Potential interaction between zinc ions and a cyclodextrin-based diclofenac formulation

• Published in: Drug development and industrial pharmacy 2016-03, Vol.42 (3), p.418-428
• Main Authors: Hamdan, Imad I., El-Sabawi, Dina, Abdel Jalil, Mariam
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; beta-Cyclodextrins - pharmacokinetics; beta-Cyclodextrins - pharmacology; Bioavailability; Biological Availability; Calorimetry, Differential Scanning; cyclodextrin; diclofenac; Diclofenac - pharmacokinetics; Diclofenac - pharmacology; dissolution; Drug Combinations; Drug Interactions; metal ions; Rats; Rats, Sprague-Dawley; Spectroscopy, Fourier Transform Infrared; zinc; Zinc - pharmacology
• ISSN: 0363-9045; 1520-5762
• DOI: 10.3109/03639045.2015.1071834

Complexes of diclofenac sodium (DF-Na) with hydroxypropyl betacyclodextrin (HPβCD) were prepared by co-evaporation in a 1:1 ratio and characterized in light of previously reported data. Phase solubility diagrams were obtained for DF-Na with HPβCD in the presence and absence of zinc ions. Dissolution profiles were obtained for DF-Na and its HPβCD complex at acidic (pH 1.2) as well as in phosphate buffer (pH 6.8), in the presence and absence of zinc. HPβCD, as expected, was shown to improve the dissolution of DF-Na in acidic medium but not in phosphate buffer (pH 6.8). The presence of zinc ions decreased the in vitro dissolution of DF-HPβCD complex in acidic medium (pH 1.2) but not in phosphate buffer (pH 6.8). It was confirmed that the precipitate that was formed by zinc ions in the presence of HPβCD and DF-Na contained no cyclodextrin and most likely it was a mixture of the complexes: DF 2 -Zn and DF-Zn with some molecules of water. In vivo experiments on rats have shown that HPβCD has no statistically significant effect on absorption or bioavailability of DF-Na in spite of the observed improvement of its in vitro dissolution by HPβCD. Moreover, zinc ions were shown to decrease the absorption rate of DF-Na in rats model but did neither significantly alter the absorption nor bioavailability of DF-HPβCD complex. The zinc induced precipitates of DF were shown to have significantly different crystalline properties when HPβCD was present. Therefore, the pharmaceutical details of a DF-Na preparation should be considered when designing the formulation and predicting possible interaction between DF-Na (or other potential NSAIDs) and zinc metal.