Investigating the Association Mechanism between Rafoxanide and Povidone

Abstract

The low aqueous solubility of most hydrophobic medications limits their oral absorption. An approach to solve this problem is to make a drug−polymer association. Herein, we investigated the association between rafoxanide (RAF), a surface-active, poorly water-soluble drug, with a commercial hydrophilic polymer povidone. We found that the association is a function of medium composition and could only take place in polar media, such as water. The association is favored by the hydrogen-bond formation between the amide group in RAF and the carbonyl group in povidone. In addition, the association is also favored by the self-association of RAF through π−π interaction between the benzene rings in adjacent RAF molecules. Twodimensional nuclear magnetic resonance has been applied to investigate the interactions and has confirmed our hypotheses. Geometry optimization confirmed that RAF exists primarily in the antiparallel configuration in the RAF aggregates. This study provides critical information for designing suitable drug−vehicle complexes and engineering the interactions between them to maximize the oral absorption. Our results shed light on drug design and delivery, drug molecule structure−functionality relationship, as well as efficacy enhancement toward interaction engineering.

Understanding Molecular Interactions in Rafoxanide–Povidone Amorphous Solid Dispersions from Ultrafast Magic Angle Spinning NMR

“…22−29 For example, due to the disruption of dimeric H-bonding within poly acrylic acid molecules, the carboxylate carbon of this molecule shifts to a higher frequency of 4.8 ppm for the ketoconazole and poly acrylic acid ASD, relative to the physical mixture. 22 Yuan et al utilized 13 C spectra to investigate hydrogen bonding interactions in ASDs of indomethacin−PVP, 23 and they showed that PVP disrupted the self-interaction in indomethacin dimers and formed hydrogen bonding with the drug molecule. Multidimensional ssNMR spectroscopy can correlate homo-and heteronuclear proximities and represents an advanced and sensitive technique to probe intermolecular interactions of a drug and polymer in ASDs.…”

“…Previous studies have demonstrated that RAF interacts with PVP in aqueous media, forming a water-soluble complex. 13 Due to this complexation, the apparent solubility of RAF increased drastically in the presence of PVP. In addition, the molecular interaction between RAF and PVP in solution is highly dependent on the solvent.…”

“…13 We have also thoroughly investigated the feasibility of improving in vitro dissolution and in vivo absorption of RAF by using the ASD technique. 13,55 We spray-dried two RAF ASDs obtained from feed solutions based on two different media. The first ASD is a complexation-based spray-drying using a NaOH solution with acetone, referred to as RAF−ASD (aq).…”

Characterizing Drug–Polymer Interactions in Aqueous Solution with Analytical Ultracentrifugation

“…24 While organic solvents can be used, interactions probed in such systems do not reflect interactions in aqueous solution. 25 Other techniques that can address the challenge of poor signal sensitivity in aqueous media must therefore be explored.…”

“…Similarly, the need for very high drug concentrations almost entirely precludes the use of isothermal titration calorimetry (ITC) . While organic solvents can be used, interactions probed in such systems do not reflect interactions in aqueous solution . Other techniques that can address the challenge of poor signal sensitivity in aqueous media must therefore be explored.…”