Supramolecular derivatisation of bioactive molecules via co-crystallization and cyclodextrin inclusion complexation

Sala, Andrea

Supramolecular derivatisation of bioactive molecules via co-crystallization and cyclodextrin inclusion complexation

Master Thesis

2018

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

Abstract

The objective of this study was to modify the physicochemical properties of two common drugs via supramolecular derivatization. Sulfasalazine is a powerful anti-inflammatory drug and fluconazole has a strong antibacterial and antifungal activity. The common feature is their very low solubility in water. Cyclodextrin inclusion complexation and co-crystallization were carried out with the aim of ultimately improving the bioavailability of both drugs. Each new crystal phase isolated was analysed using X-ray diffraction, thermal and spectroscopic techniques. Sulfasalazine presents two tautomeric forms which were isolated using different preparative methods via recrystallization from different solvents. Each form was used in combination with nine different co-formers in attempts to form co-crystals. This approach yielded negative results. Cyclodextrin inclusion complexation of sulfasalazine was studied with a variety of cyclodextrins (αCD, β-CD, γ-CD, dimethylated β-CD and permethylated β-CD). The complexation attempts yielded an inclusion complex between one of the tautomers of sulfasalazine and γ-cyclodextrin. No single crystals were obtained and hence it was impossible to resolve the crystal structure. However, it was possible to analyse the complex thermally and spectroscopically. The co-crystallization of fluconazole with biocompatible co-formers was not investigated due to the appearance of extensive previous reports on its co-crystal formation in the literature. Thus, only cyclodextrin inclusion complexation (with the same CDs listed above) was studied. Three inclusion complexes with native CDs were successfully prepared. Two crystallographically distinct complexes of β-CD with fluconazole as guest having 2:1 host-guest stoichiometry were isolated. While these two hydrated complexes had been identified recently by previous researchers and the X-ray structure of one of the crystal forms had been partially resolved, their characterization was incomplete. In the present study, significant advances on the previous work included the complete X-ray structural resolution of both crystal forms, designated TBCDFLU (triclinic) and MBCDFLU (monoclinic), as well as a systematic study of the conditions under which these individual forms could be isolated. The occurrence of these crystal forms was dependent on two variables, namely β-CD concentration in the aqueous mother liquor and the incubation temperature of the solution. Careful examination of the sensitive crystallization equilibrium indicated that, at a solution concentration of 6.52  10-2 M, pure TBCDFLU could be isolated at an incubation temperature of 45 C or lower, while pure MBCDFLU crystallized at an incubation temperature of 60 C (for both cases the incubation period is more than 48 h). MBCDFLU and TBCDFLU crystals displayed different stabilities with respect to dehydration when exposed to air and hence determination of their respective water contents was performed using thermogravimetry on fresh crystals immersed in silicone oil. From a phase solubility study, it was established that the association constant for complex formation between - CD and fluconazole in solution was very low (27.2 M-1), implying weak host-guest binding. Finally, a 1:1 inclusion complex between -CD and fluconazole was isolated and characterized by thermal and spectroscopic techniques.

Keywords

Chemistry

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