Analysis of Caffeine-Etoricoxib Pi-Electron Stacked Complexes: a Basis for Future Parenteral Preparations

Abstract

Etoricoxib, although exhibiting superior and selective anti-inflammatory properties, exhibits poor aqueous solubility which precludes its formulation into parenteral preparations. This study aims to increase the aqueous solubility of this drug by complexation with caffeine, an aromatic base known to exhibit a pi-pi stacked complex with aromatic drugs. The molar complexation between caffeine and etoricoxib was analyzed by phase solubility studies, Jacob’s continuous variation, and Ardon’s plots. Solid-state analyses and in vitro diffusion experiments were employed to analyze the optimized caffeine-etoricoxib complex (OCEC). The in vitro inhibitory properties of OCEC against cyclooxygenase 2 enzyme (COX-2) were compared to plain etoricoxib (PE). Phase solubility diagrams showed that the solubility of etoricoxib (0.25 M) was continuously elevated with increasing caffeine concentration as a result of complexation. Optimization experiments showed that caffeine complexes with etoricoxib at a 1:1 molar ratio. The effects of pH on degradation showed that etoricoxib within the OCEC is most stable at pH 7.4. The release of etoricoxib from OCEC follows super case 2 transport mechanisms with high diffusivity. In terms of in vitro inhibition against COX-2, OCEC (IC50 = 0.125 mcg/mL) is more potent than PE (IC50 = 3.1 mcg/mL). This study revealed that a 1:1 molar stacked complex between caffeine and etoricoxib drastically increases the aqueous solubility of the latter, a greater stability of the drug at pH 7.4, a Korsmeyer-Peppas diffusion kinetics involving non-Fickian drug release, and enhanced in vitro COX-2 inhibitory effects.