title: Determination of enantiomeric vigabatrin by derivatization with diacetyl-l-tartaric anhydride followed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry.
abstract: Vigabatrin, one of the most widely used antiepileptic drugs, is marketed and administered as a racemic mixture, while only S-enantiomer is therapeutically effective. In the present study, diacetyl-l-tartaric acid anhydride was used as an inexpensive and effective chiral derivatization reagent to produce tartaric acid monoester derivatives of vigabatrin enantiomers that could be readily resolved by reversed phase chromatography. Derivatization conditions were statistically optimized by response surface methodology, resulting in an optimal reaction temperature of 44°C and an optimal reaction time of 30min. The derivatized diastereomers of vigabatrin and internal standard (gabapentin) were analyzed using ultra-high performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry. For this analysis, an Agilent ZORBAX Rapid Resolution High Definition Eclipse Plus C18 column (100mm×2.1mm, 1.8μm) was employed for chromatographic separation using 10mM ammonium formate (pH 3.0) and methanol as mobile phase at a flow rate of 0.2mLmin-1. The established method was validated in terms of specificity, linearity, precision, accuracy, dilution integrity, recovery, matrix effect, stability, and incurred sample reanalysis. It was linear over a range of 0.25-100.0mgL-1for both S- and R-enantiomers (R2≥0.9987 for both). Intra- and inter-day precisions and accuracies were within acceptable ranges. The method was successfully applied to determine the levels of vigabatrin enantiomers in mouse serum after administration of vigabatrin racemate.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Shin
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Jeong
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address: jlee0610@skku.edu.
authors.forename: Jeongmi
authors.initials: J
authors.lastname: Lee
mesh_terms: D000812:Anhydrides / Q000737:chemistry; D000818:Animals; D000927:Anticonvulsants / Q000032:analysis / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003931:Diacetyl / Q000737:chemistry; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008813:Mice, Inbred ICR; D013237:Stereoisomerism; D013644:Tartrates / Q000737:chemistry; D020888:Vigabatrin / Q000032:analysis / Q000097:blood*
chemical_list: D000812:Anhydrides; D000927:Anticonvulsants; D013644:Tartrates; D020888:Vigabatrin; D003931:Diacetyl; C029768:tartaric acid
keywords: Chiral derivatization; Diacetyl-l-tartaric anhydride; Diastereomer; Enantioseparation; Vigabatrin