Development and evaluation of orally disintegrating tablets of cilostazol-β-cyclodextrin inclusion complexes

Abstract

Context: The clinical applications of cilostazol (CLZ) are limited by its low aqueous solubility (<5 µg/ml) and high biovariability.

Objective: The aim of this study was to enhance the solubility of CLZ by forming inclusion complexes (ICs) with beta cyclodextrin (β-CD) and formulating them into oral disintegrating tablets.

Methods: Phase solubility study of CLZ with β-CD was performed in water. Job’s plot was constructed to determine the stoichiometry of ICs. ICs, prepared by spray-drying technique, were characterized using Fourier transform infrared spectroscopy, differential scanning calorimetry, hot stage microscopy, powder X-ray diffraction and nuclear magnetic resonance. Molecular modeling studies were performed to understand the mode of interaction of CLZ with β-CD. The formulation process was undertaken using a reproducible design of experiment generated model, attained by variation of diluents and disintegrants at three levels. Tablets were evaluated for drug content, hardness, friability, disintegration time (DT), wetting time (WT) and dissolution profiles.

Results and discussion: Phase solubility studies suggested an A_L type curve with stability constant (K_s) of 922.52 M⁻¹. Job’s plot revealed 1:2 stoichiometry. All analytical techniques confirmed inclusion complexation. Molecular modeling revealed dispersive van der Waals interaction energy as a major contributor for stabilization of complex. The spray-dried complexes showed higher solubility and faster dissolution compared to plain CLZ. The optimized formulation showed DT of 11.1 ± 0.8 s, WT of 8.7 ± 0.9 s and almost complete dissolution of CLZ in 15 min.

Conclusion: The prepared tablets with low DT and fast dissolution will prove to be a promising drug delivery system with improved bioavailability and better patient compliance.

• Design of experiment
• direct compression
• disintegration and dissolution
• factorial design
• Kollidon-CL
• molecular modeling
• Pearlitol SD 200
• spray drying

Acknowledgements

The authors are grateful to Mr Elvis Martis, Dr. Raghuvir Pissurlenkar and Dr Evans Coutinho, Molecular Simulations Group, Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, for helping us with molecular modeling studies; Mrs. Sandhya Shenoy, Cadila Healthcare, Thane, for her support with DSC studies; Mr. Nilesh Kulkarni and Mrs. Bhagyashree Chalke, Tata Institute of Fundamental Research (TIFR), Mumbai, for their assistance with XRD and SEM studies; and Dr S. S. Bhagwat, Chemical Engineering Division, Institute of Chemical Technology (ICT), Mumbai, for providing facility for contact angle study.

Declaration of interest

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