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 ϕMeOH 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.
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Arakaki, R., & Welles, B. (2010). Ketoconazole enantiomer for the treatment of diabetes mellitus. Expert Opinion on Investigational Drugs, 19, 185–194. DOI: 10.1517/13543780903381411.
Bernal, J. L., del Nozal, M. J., Toribio, L., Montequi, M. I., & Nieto, E. M. (2000). Separation of ketoconazole enantiomers by chiral subcritical-fluid chromatography. Journal of Biochemical and Biophysical Methods, 43, 241–250. DOI: 10.1016/s0165-022x(00)00060-9.
Corradini, R., Dossena, A., Impellizzeri, G., Maccarrone, G., Marchelli, R., Rizzarelli, E., Sartor, G., & Vecchio, G. (1994). Chiral recognition and separation of amino acids by means of a copper(II) complex of histamine monofunctionalized β-cyclodextrin. Journal of the American Chemical Society, 116, 10267–10274. DOI: 10.1021/ja00101a050.
Castro-Puyana, M., García-Ruiz, C., Cifuentes, A., Crego, A. L., & Marina, M. L. (2006). Identification and quantitation of cis-ketoconazole impurity by capillary zone electrophoresis-mass spectrometry. Journal of Chromatography A, 1114, 170–177. DOI: 10.1016/j.chroma.2006.02.030.
Del Valle, E. M. M. (2004). Cyclodextrins and their uses: a review. Process Biochemistry, 39, 1033–1046. DOI: 10.1016/s0032-9592(03)00258-9.
Demirel, M., Yurtdaş, G., & Genç, L. (2011). Inclusion complexes of ketoconazole with beta-cyclodextrin: physicochem-ical characterization and in vitro dissolution behaviour of its vaginal suppositories. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 70, 437–445. DOI: 10.1007/s10847-010-9922-1.
Fujimura, K., Ueda, T., Kitagawa, M., Takayanagi, H., & Ando, T. (1986). Reversed-phase retention behavior of aromatic compounds involving β-cyclodextrin inclusion complex formation in the mobile phase. Analytical Chemistry, 58, 2668–2674. DOI: 10.1021/ac00126a020.
Guan, J., Yang, J., Bi, Y., Shi, S., Yan, F., & Li, F. (2008). Determination of the enantiomeric impurity in S-(−)pantoprazole using high performance liquid chromatography with sulfobutylether-beta-cyclodextrin as chiral additive. Journal of Separation Science, 31, 288–293. DOI: 10.1002/jssc.200700369.
Healy, L. O., Murrihy, J. P., Tan, A., Cocker, D., McEnery, M., & Glennon, J. D. (2001). Enantiomeric separation of R, S-naproxen by conventional and nano-liquid chromatog-raphy with methyl-β-cyclodextrin as a mobile phase additive. Journal of Chromatography A, 924, 459–464. DOI: 10.1016/s0021-9673(01)01044-5.
Lerch, C., & Blaschke, G. (1998). Investigation of the stereoselective metabolism of praziquantel after incubation with rat liver microsomes by capillary electrophoresis and liquid chromatography-mass spectrometry. Journal of Chromatography B, 708, 267–275. DOI: 10.1016/s0378-4347(97)00638-5.
Liu, Y., Li, X. Q., Chen, Y., & Guan, X. D. (2004). Spectrophotometric study of selective binding behaviors of dye molecules by pyridine- and bipyridine-modified β-cyclodextrin derivatives with a functional tether in aqueous solution. The Journal of Physical Chemistry B, 108, 19541–19549. DOI: 10.1021/jp046363t.
Liu, J. J., Liu, C., Tang, K. W., & Zhang, P. L. (2014). Biphasic recognition chiral extraction — novel way of separating pan-toprazole enantiomers. Chemical Papers, 68, 599–607. DOI: 10.2478/s11696-013-0501-y.
