage is beneficial for peak shape, resolution, analysis speed, sample solubility and MS detection performance. The involvement of acetonitrile (ACN) or tetrahydrofuran (THF) can help for adjusting retention time and selectivity. Incorporation of a suitable pair of acidic-basic additives at a right ratio in the mobile phase is determinant as well for the double ion-pairing mechanism. 50 mM formic acid+25mM diethylamine (or ammonium hydroxide) in MeOH/ACN/H2O and in MeOH/THF/H2O at 49:49:2 (by volume) are recommended as the starting mobile phases for method development. Some other parameters are also considered in the proposed scheme to achieve successful enantioselective or stereoselective separation of the ampholytes. © 2014 Elsevier B.V.


Franco P.,Chiral Technologies Europe | Zhang T.,Chiral Technologies Europe | Gargano A.,University of Vienna | Mahut M.,University of Vienna | And 2 more authors.
LC GC Europe | Year: 2012

Quinine- and quinidine-derived anion-exchanger chiral stationary phases are versatile tools for enantiomer separation of acidic compounds in high performance liquid chromatography (HPLC). This article demonstrates their recognition ability in specific HPLC applications, involving enantiomer resolution and piasmid topoisomer separation. The extension of their applications from HPLC to supercritical fluid chromatography (SFC) was also investigated, with the aim of assessing the influence of a series of parameters and gaining insight into the general approaches for SFC method development and optimization.


CHIRALPAK ZWIX(+) and ZWIX(-) are cinchona alkaloid-derived zwitterionic chiral stationary phases (CSPs) containing a chiral sulfonic acid motif which serves as negatively charged interaction site. They are versatile for direct enantiomer resolution of amino acids and many other ampholytic compounds by HPLC. The synergistic double ion-pairing between the zwittrionic chiral selector and the ampholyte is the basis for interaction and chiral recognition mechanisms. ZWIX(+) and ZWIX(-) type CSPs or columns behave pseudo-enantiomerically and provide the feature of reversing enantiomer elution order by column switching. In the current study, extensive experimental work was carried out with the aim of developing schemes for an efficient generic screening and proposing straightforward approaches for method optimization on these ZWIX columns. Various chromatographic parameters were investigated using a large series of diverse amino acids and analogues for the purpose. The role of methanol (MeOH) as the protic solvent in the mobile phase is confirmed to be essential. The presence of water in a low percentage is beneficial for peak shape, resolution, analysis speed, sample solubility and MS detection performance. The involvement of acetonitrile (ACN) or tetrahydrofuran (THF) can help for adjusting retention time and selectivity. Incorporation of a suitable pair of acidic-basic additives at a right ratio in the mobile phase is determinant as well for the double ion-pairing mechanism. 50 mM formic acid+25 mM diethylamine (or ammonium hydroxide) in MeOH/ACN/HO and in MeOH/THF/HO at 49:49:2 (by volume) are recommended as the starting mobile phases for method development. Some other parameters are also considered in the proposed scheme to achieve successful enantioselective or stereoselective separation of the ampholytes.


PubMed | Chiral Technologies Europe, University of Barcelona and Irccs Instituto Of Ricerche Farmacologiche Mario Negri
Type: Journal Article | Journal: Molecules (Basel, Switzerland) | Year: 2015

We describe the multigram synthesis and in vivo efficacy studies of a donepezilhuprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimers disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human A42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by A42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of A peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of A lowering effect in vivo might be related to its lower in vitro potency toward A aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.


Harrison A.,Palacky University | Melchionna M.,Palacky University | Franco P.,Chiral Technologies Europe | Hlavac J.,Palacky University
New Journal of Chemistry | Year: 2014

3,6-Dihydro-2H-1,2-oxazines were synthesised via solid-phase synthesis to afford mixtures of stereo- and regioisomers. The analytical conditions for the analysis of the isomer ratio suitable for checking of reaction conditions of possible stereoselective synthesis were developed with the use of HPLC including chiral stationary phases (CSPs) based on chiral polysaccharide derivatives immobilized on a silica support. It was found that those CSPs based on an amylose backbone were more efficient than those based on cellulose for the molecules investigated. Additionally, analytical samples without complete purification could be separated under the same conditions. The asymmetric induction causing the difference in the stereoisomer ratio was observed, when an oxazine ring was built up directly on a chiral moiety. A chiral aminoacid separated from the construction site by an achiral aromatic ring did not influence the ratio of stereoisomers. The analytical conditions developed were thus verified for use in the optimisation of the regio- and stereoselective synthesis of 3,6-dihydro-2H-1,2-oxazines. The conditions are suitable for solid-phase synthesis methodology often used in high throughput synthesis of biologically active compounds. This journal is © the Partner Organisations 2014.


