Liquid Chromatographic Resolution of Mexiletine and Its Analogs on Crown Ether‐Based Chiral Stationary Phases

Abstract

Mexiletine, an effective class IB antiarrhythmic agent, and its analogs were resolved on three different crown ether-based chiral stationary phases (CSPs), one (CSP 1) of which is based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid and the other two (CSP 2 and CSP 3) are based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. Mexiletine was resolved with a resolution (R(S)) of greater than 1.00 on CSP 1 and CSP 3 containing residual silanol group-protecting n-octyl groups on the silica surface, but with a resolution (R(S)) of less than 1.00 on CSP 2. The chromatographic behaviors for the resolution of mexiletine analogs containing a substituted phenyl group at the chiral center on the three CSPs were quite dependent on the phenoxy group of analytes. Namely, mexiletine analogs containing 2,6-dimethylphenoxy, 3,4-dimethylphenoxy, 3-methylphenoxy, 4-methylphenoxy, and a simple phenoxy group were resolved very well on the three CSPs even though the chiral recognition efficiencies vary with the CSPs. However, mexiletine analogs containing 2-methylphenoxy group were not resolved at all or only slightly resolved. Among the three CSPs, CSP 3 was found to show the highest chiral recognition efficiencies for the resolution of mexiletine and its analogs, especially in terms of resolution (R(S)).

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.…”

Development of HPLC Chiral Stationary Phases Based on (+)‐(18‐Crown‐6)‐2,3,11,12‐tetracarboxylic Acid and Their Applications

“…Mexiletine, an effective antiarrhythmic agent (Fig. ), and its analogs containing a phenyl (or 4‐substituted phenyl) group at the chiral center instead of a methyl group were resolved on CSP 1 with a mobile phase consisting of 80% methanol in water containing 10 mM sulfuric acid or 10 mM perchloric acid . When the methyl group at the chiral center of mexiletine was changed with a phenyl or 4‐substituted phenyl group (such as 4‐trifluorophenyl, 4‐chlorophenyl, 4‐nitrophenyl, 4‐methoxyphenyl, and 4‐methylphenyl), the chiral recognition by CSP 1 was found to improve quite a lot.…”

“…After that, other CSPs based on (3,3’‐diphenyl‐1,1’‐binaphthyl)‐20‐crown‐6 dynamically coated on octadecyl silica gel or covalently bonded to silica gel were developed and reported to be successful in the resolution of racemic compounds containing a primary amino group. For example, α‐amino acids, β‐amino acids, primary amino alcohols, chiral primary amines, and various chiral drugs such as fluoroquinolone antibaterials, cathinone (central nervous system stimulant), tocainide (antiarrhythmic agent), 3‐amino‐5‐phenyl‐1,4‐benzodiazepin‐2‐ones, mexiletine (antiarrhythmic agent), and valacyclovir (a prodrug for the treatment of patients with herpes simplex and herpes zoster) were resolved well on the CSPs based on (3,3’‐diphenyl‐1,1’‐binaphthyl)‐20‐crown‐6 covalently bonded to silica gel.…”

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

“…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 ].…”