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

Abstract

Developing surfactant-based aqueous solvents as alternatives to organic solvents for chromatographic enantioseparation is highly desired. Surfactants are inexpensive, nontoxic, environmental friendly, and increase the solubility of organic compounds in aqueous solutions. In this work, the impact of surfactant-based aqueous solvents on RP-HPLC enantioseparation of (RS)-mexiletine is studied. The in situ derivatization of (RS)-mexiletine with chirally pure moieties [(S)-levofloxacin, (S)-ketoprofen, (S)-ibuprofen)] was carried out/performed to reduce consumption of organic solvents and side wastes, and to maintain a green approach. We report the impact of increasing concentration of surfactants on separation of diastereomeric derivatives of (RS)-mexiletine on a C18 column of HPLC. Surfactant in water increased the solubility of a diastereomeric derivative, provided the lowest elution time (t R between 2.152 and 10.87 min), and minimized the consumption of solvent. The use of surfactant-containing aqueous mobile phases in chromatographic separations is a good alternative for replacement of organic solvents. The hydrolysis of the synthesized diastereomeric derivatives was carried out, and native enantiomers of mexiletine were isolated and characterized. In addition, the lowest-energy optimized structures were developed using the Gaussian 09 Rev. A.02 program for determination of elution order, and the method was validated for linearity, accuracy, limit of detection (LOD), and limit of quantitation (LOQ).

Micellar liquid chromatographic green enantioseparation of racemic amino alcohols and determination of elution order

“…In this study, we reported the development of a micellar liquid chromatographic method for the enantioseparation of racemic amino alcohols using an indirect approach. The diastereomeric derivatives (DDs) of racemic amino alcohols were synthesized, under microwave heating conditions, by the activated ester (AE) of ( S )‐(−)‐levofloxacin (Lfx) moiety (Alwera, 2018). The synthesized diastereomeric pairs were subjected to separation on the C 18 column using HPLC, and the aqueous solution of sodium dodecyl sulfate (SDS) and Brij‐35 was used as a mobile phase for the separation.…”

An efficient method for the determination of enantiomeric purity of racemic amino acids using micellar chromatography, a green approach

“…Also, the surfactant‐based mobile phase in chromatography provides a moderate interaction between the column and analyte during separation, and these interactions can be manipulated by varying the concentration of surfactant. The amalgamation of single or mixed surfactant‐based aqueous solutions with organic modifiers in chromatography, has been used for the establishment of a variety of biological and organic product samples (Alwera & Bhushan, 2017; Alwera, 2018; Esteve‐Romero, Carda‐Broch, Gil‐Agustí, Capella‐Peiró, & Bose, 2005; Ruiz‐Angel, Peris‐García, & García‐Alvarez‐Coque, 2015; Stępnik, 2017). Surfactants are eco‐friendly, nontoxic, nonvolatile and economical, and their aqueous solution as an eluent in liquid chromatography favors green development.…”

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

“…The most stable LM-1 and LM-2 conformers were true conformers (no IR imaginary frequencies) and did not display any significant difference in size with their corresponding longest axes being equal to 16.8 Å. Thus, the proposed molecular modeling analysis in Alwera’s method should not be used to predict the order of elution of levofloxacin derivatives of mexiletine.…”

“…Recently, Alwera presented a micellar liquid chromatography system as a novel green method for enantioseparation of (±)-mexiletine diastereomers. The paper described in situ derivatization of ( RS )-mexiletine with chirally pure drugs (e.g., levofloxacin) followed by separation of the diastereomers using surfactant-based aqueous solvent RPHPLC.…”

“…(3) Enantiomeric Purity Analysis . Based on high optical purity (op) values, Alwera’s paper asserts that good ep was obtained for both mexiletine enantiomers. However, op values should not be considered as reliable succedanea of ep values, since the difference between op and ep can be large (see the Horeau effect) .…”