Synthesis of highly functionalised calix[4]resorcinarenes and their application as drug solubilising agents

Abdulrahman, May Fahmi A

Abstract

The rate-limiting step for oral absorption of hydrophobic drugs and solubility is the drug dissolution rate in the GI fluids. Several novel and traditional methods have been used to improve the solubility rates of poorly water soluble drugs. The proficient encapsulation of hydrophobic drugs in specially designed, functionalized carriers and controlling the drug dissolution and release is considered a major challenge. Approaches to prepare water soluble receptors based on calix[n]arene scaffolds capable of selectively binding guests, including hydrophobic drugs in aqueous media, have been reported but there is no universal solution.
The goal of this project was to study the self-assembly and potential applications of functionalised calix[4]resorcinarenes and calix[4]pyrogallolarenes as drug solubilising agents. These goals were addressed by synthesizing several series of calix[4]resorcinarene and calix[4]pyrogallolarene hosts bearing different lower rim alkyl chain lengths (C4 and C7). Further modifications were performed by functionalisation of the upper rim of the calix[4]resorcinarene and calix[4]pyrogallolarenes, by exploiting 2-substituted resorcinols and by attaching ester moieties to the phenolic hydroxyl groups. The synthesis of deep-cavity cavitands was explored also. These amphiphilic carriers were fully characterised using spectroscopy and physico-chemical measurements.
Six water-soluble hosts were formed into nanoparticles using the appropriate method. Their ability to self assemble in aqueous environments and the resultant particle size and zeta potential of the aggregates were compared. These hosts were tested for their ability to improve the solubility, dissolution rate and release behaviour of different hydrophobic drugs. Interestingly, all of these novel formulations significantly improved the aqueous solubility and dissolution of three of the hydrophobic drugs tested, indicating that these amphiphilic carriers can be used as drug solubilising agents for formulation. In vitro release profiles showed that all the novel formulations derived from calix[4]resorcinarenes and calix[4]pyrogallolarenes bearing long alkyl chains on the lower rim achieved sustained release.

Citation

Abdulrahman, M. F. A. (2020). Synthesis of highly functionalised calix[4]resorcinarenes and their application as drug solubilising agents. (Thesis). Keele University

• Thesis Type: Thesis
• Publicly Available Date: May 26, 2023
• Award Date: 2020-07