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Interaction of native cyclodextrins and their hydroxypropylated derivatives with parabens in aqueous solutions. Part 1: evaluation of inclusion complexes

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Abstract

Due to their antimicrobial activity, parabens (i.e. alkyl esters of p-hydroxybenzoic acid) are widely used as preservatives in several industries (pharmaceutical, food, cosmetic). Although being extremely effective, their usage is hampered by their low aqueous solubility. Several formulation strategies can be applied to enhance their solubility, one of which is formation of water-soluble cyclodextrin (CD) complexes. Formation of inclusion complexes has been proved to be a good approach to increase solubility of lipophilic drugs and other active ingredients. Some research has been done in this field. However, a complete and comprehensive study on how the alkyl chain length of parabens influences the complex formation, aggregation and formation of insoluble complexes is still lacking. Phase-solubility studies showed that all the very water-soluble hydroxypropylated CDs form linear (AL) type phase-solubility profiles with all tested parabens. The poorly soluble βCD did also form AL-type profiles with methyl and ethyl paraben while the βCD complexes of propyl and butyl paraben have limited solubility in water and, thus displayed B-type profiles. The paraben complexes of αCD and γCD all had limited solubility in water and, thus, displayed B-type phase-solubility profiles. Fourier-transformed infrared spectroscopy, Differential scanning calorimetry and X-ray powder diffraction were applied to elucidate the nature of the solid phases from the phase-solubility studies. They consistently showed the presence of solid pure paraben over the CD concentration range studied when AL-type profiles were observed, and precipitation of poorly soluble paraben/CD complexes when B-type were observed (i.e. during and after the B-type plateau region). These studies demonstrate that the composition of solid phases is related to the type of phase-solubility profile. It was also shown that in aqueous CD solutions, paraben solubilization increase with increasing side chain length (i.e. methyl < ethyl < propyl < butyl), as well as, with increasing size of the CD cavity (i.e. αCD < βCD < γCD). This statement is valid for linear region of phase-solubility diagrams (i.e. A- and B-type).

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Acknowledgements

The financial support received from the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT) (Grant No. 135040) is gratefully acknowledged.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, 107, Reykjavik, Iceland

    André Rodrigues Sá Couto, Sara Aguiar, Alexey Ryzhakov & Thorsteinn Loftsson

  2. Dept. of Chemistry and Bioscience, Aalborg University, Frederik Bajers Vej 7H, 9220, Aalborg, Denmark

    Kim Lambertsen Larsen

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  1. André Rodrigues Sá Couto
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Couto, A.R.S., Aguiar, S., Ryzhakov, A. et al. Interaction of native cyclodextrins and their hydroxypropylated derivatives with parabens in aqueous solutions. Part 1: evaluation of inclusion complexes. J Incl Phenom Macrocycl Chem 93, 309–321 (2019). https://doi.org/10.1007/s10847-018-00876-5

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