Zwitterions as hydrotropes to enhance the solubility of drugs in water

• Autor(a) principal: Cruz, Brayan Isak
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/31946
• topic: Bioactive solutes; Hydrotropy; Pharmaceutical industry; Solubility; Zwitterions

One of the major limitations found in the development of new pharmaceutical products lies in the low solubility in water of oral drugs. The study on hydrotropes application – compounds with the capacity to increase the solubility of hydrophobic compounds in aqueous solutions – for molecules solubility enhancement has been increasing over the past years. Several new types of hydrotropes have been identified and evaluated to develop more effective and biocompatible drug formulations. Nevertheless, despite the large number of studies about hydrotropy, the mechanisms that rule hydrotropic effect are still not clearly understood, and hydrotropes selection is still based on a trial-and-error approach. In this work, aqueous solutions of zwitterionic compounds structurally similar to ionic liquids were investigated to improve the solubility of poorly water-soluble bioactive compounds. Zwitterionic compounds present several chemical properties of high interest and are already widely used in the pharmaceutical industry. The solubility of four bioactive molecules - gallic acid, vanillin, syringic acid and tryptophan - and one pharmaceutical drug, the ibuprofen, in aqueous solutions of ammonium-based zwitterions (ZIs) were ascertained. The effect of the cation alkyl chain length and the size of the spacer between the cationic and anionic groups that compose the ZIs, were evaluated. The obtained results demonstrated that studied ZIs are potential hydrotropes for bioactive solutes. These compounds were able to induce considerable increments in water solubility of the studied solutes, with the highest being attained for ibuprofen solubility, reaching a value 2600 times higher than its solubility in water. It was also observed that the hydrotropic effect depends on both the solute and the hydrotrope. The hydrotropic effect tends to be higher for more hydrophobic solutes (here measured by their octanol-water partition coefficients); however, the increase of the alkyl chain length of ZIs is not always favorable being needed a balance between these two effects. The obtained solubility curves were fitted using a statistical thermodynamic-based model. Remarkably, it was also observed that ZIs present a very similar hydrotropic effect to their ionic liquid counterparts, which is especially relevant when considering the lower (eco)toxicity of ZIs. In summary, very positive signs were gathered throughout this work in order to enhance the solubility of poorly water-soluble solutes, such as pharmaceutical drugs, by using ZI hydrotropes.