Tese
Efeitos do ultrassom na preparação de emulsões do fluconazol usando líquidos iônicos N-alquil-N-metilimidazolíneos
Autor
Hennemann, Bruno Luís
Institución
Resumen
Fluconazole is an active drug against a wide spectrum of species of fungi, this compound is used to treat
superficial and systemic fungal infections. However, this medicine has dissolution problems, which causes
limitations in the preparation and release of this drug. This limitation can be overcome by preparing emulsions.
Ultrasound (US) is considered one of the most efficient and effective methods for preparing emulsions. Due to
their amphiphilic characteristics, ionic liquids (ILs) based on imidazoline have potential application as a
surfactant. Thus, combining US and LIs can be an alternative to prepare stable and simpler emulsions of
fluconazole. Therefore, the objective of this work was to evaluate the influence of US on the properties of the
fluconazole emulsion prepared using ILs derived from imidazole. Properties such as particle size, polydispersity
index, morphology, encapsulation efficiency, viscosity, stability and release kinetics were evaluated. The
preparation method (mechanical stirring - MS and US), the amplitude of the US (20% and 40%), size of the IL
side chain (C12MIM[Br] or C16MIM[Br]) and IL concentration (1.5, 2.4 and 3.6 mM for C12MIM[Br] and 1.3,
2.06 and 3.1 mM for C16MIM[Br]) were evaluated. The results showed particle size and a lower polydispersity
index for emulsions prepared in the US than in systems prepared by AM. This shows that the US was efficient in
decreasing the particle size and polydispersity index of emulsions with ILs. TEM images proved that the particle
morphology and the stability of the emulsions containing C16MIM[Br] are dependent on the preparation method
and the concentration of IL. The emulsions prepared in the US showed spherical particles and an increase in
stability compared to emulsions prepared by MS. The creaming and flocculation phenomena were less
pronounced in systems with a higher concentration of IL. In all cases, the US with 40% amplitude increased the
efficiency of the encapsulation. The use of US in the preparation of emulsions demonstrated a decrease in the
viscosity of systems containing C12MIM[Br], although in general all emulsions had viscosity close to that of
water and emulsions containing IL C16MIM[Br] had the lowest viscosities between the systems studied. In
addition, all emulsions showed pseudo-plastic behavior. The drug release kinetics did not show any dependence
on the preparation method, but on the type of IL - emulsions containing IL C16MIM[Br] showed a more
controlled release and a lower total drug release than emulsions containing IL C12MIM[Br] in most cases. The
DOSY experiments demonstrated that the addition of medium chain triglycerides (MCT) decreases the diffusion
of ILs in the emulsion. In addition, the MCT titration experiments on the IL performed on the 1H NMR showed
variation in the chemical displacement and multiplicity of the IL signals, which indicates interaction between the
MCT and the IL. Finally, the emulsion stability results at 25 oC and 37 oC (body temperature) demonstrated that
the use of US was one of the factors responsible for increasing the stability of the systems containing IL
C16MIM[Br], since the instability index was lower for systems prepared by high energy. However, for emulsions
containing C12MIM[Br], the instability index of emulsions prepared by US was higher than the index for
emulsions prepared by MS, indicating that high energy causes destabilization of the emulsion. In summary, US
was an effective method for preparing stable emulsions of fluconazole using C12MIM[Br] and C16MIM[Br]
without additional surfactant. The concentration of ILs to prepare these emulsions was lower than the
concentration of conventional surfactant, exhibiting the potential synergistic effects of ILs and US in the
emulsion preparation of insoluble drugs.