Luong, J. H. T., & Guo, Y. (1998). Mixed-mode separation of polycyclic aromatic hydrocarbons (PAHs) in electrokinetic chromatography. Electrophoresis, 19, 723–730. DOI: 10.1002/elps.1150190521.
Mskhiladze, A., Karchkhadze, M., Dadianidze, A., Fanali, S., Farkas, T., & Chankvetadze, B. (2013). Enantioseparation of chiral antimycotic drugs by HPLC with polysaccharide-based chiral columns and polar organic mobile phases with emphasis on enantiomer elution order. Chromatographia, 76, 1449–1458. DOI: 10.1007/s10337-013-2396-8.
Rabanes, H. R., & Quirino, J. P. (2013). Sweeping of alprenolol enantiomers with an organic solvent and sulfated β-cyclodextrin in capillary electrophoresis. Electrophoresis, 34, 1319–1326. DOI: 10.1002/elps.201200595.
Redenti, E., Ventura, P., Fronza, G., Selva, A., Rivara, S., Plazzi, P. V., & Mor, M. (1999). Experimental and theoretical analysis of the interaction of (±)-cis-ketoconazole with β-cyclodextrin in the presence of (+)-l-tartaric acid. Journal of Pharmaceutical Sciences, 88, 599–607. DOI: 10.1021/js980468o.
Szejtli, J. (1998). Introduction and general overview of cyclodextrin chemistry. Chemical Reviews, 98, 1743–1754. DOI: 10.1021/cr970022c.
Tang, K., Zhang, P., Pan, C., & Li, H. (2011). Equilibrium studies on enantioselective extraction of oxybutynin enantiomers by hydrophilic β-cyclodextrin derivatives. AIChE Journal, 57, 3027–3036. DOI: 10.1002/aic.12513.
Tang, K., Zhang, H., & Liu, Y. (2013). Experimental and simulation on enantioselective extraction in centrifugal contactor separators. AIChE Journal, 59, 2594–2602. DOI: 10.1002/aic.14004.
Tao, Y., Dai, J., Kong, Y., & Sha, Y. (2014). Temperature-sensitive electrochemical recognition of tryptophan enantiomers based on β-cyclodextrin self-assembled on poly(l-glutamic acid). Analytial Chemistry, 86, 2633–2639. DOI: 10.1021/ac403935s.
Taschwer, M., Seidl, Y., Mohr, S., & Schmid, M. G. (2014). Chiral separation of cathinone and amphetamine derivatives by HPLC/UV using sulfated β-cyclodextrin as chiral mobile phase additive. Chirality, 26, 411–418. DOI: 10.1002/chir.22341.
Tong, S., Yan, J., Guan, Y. X., & Lu, Y. (2011). Enantioseparation of phenylsuccinic acid by high speed counter-current chromatography using hydroxypropyl-β-cyclodextrin as chiral selector. Journal of Chromatography A, 1218, 5602–5608. DOI: 10.1016/j.chroma.2011.06.023.
Toribio, L., Bernal, J. L., del Nozal, M. J., Jiménez, J. J., & Nieto, E. M. (2001). Applications of the Chiralpak AD and Chiralcel OD chiral columns in the enantiomeric separation of several dioxolane compounds by supercritical fluid chromatography. Journal of Chromatography A, 921, 305–313. DOI: 10.1016/s0021-9673(01)00844-5.
Wang, S., Wang, Y., Zhou, J., Lu, Y., Tang, J., & Tang, W. (2014). Mono-6A-(4-methoxybutylamino)-6A-β-cyclodextrin as a chiral selector for enantiomeric separation. Journal of Separation Science, 37, 2056–2061. DOI: 10.1002/jssc.201400248.
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Sun, BZ., He, K., Chen, XM. et al. Resolution of ketoconazole enantiomers by high-performance liquid chromatography and inclusion complex formation between selector and enantiomerss. Chem. Pap. 69, 1284–1290 (2015). https://doi.org/10.1515/chempap-2015-0133
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DOI: https://doi.org/10.1515/chempap-2015-0133