High-performance liquid chromatography for analytical and small-scale preparative separation of (R,S)-mexiletine using (S)-(—)-(N)-trifluoroacetyl-prolyl chloride and (1S)-(—)-camphanic chloride and recovery of native enantiomer by detagging

Abstract

Summary.A reversed phase high-performance liquid chromatographic method has been established for enantioseparation of (R, S)-mexiletine. Two volatile and thermally stable acyl chlorides, viz., (S)-(−)-(N)-trifluoro acetyl prolyl chloride and (1S)-(−)-camphanic chloride, were used as chiral derivatizing reagents. Binary composition of aqueous trifluoroacetic acid (0.1%)-acetonitrile as mobile phase was successful with ultraviolet (UV) detection at 210 nm. The method was optimized and validated for accuracy, precision, and limit of detection. The limit of detection was found to be 45 ng mL −1 and 80 ng mL −1 for the two types of diastereomers. Besides, kinetic resolution was achieved, and the experimental conditions optimized for this purpose provided diastereomeric excess up to 74% for (R)-isomer. On achieving a resolution value greater than 2, the optimized method for analytical enantioseparation was scaled-up to smallscale preparative level, and the native (R)-mexiletine was recovered by acid hydrolysis of the diastereomer.

In Situ Derivatization of (RS)-Mexiletine and Enantioseparation Using Micellar Liquid Chromatography: A Green Approach

“…Present work shows very good enantioseparation of the diastereomeric derivatives of ( RS )-Mex in terms of resolution (8.28–10.91), separation factor (1.39–1.77), and retention times (2.512–10.87 min). The calculated values of resolution ( Rs ), separation factor (α) and retention time were better than diastereomeric derivatives of ( RS )-Mex prepared with Marfey’s reagent, , cyanuric chloride, , chloroformates, isothiocyanate, , naproxen, , ( S,S )-O,O′-di- p -toluoyl tartaric acid anhydride, divinyl dicarboxylates, ( S )-(−)-( N )-trifluoroacetyl-prolyl chloride, (1 S )-(−)-camphanic chloride, 2-anthroyl chloride-based chiral reagents; furthermore, the current results are also better than direct enantioseparation methods in which different chiral stationary phases are used. − The current method provides very low values of LOD and LOQ when compared with the literature. − ,− Also, the method provided decreasing elution time for diastereomeric derivatives of ( RS )-Mex as compared with literature, − ,− resulting in lesser consumption of mobile phase. During this whole work, only aqueous WMP mobile phase was used for HPLC analysis, and so this method does not show any negative impact on the environment as in previously reported methods.…”

“…Present work shows very good enantioseparation of the diastereomeric derivatives of (RS)-Mex in terms of resolution (8.28−10.91), separation factor (1.39−1.77), and retention times (2.512−10.87 min). The calculated values of resolution (Rs), separation factor (α) and retention time were better than diastereomeric derivatives of (RS)-Mex prepared with Marfey's reagent, 15,16 cyanuric chloride, 17,18 chloroformates, 19 isothiocyanate, 19,20 naproxen, 16,23 (S,S)-O,O′-di-p-toluoyl tartaric acid anhydride, 21 divinyl dicarboxylates, 22 (S)-(−)-(N)trifluoroacetyl-prolyl chloride, 23 (1S)-(−)-camphanic chloride, 23 2-anthroyl chloride-based 24 chiral reagents; furthermore, the current results are also better than direct enantioseparation methods in which different chiral stationary phases are used. 45−47 The current method provides very low values of LOD and LOQ when compared with the literature.…”

“…Previous literature on enantioseparation reveals the use of huge amounts of hazardous organic solvents during chromatographic separation, whereas in current studies, only aqueous-surfactant-based nonhazardous mobile phase (WMP) was used. Also, the single-step in situ covalent derivatization of ( RS )-Mex reduced the consumption of organic solvent and minimized the waste, and led to fast derivatization as compared with reported methods − (reported methods require the synthesis of the CDRs and then synthesis of diastereomeric derivative, i.e., multistep synthesis). Also, the developed method is examined by Analytical Eco-Scale method and Green Analytical Procedure Index method (GAPI), and it is observed that the developed method is an excellent green analytical method (green score value is 76).…”

“…By learning from previous limitations, here, we describe a green micellar liquid chromatographic method for enantioseparation of ( RS )-mexiletine (Mex; a nonselective voltage-gated sodium channel blocker, IB antiarrhythmic class drug; marketed and administered as racemate) through the direct covalent derivatization (indirect approach of enantioseparation). The literature on covalent derivatization of enantiomers shows their advantages in the establishment of the chiral purity. ,,− The covalent derivatization of enantiomers provides sensitive chromatographic UV–visible detection with fast elution and high resolution. For the covalent derivatization, literature reveals that many chiral derivatizing reagents have been developed (e.g., CDRs based on Marfey’s reagent, , Sanger reagent, cyanuric chloride, , isothiocyanate, , chloroformates, ( S,S )-O,O′-di-p-toluoyl tartaric acid anhydride, divinyl dicarboxylates, ( S )-(−)-( N )-trifluoroacetyl-prolyl chloride, (1 S )-(−)-camphanic chloride, 2-anthroyl chloride, ( S )-naproxen ester, , levofloxacin ester and ( S )-ketoprofen ester), and these provided easy derivatization with target analyte.…”

Chiral Discrimination of Mexiletine Enantiomers by Capillary Electrophoresis Using Cyclodextrins as Chiral Selectors and Experimental Design Method Optimization

“…Several direct and indirect HPLC methods were published for the chiral separation of MXL enantiomers. For MXL enantioseparation through an indirect approach, several chiral derivatizing reagents have been used: Sanger reagent (2,4-dinitrofluorobenzene) [ 23 ], ( S , S )-O,O’-di-p-toluoyl tartaric acid anhydride [ 24 ], ( S )-naproxen [ 24 , 25 ], cyanuric chloride [ 26 ], ( S )-(-)-(N)-trifluoroacetyl-prolyl chloride, (1 S )-(-)-camphanic chloride [ 27 ], and Marfey’s reagent (1-fluoro-2,4-dinitrophenyl-5- l -alanine amide) [ 24 , 28 ]. MXL enantioseparation by HPLC was resolved also through a direct approach using different chiral stationary phases (CSPs): Pirkle-type ionic CSP (based on ( R )-(-)-3,5-dinitrobenzoylphenylglycine) [ 29 ], Chiralpak AD CSP based on a carbamoyl derivative of amylose (amylose tris(3,5-dimethylphenylcarbamate) [ 30 , 31 ], and crown ether-based CSP (1,1-binaphthyl crown ether, (18-crown-6)-2,3,11,12-tetracarboxylic acid) [ 32 , 33 ].…”