Elucidating the complexation of nifurtimox with cyclodextrins

Abstract

Chagas disease or American Trypanosomiasis, caused by the parasite Trypanosoma cruzi, is an endemic neglected infection found in 21 countries across Latin America. To date, nifurtimox is one of the only two drugs approved to treat Chagas disease but exhibits serious concerns related to its low aqueous solubility and erratic bioavailability. Thus, the aim of this work was to evaluate whether the formation of complexes with βcyclodextrin and sulfobutylether-β-cyclodextrin would improve drug solubility and dissolution rate. Drug-cyclodextrin interactions in solid-state were analyzed by differential scanning calorimetry, X-ray diffractometry, infrared spectroscopy, and nuclear magnetic resonance. The systems were characterized in solution by means of phase solubility, dissolution, and kinetic studies. Phase solubility study showed an AL-type diagram indicating the formation of inclusion complex in a 1:1 M ratio. The drug dissolution rate from sulfobutylether-β-cyclodextrin complexes was faster than that of the β-cyclodextrin complexes. The modification of the endothermic peak of nifurtimox revealed the presence of interactions between the drug and CDs. The crystalline character of the drug was greatly diminished after complexation with sulfobutylether-β-cyclodextrin. Microscopy evaluation revealed the formation of new structures of the solid particles, which suggest strong interactions between the drug and the carriers. The 1H and 13C nuclear magnetic resonance confirmed that the drug was included in the carriers. The selected nifurtimox complex stored at 25 °C and 40 °C during 6 months showed a remarkable stability in terms of drug dissolution and crystallinity.