Investigation of β-cyclodextrin–norfloxacin inclusion complexes. Part 2. Inclusion mode and stability studies

Abstract

Introduction: Norfloxacin (NFX) is a broad spectrum antibiotic with low solubility and permeability, which is unstable on exposure to light and humidity. Objective: In this study, the mode of NFX inclusion into β-cyclodextrin complexes was evaluated and a complete physical, chemical and microbiological stability study of the inclusion complexes was carried out. Methods: Potentiometric titrations were performed to evaluate changes in the pKa of the NFX molecule due to the formation of an inclusion complex and NMR analysis demonstrated that the NFX molecule is included in the β-cyclodextrin cavity. Results: Inclusion complexes obtained by kneading followed by freeze-drying showed improved NFX stability compared with the isolated drug or the physical mixture. This method was effective in terms of protecting the drug from photodegradation and also avoiding hydrolysis. Differences between NFX and the complexes could be evidenced by thermal analysis, infrared spectroscopy and x-ray powder diffraction as well as by determining the solubility and drug content. The antimicrobial potency was also preserved on applying the promising method of kneading. Conclusion: The satisfactory stability indicates that the NFX/β-cyclodextrin complexes could be useful as an alternative to the existing NFX drug formulation.

Keywords:

• β-cyclodextrin
• inclusion complexes
• inclusion mode
• norfloxacin
• stability studies

Financial & competing interests disclosure

This study was supported by the National Counsel of Technological and Scientific Development (CNPq) and Coordination for Enhancement of Higher Education Personnel (CAPES). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• NMR analysis demonstrated the mode of the norfloxacin (NFX) molecule inclusion in the β-cyclodextrin (βCD) cavity.

• The pKa determination provided information on the ionization of NFX when inserted in the βCD cavity.

• Without the formation of an inclusion complex the presence of βCD does not guarantee NFX light protection.

• The improvement of the solubility could be maintained by systems obtained by kneading followed by freeze-drying or spray-drying.

• The thermal stability of the inclusion complexes obtained by kneading followed by freeze-drying was maintained after photoexposure.

• After exposure to high humidity and temperature no NFX degradation was observed in the case of the NFX/βCD systems obtained by kneading followed by freeze-drying or spray-drying.

• After photoexposure the antibacterial potency of NFX in the inclusion complexes formed by kneading followed by freeze-drying or spray-drying was preserved.

• NFX degradation into its decarboxylated derivative (without pharmacological activity) could be prevented through the formation of inclusion complexes by kneading followed by freeze-drying or spray-drying.