ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Resolution of ketoconazole enantiomers by high-performance liquid chromatography and inclusion complex formation between selector and enantiomers

Bi-Zhu Sun, Kui He, Xiao-Ming Chen, Chun-Yan Chen, Zhao Wang, and Chang-Qun Cai

College of Chemistry, Xiangtan University, Xiangtan, 411105, Hunan, China

E-mail: cxm@xtu.edu.cn,

Abstract: The analytical resolution of ketoconazole (KTZ) enantiomers was performed by high-performance liquid chromatography with sulphobutylether-β-cyclodextrin (SBE-β-CD) as a chiral mobile phase additive (chiral selector). Some important factors affecting the resolution of KTZ enantiomers were investigated. In addition, the molecular interaction between KTZ and SBE-β-CD was studied using the UV absorption spectrum and HPLC for an understanding of the resolution process. The results show that the type and concentration of the chiral mobile phase additive, the pH of the mobile phase and the volume fraction of methanol (φMeOH) in the mobile phase all have a clear influence on the resolution of KTZ enantiomers. Under optimal conditions, namely the use of 0.5 mmol L⁻¹ SBE-β-CD as the chiral mobile phase additive, pH of 4.0 and φ_MeOH in the mobile phase of 0.6, KTZ enantiomers are resolved with a resolution of 3.74. SBE-β-CD can bind to KTZ with a stability constant of 1157. The chromatographic method can provide the complexation stability constants of (+)-KTZ with SBE-β-CD (K₍₊₎) and (-)-KTZ with SBE-β-CD (K(−)). The intrinsic enantioselectivity was calculated from the K₍₊₎ to K₍₋₎ ratio as 1.34.

Keywords: ketoconazole – cyclodextrins – chiral recognition – stability constant

Full paper is available at www.springerlink.com.

DOI: 10.1515/chempap-2015-0133

Chemical Papers 69 (10) 1284–1290 (2015)