Effect of Alkyl Chain Length and Degree of Substitution on the Complexation of Sulfoalkyl Ether β-Cyclodextrins with Steroids

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Abstract
This study was designed to test how the sulfoalkyl ether (SAE) modification of beta-cyclodextrin (beta-CD) affects the binding capacity of testosterone and progesterone, thereby enhancing their solubility. The SAE-beta-CD derivatives contain either sulfopropyl ether (SPE) or sulfobutyl ether (SBE) groups on the 2-, 3-, and 6-hydroxyl positions of the dextrose moieties. SAE-beta-CDs are a mixture of positional and regional isomers containing from one to as many as 12 SAE groups per CD. The effect of chain length and the degree of substitution on complexation behavior was investigated by the phase-solubility method. The results were compared with those obtained with beta-CD, where possible, and with hydroxypropyl-beta-CD (HP-beta-CD). To determine the effect of degree of substitution (DS) on the binding, mixtures of SAE-beta-CDs with multiple substitution levels and varying average degrees of substitution were studied as well as mixtures of SAE-beta-CDs that contained the same degree of substitution. Mixtures that contained SAE-beta-CDs of the same degree of substitution were isolated from the multiple substitution level mixtures by ion-exchange chromatography and purified for investigation. Unlike the parent beta-CD, linear increases in the apparent solubilities of testosterone and progesterone were observed, and the binding potentials were comparable to those of beta-CD or better. The results demonstrate that the binding potentials of the SAE-beta-CD derivatives were dependent on the guest molecule, the degree of substitution, and the alkyl ether chain length. Our previous study showed the inhibition of complexation by direct sulfonation of the beta-CD. However, in the present work, interferences with the charged sulfonate groups were avoided by repositioning them away from the cavity. Increasing the degree of substitution assisted in complex formation; however, its effects were limited. Reduction of the alkyl chain length, as in the case of SPE-beta-CD compared with SBE-beta-CD, decreased the complexation potential. This decrease in complexation potential was further suppressed with an increase in the number of substituents placed on the CD torus. Generally, the binding potential of SAE-beta-CD derivatives increased with increasing alkyl chain length. However, placement of more than an optimum number of SAE groups on the CD torus resulted in inhibition of complexation.

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