Chirag Desai1, Bala Prabhakar1. 1. a Department of Pharmaceutics, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management , SVKM's NMIMS , Mumbai , India.
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 AL type curve with stability constant (Ks) 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.
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 AL type curve with stability constant (Ks) 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.
Entities:
Keywords:
Design of experiment; Kollidon-CL; Pearlitol SD 200; direct compression; disintegration and dissolution; factorial design; molecular modeling; spray drying