Simple and Cost-Effective Chrysin-Theophylline Eutectic: Enhanced Solubility, Dissolution, and Oral Bioavailability with Potential for Respiratory Applications

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are the most prevalent chronic respiratory diseases. Theophylline is used for its bronchodilator and anti-inflammatory effects, but its clinical use is declining due to a narrow therapeutic index and metabolism by cytochrome enzymes, which increases the risk of drug interactions and toxicity. Chrysin, a BCS class II flavonoid, exhibits anti-inflammatory and antioxidant activities and reported to inhibit cytochrome enzymes. Drug-drug eutectic mixtures are increasingly explored to enhance the solubility and bioavailability of poorly water-soluble drugs. In this context, a eutectic mixture of chrysin and theophylline was prepared using a simple, eco-friendly grinding method, with theophylline (a BCS class I drug) serving as a coformer. The prepared eutectic was characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), hot stage microscopy (HSM), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), Scanning Electron Microscopy with energy dispersive spectroscopy (FE SEM-EDS), in vitro dissolution studies and in vivo pharmacokinetic evaluation in Wistar rats. DSC studies confirmed eutectic formation as its melting point was below than that of melting point of chrysin and theophylline. It also confirmed a stoichiometric ratio of 1:2 between chrysin and theophylline. FTIR studies suggested intermolecular hydrogen bonding between chrysin and theophylline. The eutectic mixture significantly improved the aqueous solubility and dissolution rate of chrysin. Pharmacokinetic studies in rats showed a 3-fold increase in area under the curve (AUC) and a 2.87-fold increase in relative bioavailability of chrysin. This dual-drug eutectic may offer combined anti-inflammatory benefits and improved bioavailability for both agents, with chrysin’s cytochrome inhibition potentially reducing theophylline degradation, supporting its therapeutic potential in asthma and COPD.