Zhang T.,Chiral Technologies Europe | Franco P.,Chiral Technologies Europe | Nguyen D.,Chiral Technologies Europe | Hamasaki R.,Daicel Corporation | And 3 more authors.
Journal of Chromatography A | Year: 2012

The immobilized polysaccharide-derived chiral stationary phases (CSPs) combine the benefits of broad application scope and high preparative potential with CSP robustness and universal solvent compatibility. Strategies for efficient and straightforward method development with these CSPs were previously overviewed. In the current study, six CSPs with different structural features in the immobilized series were examined for their complementary properties in separation of enantiomers. Some method development aspects related to polysaccharide-derived CSPs in general and certain specific features observed on these immobilized supports, such as the effects of mobile phase, sample solvent and mobile phase additive on chiral separation, are also discussed. © 2012 Elsevier B.V.


Zhang T.,Chiral Technologies Europe | Holder E.,Chiral Technologies Europe | Franco P.,Chiral Technologies Europe | Lindner W.,Chiral Technologies Europe
Journal of separation science | Year: 2014

An extensive series of free amino acids and analogs were directly resolved into enantiomers (and stereoisomers where appropriate) by HPLC on zwitterionic chiral stationary phases (Chiralpak ZWIX(+) and Chiralpak ZWIX(-)). The interaction and chiral recognition mechanisms were based on the synergistic double ion-paring process between the analyte and the chiral selectors. The chiral separation and elution order were found to be predictable for primary α-amino acids with apolar aliphatic side chains. A systematic investigation was undertaken to gain an insight into the influence of the structural features on the enantiorecognition. The presence of polar and/or aromatic groups in the analyte structure is believed to tune the double ion-paring equilibrium by the involvement of the secondary interaction forces such as hydrogen bonding, Van der Waals forces and π-π stacking in concert with steric parameters. The ZWIX chiral columns were able to separate enantiomers and stereoisomers of various amphoteric compounds with no need for precolumn derivatization. Column switching between ZWIX(+) and ZWIX(-) is believed to be an instrumental tool to reverse or control the enantiomers elution order, due to the complementarity of the applied chiral selectors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Michishita T.,Chiral Technologies Europe | Franco P.,Chiral Technologies Europe | Zhang T.,Chiral Technologies Europe
Journal of Separation Science | Year: 2010

Protein-based chiral stationary phases, in particular α1- acid glycoprotein, are chromatographic materials with a very broad application range. The chiral recognition ability of this selector allows the resolution of more than 90% of the molecules tested. A step-by-step description of the screening approach that we have developed is described in this article with two objectives in mind: obtaining a high success rate with a straightforward methodology that can be generally applied and allowing LC-MS compatibility. Second, the screening strategy is required to take into account the main functional nature of the racemic compound to be resolved (neutral, acidic or basic) for method optimisation step, but should be independent of other structural features, in order to allow the routine application of screening sequences and the application to the largest number of samples. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Zhang T.,Chiral Technologies Europe | Nguyen D.,Chiral Technologies Europe | Franco P.,Chiral Technologies Europe
Journal of Chromatography A | Year: 2010

Immobilised polysaccharide-based chiral stationary phases (CSPs) are chromatographic materials that combine the remarkable enantioselective performance of the polysaccharide derivatives in addition to solvent versatility for enantiomeric resolution. Their behaviour under normal phase conditions and polar organic mode has been quite extensively discussed in several scientific communications. This article will focus on an approach to developing efficient chiral analytical methods with these immobilised CSPs (CHIRALPAK IA, CHIRALPAK IB and CHIRALPAK IC) by applying a limited number of mobile phases under reversed-phase conditions. The manuscript will review the development of screening strategies by liquid chromatography for the separation of enantiomers in combination with applications compatible with LC-MS. The rational combination of this technique and the different supports will allow the identification of enantiomeric resolutions in reasonable time frames and with high success rates. © 2009 Elsevier B.V. All rights reserved.

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