Sulfated 3-cyclodextrin

Recently, two examples of the separation of enantiomers using CCC have been published (Fig. 1-2). The complete enantiomeric separation of commercial d,l-kynurenine (2) with bovine serum albumin (BSA) as a chiral selector in an aqueous-aqueous polymer phase system was achieved within 3.5 h [128]. Moreover, the chiral resolution of 100 mg of an estrogen receptor partial agonist (7-DMO, 3) was performed using a sulfated (3-cyclodextrin [129, 130], while previous attempts with unsubstituted cyclodextrin were not successful [124]. The same authors described the partial resolution of a glucose-6-phosphatase inhibitor (4) with a Whelk-0 derivative as chiral selector (5) [129]. 

In a different approach, Stalcup and co-workers [25] used sulfated (3-cyclodextrin for the enantioseparation of piperoxan in work directly derived from earlier CE and classical gel results. Their results were obtained using a continuous free flow apparatus developed by R S Technologies, Inc. Processing rates on the order of 4.5 mg h were reported. 

LOD, limit of detection a-CD, a-cyclodextrin, fS-CD, (3-cyclodextrin CM-(3-CD, carboxymethyl- -cyclodextrin DM-p-CD, dimethyl- -cyclodextrin HP-(3-CD, hydroxpropyl- -cyclodextrin TM-(3-CD, trimethyl-(3-cyclodextrin, S- -CD, sulfated (3-cyclodextrin, SB- -CD, sulfobutyl-/i-cyclodextrin. 

Fig. 3. The chiral separation obtained for oxa2epam on a sulfated cyclodextrin hplc column (4.6 mm ID x 25 cm) using a 10% acetonitrile/buffer (25 mM...

Recently, the separation of some milligram quantities of terbutaline by classical gel electrophoresis has been reported [194]. A sulfated cyclodextrin impregnated on the agarose gel was used as a chiral selector and the complete resolution was achieved in 5 h. Analogously, small amounts of enantiomers can be isolated using thin-layer... 

Fig. 11-1. Effect of the addition of methanol on the enantiomeric separation of terbutaline using 2 % sulfated cyclodextrin in 25 mM phosphate buffer (pH 3).

The author would like to acknowledge R S Technologies, Inc. (Wakefield, RI, USA) for the loan of the continuous free flow electrophoresis system, and Cerestar, Inc. for the donation of the sulfated cyclodextrin. The author would also like to thank Drs. Chris Welch and Prabha Painuly for helpful discussions. 

Table 11-3. Migration times for piperoxan enantiomers for four consecutive runs on the same agarose gel using sulfated cyclodextrin as the chiral selector.

Fig. 11-6. Histograms showing the distribution of piperoxan enantiomers in the absence (a) and presence (b) of sulfated cyclodextrin in continuous free flow electrophoresis.

Sulfated alkenes, 23 538 Sulfated carbohydrate products, 23 538 Sulfated cyclodextrin-based chiral stationary phase, 6 87 Sulfated fatty acids, 23 538 Sulfated fatty alcohol ethoxylates, 23 537 Sulfated fatty oils, 23 538 Sulfated products... 

The short-end injection was also used in a paper by Perrin et al. [28]. They saw a very high chiral recognition capability of highly sulfated cyclodextrins (HS-CD). Using a test set of 27 amino acid derivatives, the application of HS-a-CD, HS-fl-CD, and HS-y-CD in a 5% w/v concentration allowed the separation of 26 compounds, of which 22 had a Rs > 2. From their experiments, a screening and optimization scheme was derived (Figure 3.3), and based on this scheme, a separation strategy was defined... 

Perrin, C., Vander Heyden, Y, Maftouh, M., Massart, D.L. Rapid screening for chiral separations by short-end injection capillary electrophoresis nsing highly sulfated cyclodextrins as chiral selectors. Electrophoresis 2001, 22, 3203-3215. 

Zhou, L., Thompson, R., Song, S., Elhson, D., Wyvratf J.M. A strategic approach to the development of capillary electrophoresis methods for pharmaceutical basic compounds nsing sulfated cyclodextrins. J. Pharm. Biomed. An. 2002, 27, 541-553. 

