Browsing by Author "Sala, Andrea"

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    Supramolecular derivatisation of bioactive molecules via co-crystallization and cyclodextrin inclusion complexation
    (2018) Sala, Andrea; Caira, Mino R; Bacchi, Alessia
    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.
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    Two Crystal Forms of a Hydrated 2:1 β-Cyclodextrin Fluconazole Complex: Single Crystal X-ray Structures, Dehydration Profiles, and Conditions for Their Individual Isolation
    (2021-07-22) Sala, Andrea; Hoossen, Zakiena; Bacchi, Alessia; Caira, Mino R
    Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and physicochemical properties to optimize pharmaceutical candidate selection. Here, we report the preparation and characterization of two crystallographically distinct hydrated forms of an inclusion complex between β-cyclodextrin (β-CD) and the antifungal API fluconazole (FLU) as well as temperature–concentration conditions required for their individual isolation. Determination of crystal water contents was achieved using thermoanalytical methods. X-ray analyses revealed distinct structural differences between the triclinic (TBCDFLU, space group P1) and monoclinic (MBCDFLU, space group C2) crystal forms. Removal of the crystals from their mother liquors led to rapid dehydration of the MBCDFLU crystal, while the TBCDFLU crystal was stable, a result that could be reconciled with the distinct packing arrangements in the respective crystals. This study highlights (a) the importance of identifying possible multiple forms of a cyclodextrin API complex and controlling the crystallization conditions, and (b) the need to characterize such crystal forms to determine the extent to which their physicochemical properties may differ.