Preparation and tableting of long-term stable amorphous rutin using porous silica

Amorphous state of drugs increases the oral bioavailability, but typically faces physical stability problems. Amorphous rutin was generated and physically stabilized by encapsulating inside mesopores of porous AEROPERL® 300 Pharma and named as rutin CapsMorph® in this study. AEROPERL® 300 Pharma was loaded with rutin dissolved in DMSO containing Tween 80, and subsequently the solvent evaporated (wetness impregnation method). The loading process was monitored by light microscopy and scanning electron microscopy (SEM). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to confirm the amorphous state in AEROPERL® 300 Pharma. A loading of 20% of the rutin-AEROPERL® 300 Pharma mixture was obtained. The amorphous state proved to be stable over 2years of storage at room temperature. Due to the amorphous state and the nanosize of the rutin in the mesopores, the kinetic saturation solubility increased to about 4mg/ml (water, 0.1MHCl, pH 6.8PBS) compared to the maximum observed thermodynamic equilibrium solubility of rutin raw drug powder of only 74.48±1.42μg/ml in pH 6.8PBS (=increase by factor about 54). The dissolution velocity also increased distinctly, e.g. about 96.1% of rutin dissolution from CapsMorph® powder in water within 5min compared to less than 40% of raw drug powder after 3h. Tablets were produced with rutin CapsMorph®, raw drug powder and their dissolution velocity compared to a marketed product. About 83.0-95.6% were released from the rutin CapsMorph® tablet within 5min, compared to 42.7-52.5% from the marketed tablet after 3h (water, 0.1MHCl, pH 6.8PBS). After dissolution the supersaturation level of rutin CapsMorph® remained over about 2h, then solubility slowly reduced, but remained after 48h still multifold above the thermodynamic rutin solubility. This should be sufficient for many poorly soluble drugs to achieve a sufficient bioavailability. For optimal exploitation of the supersaturation, a multiple step release system could be used, e.g. release of CapsMorph® particles every 2-3h.