P/ACE System MDQ chiral methods development P/ACE System MDQ highly sulfated cyclodextrin trial kit eCAP Amine Capillary Method Development Kit/Small Molecules eCAP Carbohydrate Labeling Kit... 

Rudaz, S., Calleri, E., Geiser, L., Gherkaoui, S., Prat, J., and Veuthey, J. L. (2003). Infinite enantiomeric resolution of basic compounds using highly sulfated cyclodextrin as chiral selector in capillary electrophoresis. Electrophoresis 24, 2633—2641. 

AM Stalcup, KH Gahm. Application of sulfated cyclodextrin to chiral separations by capillary zone electrophoresis. Anal Chem 68 1360—1368, 1996. 

Cyclodextrins are cyclic maltooligosaccharides available by enzymatic syntheses from starch. Due to their easy access, sulfated cyclodextrins had been investigated back in the early 1960s for their plasma clearing activity [53]. More recently, the activities of -cyclodextrin (cycloheptamaltaose,)3-CD) tetradecasulfate (24) were evaluated in more detail. It was prepared by sulfetion of -CD which led to the sulfation of the primary and one of the secondary hydroxyl groups per pyranose ring so that a mixture of differently sulfated compounds resulted (Structures 7). 

Cyclodextrins have been used for enhancing the solubility of poorly water-soluble small molecules (Shimpi et ah, 2005). The mechanism of solubilization is formation of reversible complexes between the hydrophobic moiety of the drug molecule and the hydrophilic cyclodextrin that is highly water soluble. A similar observation has been made with some proteins and peptides (Brewster et ah, 1991 Johnson et ah, 1994 Flores et ah, 2001). Sulfated cyclodextrins and 2-hydroxypropyl-beta-cyclodextrins are approved excipients for parenteral administration, however, use of these compounds should take into consideration the cost involved. 

Electrophoretic methods are widely used alternatives for the analytical determination of the enantiomeric purity of chiral compounds [194]. Due to the high elTi-ciency of capillary electrophoresis, separations can be achieved even when very low selectivities are observed. At a preparative scale, these methods are well established for the purification of proteins and cells [195] but there is very little published on enantioselective separations. Only recently, some interest in chiral preparative applications has been manifested. Separation of the enantiomers ofterbu-taline [196] and piperoxan [197] have been reported by classical gel electrophoresis using sulfated cyclodextrin as a chiral additive, while the separation of the enantiomers of methadone could be successfully achieved by using free-fluid isotachophoresis [198] and by applying a process called interval-flow electrophoresis [199]. 

K-H Gahm, AM Stalcup. Sulfated cyclodextrins for the chiral separations of cathe-colamines and related compounds in the reversed electrophoretic polarity mode. Chirality 8 316-324, 1996. 

JB Vincent, G Vigh. Systematic approach to methods development for the capillary electrophoretic analysis of a minor enantiomer using a single-isomer sulfated cyclodextrin. A case study of L-carbidopa analysis. J Chromatogr A 817 105-111,... 

Li WW, Casey R, Gonzalez EM, Folkman J. Angiostatic steroids potentiated by sulfated cyclodextrins inhibit corneal neovascularization. Invest Ophthalmol Vis Sci 1991 32 2898-2905. 

Crandall, I. E., Szarek, W. A., Vlahakis, J. Z., Xu, Y., Vohra, R., Sui, J., and Kisilevsky, R. (2007). Sulfated cyclodextrins inhibit the entry of Plasmodium into red blood cells. Implications for malarial therapy. Biochem. Pharmacol. 73, 632-642. 

Iwata, Y. T., Garica, A., Kanamori, T., Inoue, H., Kishi, T., and Lurie, I. S. The use of a highly sulfated cyclodextrin for the simultaneous chiral separation of amphetamine-type stimulants by capillary electrophoresis. Electrophoresis, 23, 1328, 2002. 

Evans C.E., Stalcup A.M., Comprehensive strategy for chiral separations using sulfated cyclodextrins in capillary electrophoresis. Chirality, 15, 709-723 (2003). 

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