Characterisation of the apparent aqueous solubility enhancement of testosterone analogues in micelles of dodecyl-chained surfactants with different headgroups

Abstract

The solubilisation capacities of the micelles formed by a range of surfactants possessing a dodecyl (C12) hydrocarbon ‘tail’ and a variety of hydrophilic ‘headgroups’ have been studied for a range of hydrophobic steroids (testosterone (T) and its propionate (TP) and enanthate (TE) esters). The solubilisation studies were performed at ambient temperature, with drug concentration monitored (over 48–72 h) by UV absorbance. The various surfactant systems were characterised in terms of their physicochemical properties, including their surface tension, critical micelle concentration, viscosity, and density. Results show that while the apparent aqueous solubility of the poorly water-soluble steroids increases upon solubilisation within the surfactant micelles, the extent of this increase varies with the nature of the hydrophilic headgroup and the hydrophobicity of the drug. Specifically, changing the surfactant headgroup from non-ionic to zwitterionic, then to ionic, results in a marked increase in solubility of the two least hydrophobic steroids, testosterone and testosterone propionate, suggesting rather counter-intuitively that these steroidal drugs tend to associate to a greater extent with micelles formed by surfactants with more hydrophilic/charged head groups. The more hydrophobic steroid, TE, was solubilised to the greatest extent, being predominantly solubilised within the micelle core. In this case, the influence of surfactant head group on TE solubilisation was less obvious, with surfactants containing ionic and zwitterionic head groups exhibiting high levels of solubilisation. The physicochemical properties that had most influence on solubilisation of the testosterone analogues, as evaluated using multiple linear regression, were micelle shape for T and TP, and critical micelle concentration for TE. Through the findings of this comparative study, the essential molecular descriptors of optimal solubilisation for improved drug delivery and the loci of solubilisation of the testosterone analogues have been identified.