Interaction pathways of specific co-solvents with hydroxypropyl-β-cyclodextrin inclusion complexes with benznidazole in liquid and solid phase

Abstract

The main purpose of the study was to assess the mechanism whereby the co-solvents triethanolamine (TEA) and 1-methyl-2-pyrrolidone (NMP) interacted with hydroxypropyl-beta-cyclodextrin (HP-β-CD) in ternary associations for improving the solubility and dissolution rate of the insoluble ingredient benznidazole (BNZ). In liquid phase, the solubility diagrams and Job's plot results were further explored by in silico molecular modeling and experimental 1H NMR spectroscopy studies. The structure of the inclusion complexes in the binary and ternary association were established. The competition of NMP with the drug for the HP-β-CD cavity was evidenced, while TEA stabilized the drug-CD interactions, forming ternary complexes. FTIR analysis confirmed distinct intermolecular interactions among the compounds in the different solid dispersions prepared by physical mixture (PM) and spray drying (SD). The co-solvents improved the drug dissolution performance from PM ternary associations due to their enhanced wettability of particles changing the drug-CD interaction. In addition to the SD samples exhibiting spherical particles, the co-solvents increased the crystallinity of drug in the particles and the ternary associations did not reproduce the drug dissolution rate identified in the PM samples. The experimental results proved the importance of the co-solvents to improve the drug dissolution performance from ternary complexes and established the mechanism whereby these substances worked together with the CD in a new and promising raw material. Due to the high temperature, the spray drying was not a suitable method for preparing the specific ternary complexes.