Interactions of Cyclodextrins and their Hydroxyl Derivatives with Etodolac: Solubility and Dissolution Enhancement.

BACKGROUND: Poor solubility and dissolution rate of drugs are largely responsible for erratic drug absorption and limited oral bioavailability. Etodolac (ETO) is a non-steroidal anti-inflammatory drug (NSAID) that is classified as BCS class II (dissolution rate-dependent absorption). ETO has high safety and efficacy in pain relief and control of inflammation. ETO is commercially available as (400-600 mg) tablets; poor solubility and dissolution rate of ETO could result in variable oral absorption and inconsistent analgesic responses. The aim of this study was to improve solubility and dissolution rates of ETO by complexation with cyclodextrins (CDs).

METHODS: Four different CDs namely β-, γ-, HP β-CDs, and HP γ-CDs were prepared using three different methods; solvent evaporation (CO), freeze-drying (FD), and physical mixing (PM). The prepared drug: excipient mixtures were investigated for aqueous solubility, as well as via DSC, XRD, FTIR, SEM, dissolution, and docking.

RESULTS: The results revealed a solubility phase diagram of the AL type, indicating a 1:1 complexation of ETO: CD. These results agreed with our molecular docking calculations. DSC, FTIR, XRD, and SEM results confirmed the formation of an inclusion complex. The complexation efficiency, solubility, and dissolution enhancement were in the order of HPγ-CD > γ-CD > HPβ-CD > β-CD. FD method was superior to both CO and PM.

CONCLUSION: Superior dissolution enhancements of ETO were recorded for the FD mixture (up to 90% dissolved in less than 10 min). In conclusion, γ- and hydroxypropyl γ-derivative of cyclodextrins can be considered a promising excipient for enhancement of dissolution rates concerned for ETO.