Clotrimazole–cyclodextrin based approach for the management and treatment of Candidiasis – A formulation and chemistry-based evaluation

Abstract

Clotrimazole (CT) is a poorly soluble antifungal drug that is most commonly employed as a topical treatment in the management of vaginal candidiasis. The present work focuses on a formulation approach to enhance the solubility of CT using cyclodextrin (CD) complexation. A CT–CD complex was prepared by a co-precipitation method. Various characterization techniques such as differential scanning calorimetry, infrared (IR) and X-ray spectroscopy, scanning electron microscopy and nuclear magnetic resonance (NMR) spectroscopy were performed to evaluate the complex formation and to understand the interactions between CT and CD. Computational molecular modeling was performed using the Schrödinger suite and Gaussian 09 program to understand structural conformations of the complex. The phase solubility curve followed an A_L-type curve, indicating formation of a 1:1 complex. Molecular docking studies supported the data obtained through NMR and IR studies. Enthalpy changes confirmed that complexation was an exothermic and enthalpically favorable phenomenon. The CT–CD complexes were formulated in a gel and evaluated for release and antifungal activity. The in vitro release studies performed using gels demonstrated a sustained release of CT from the CT–CD complex with the complex exhibiting improved release relative to the un-complexed CT. Complexed CT–CD exhibited better fungistatic activity toward different Candida species than un-complexed CT.

• Candidiasis
• complexation
• computational molecular modeling
• cyclodextrin
• solubility enhancement

Acknowledgements

A special thanks is extended to Dr. Ziyaur Rahman who supervised this work as a research associate at The University of Mississippi. Thanks to Melissa Jacob from the National Center for Natural Products Research for her help with fungal cultures. The authors also thank the Pii Center for Pharmaceutical Technology for contributions to this project.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

This work was partially supported by Grant Number P20GM104932 and NCRR C06 RR-14503-01 from the National Institute of General Medical Sciences (NIGMS), a component of NIH.

Supplementary material available online

Supplementary Table S1