Stereoselective interactions and liquid chromatographic enantioseparation of thalidomide on cyclodextrin-bonded stationary phases

Szabó, Zoltán‐István; Foroughbakhshfasaei, Mohammadhassan; Szöcs, Levente; Nagy, József; Komjáti, Balázs; Noszál, Béla; Tóth, Gergő

doi:10.1007/s10847-016-0622-3

Cited by 22 publications

(10 citation statements)

References 41 publications

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“…As opposed to EtOH, addition of IPA to MeOH increased R s1 values and results prompted for further method optimization. As a next step, a Taguchi L 16 orthogonal array design was employed altering three parameters at four different levels such as concentration of IPA in the mobile phase (5, 10, 15, 20%), column temperature (10, 20, 30, 40°C) and flow rate (0.5, 0.6, 0.7, 0.8 mL/min) in a multivariate manner . As response R s1 values were recorded and results are presented in Table .…”

Section: Resultsmentioning

confidence: 99%

Enantiomeric quality control of R‐Tofisopam by HPLC using polysaccharide‐type chiral stationary phases in polar organic mode

et al. 2018

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A novel, fast and economic chiral HPLC method was developed and validated for the resolution of the four isomers of tofisopam. The separation capacity of eleven different chiral columns: six polysaccharide-type including three amylose-based (Chiralpak AD, Chiralpak AD-RH and Chiralpak AS) and three cellulose-based (Chiralcel OD, Chiralcel OJ and Lux Cellulose-4); three cyclodextrin- (Quest-BC, Quest-C2 and Quest-CM) and two macrocyclic glycopeptide antibiotic-type (Chirobiotic T and Chirobiotic TAG) were screened using polar organic or reversed-phase mode. Chiralpak AD, based on amylose tris(3,5-dimethylphenylcarbamate) as chiral selector with neat methanol was identified as the most promising system. In order to improve resolution, an orthogonal experimental design was employed, altering the concentration of 2-propanol, column temperature, and flow rate in a multivariate manner. Using the optimized method (85/15 v/v methanol/2-propanol, 40°C, flow rate: 0.7 mL/min) we were not only able to separate the four isomers but also detect 0.1% S-enantiomer as chiral impurity in R-tofisopam. This is important since the latter is under development as a single enantiomeric agent. Thermodynamic investigation revealed an unusual entropy and enthalpy-entropy co-driven controlled enantioseparation on Chiralcel OJ and on Chiralpak AD column, respectively. Our newly developed HPLC method was validated according to the ICH guidelines and its application was tested on a pharmaceutical formulation containing the racemic mixture of the drug. As a further novelty, a separate circular dichroism method was applied for the investigation of the interconversion kinetics of tofisopam conformers, which proved to be crucial for sample preparation and method validation.

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Section: Resultsmentioning

confidence: 99%

Enantiomeric quality control of R‐Tofisopam by HPLC using polysaccharide‐type chiral stationary phases in polar organic mode

et al. 2018

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“…During chiral separations, temperature changes affect both analyte retention and enantioselective interactions . In order to obtain information about the mechanistic aspects of chiral discrimination process, the differences in the change of standard enthalpy Δ(ΔH°) and standard enthropy Δ(ΔS°) for the 2 enantiomers moving from the mobile to the stationary phase were calculated according to the modified van't Hoff equation:

ln α = - \frac{italicΔΔ H^{°}}{RT} + \frac{italicΔΔ S^{°}}{R}

where R is the universal gas constant, T is the temperature, expressed in Kelvin, while α is the selectivity factor.…”

Section: Resultsmentioning

confidence: 99%

Enantioseparation of racecadotril using polysaccharide‐type chiral stationary phases in polar organic mode

et al. 2017

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Enantioseparation of the antidiarrheal drug, racecadotril, was investigated by liquid chromatography using polysaccharide-type chiral stationary phases in polar organic mode. The enantiodiscrimininating properties of 4 different chiral columns (Chiralpak AD, Chiralcel OD, Chiralpak AS, Chiralcel OJ) with 5 different solvents (methanol, ethanol, 1-propanol, 2-propanol, and acetonitrile) at 5 different temperatures (5-40°C) were investigated. Apart from Chiralpak AS column the other 3 columns showed significant enantioseparation capabilities.Among the tested mobile phases, alcohol type solvents were superior over acetonitrile, and significant differences in enantioselective performance of the selector were observed depending on the type of alcohol employed. Van't Hoff analysis was used for calculation of thermodynamic parameters which revealed that enantioseparation is mainly enthalpy controlled; however, enthropic control was also observed. Enantiopure standard was used to determine the enantiomer elution order, revealing chiral selector-and mobile-phase dependent reversal of enantiomer elution order. Using the optimized method (Chiralcel OJ stationary phase, thermostated at 10°C, 100% methanol, flow rate: 0.6 mL/min) baseline separation of racecadotril enantiomers (resolution = 3.00 ± 0.02) was achieved, with the R-enantiomer eluting first. The method was validated according to the ICH guidelines, and its application was tested on capsule and granules containing the racemic mixture of the drug.

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“…Stability constants ( K ) of the inclusion complexes were calculated by non‐linear parameter fitting of Eq. to the δ obs versus [CD] T datasets using OriginPro 8 program based on previous works .…”

Section: Methodsmentioning

confidence: 99%

Chiral separation of rasagiline using sulfobutylether‐β‐cyclodextrin: capillary electrophoresis, NMR and molecular modeling study

et al. 2019

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Pressure‐assisted stereospecific capillary electrophoresis method was developed for the determination of enantiomeric purity of the antiparkinsonian agent (R)‐rasagiline. The optimized method, 50 mM glycine‐HCl buffer pH 2, supplied with 30 mM sulfobutylether‐β‐cyclodextrin, at 35°C, applying 12 kV in reversed polarity, and –8 mbar pressure (vacuum), short‐end injection with ‐25 mbar × 2 s, was successful for baseline separation of rasagiline enantiomers (Rs = 3.5 ± 0.1) in a short analysis time. The method was validated according to current guidelines and proved to be reliable, linear, precise and accurate for determination of 0.15% S‐enantiomer as chiral impurity in R‐rasagiline sample, as well as quantification of the eutomer. Method application was tested on a commercial tablet formulation. Determination of spatial structure of diastereomeric associates was based on 1H and 2D ROESY NMR, indicating that the aromatic moiety of the molecule can enter the cyclodextrin cavity. NMR titration and molecular modeling revealed that S‐rasagiline formed a more stable inclusion complex with sulfobutylether‐β‐cyclodextrin, than its antipode, which is in agreement with electrophoretic results.

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Stereoselective interactions and liquid chromatographic enantioseparation of thalidomide on cyclodextrin-bonded stationary phases

Cited by 22 publications

References 41 publications

Enantiomeric quality control of R‐Tofisopam by HPLC using polysaccharide‐type chiral stationary phases in polar organic mode

Enantiomeric quality control of R‐Tofisopam by HPLC using polysaccharide‐type chiral stationary phases in polar organic mode

Enantioseparation of racecadotril using polysaccharide‐type chiral stationary phases in polar organic mode

Chiral separation of rasagiline using sulfobutylether‐β‐cyclodextrin: capillary electrophoresis, NMR and molecular modeling study

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