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 beta-, gamma-, HP beta-CDs, and HP gamma-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 A(L) 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 HP gamma-CD > gamma-CD > HP beta-CD > beta-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, gamma- and hydroxypropyl gamma-derivative of cyclodextrins can be considered a promising excipient for enhancement of dissolution rates concerned for ETO.