Efficient loading of ethionamide in cyclodextrin-based carriers offers enhanced solubility and inhibition of drug crystallization

Ethionamide (ETH) is a second line antitubercular drug suffering from poor solubility in water and strong tendency to crystallize. These drawbacks were addressed by loading ETH in ?-cyclodextrin (?CyD)-based carriers. The drug was incorporated in a molecular state avoiding crystallization even for long-term storage and obtaining a tenfold increased solubility up to 25. mM. The binding of ETH to polymeric ?CyD nanoparticles (p?CyD NPs) was investigated in neutral aqueous medium by means of solubility phase diagrams, circular dichroism (CD) and UV-vis absorption and compared with the corresponding ?CyD monomer. The binding constants and the absolute CD spectra of the drug complexes were determined by global analysis of multiwavelength data from spectroscopic titrations. The spectroscopic and photophysical properties of the complexes evidenced an alcohol-like environment for ETH included in the cavity. Additionally, ETH was found to be located not only in ?CyD cavities, but also in confined microdomains inside the crosslinked NPs. This double modality of complexation together with a slightly higher binding constant makes the utilization of p?CyD NPs preferable over the monomeric ?CyDs. In order to pave the way to future in vitro experiments, fluorescein labeled p?CyDs were synthesized. Interestingly the FITC labeling did not hamper the encapsulation of ETH and the drug improved the fluorescent signal of FITC molecules. The ?CyD-based carriers appeared as versatile "green" systems for efficient incorporation and future delivery of ETH.