Effect of Deep Eutectic System (DES) on Oral Bioavailability of Celecoxib: In Silico, In Vitro, and In Vivo Study

Different deep eutectic systems (DES) of choline chloride (CC)-urea (UA) (1:2), CC-glycerol (GLY) (1:2), CC-malonic acid (MA) (1:1), and CC-ascorbic acid (AA) (2:1) were generated and characterized by polarized light microscope (PLM) and Fourier transform infrared spectroscope (FTIR). The equilibrium solubility of celecoxib (CLX) in DES was compared to that in deionized water. The CC-MA (1:1) system provided similar to 10,000 times improvement in the solubility of CLX (13,114.75 mu g/g) and was used for the generation of the CLX-DES system. The latter was characterized by PLM and FTIR to study the microstructure and intermolecular interaction between the CLX and CC-MA (1:1) DES. FTIR demonstrated the retention of the chemical structure of CLX. In vitro drug release studies in FaSSIF initially demonstrated high supersaturation, which decreased by similar to 2 fold after 2 h. Density functional theory (DFT)-based calculations provided a molecular-level understanding of enhanced solubility. Gibbs free energy calculations established the role of the strongest binding of CLX with CC and MA. A phase solubility study highlighted the role of hydrotropy-induced solubilization of the CLX-DES system. Animal pharmacokinetic studies established 2.76 times improvement in C-max, 1.52 times reduction in t(max), and 1.81 times improvement in AUC(0-infinity). The overall results demonstrated the potential of developing a DES-based supersaturating drug-delivery system for pharmaceutical loading of drugs having solubility and dissolution rate-limited oral bioavailability.