Oral hesperidin-Amorphization and improved dissolution properties by controlled loading onto porous silica

The oral bioavailability of poorly soluble drugs can be improved by amorphization generated by loading into the pores of mesoporous particles (pore size 2-50 nm). The main mechanisms are increased kinetic saturation solubility and dissolution velocity due to the amorphous drug state and the nano-size of the drug (=increased dissolution pressure). In this study, the maximum achievable drug loading compared to the theoretical drug loading, and the effect of drug loading degree on the dissolution properties (solubility, dissolution velocity) were investigated. Hesperidin was used as the model active (having also practical relevance for e.g. nutraceutical products), loading was performed onto AEROPERL® 300 Pharma. Degree of successful drug loading could be easily followed by simple light microscopy (=useful tool for formulation optimization), and was in agreement with scanning electron microscopy. Amorphous versus crystalline state was followed by X-ray diffraction and differential scanning calorimetry. Loadings prepared were 28.6 wt.%, 54.5 wt.% and 60.0 wt.%, the maximum theoretical loading was 72.5 wt.%. Obviously the maximum drug loading is not achievable, the 54.5 wt.% drug loading was the practical maximum with already some minor crystalline hesperidin on the surface. Interestingly, the maximum kinetic saturation solubility was obtained for the 54.5 wt.% drug loading (941.74 μg/ml in pH 6.8 PBS), versus 408.80 μg/ml for the 60.0 wt.% drug loading (=overloaded system). The raw drug powder had a thermodynamic solubility of only 18.40 μg/ml. The fastest in vitro release was obtained with the 28.6 wt.% loaded system, followed by the 54.5 wt.% and 60.0 wt.% loadings. The dissolution properties (solubility, dissolution velocity) can obviously be influenced by a “controlled loading”. This is a simple, cost-effective technological alternative to modulating this property by chemical modification of silica, requiring a new costly regulatory approval of these chemically modified materials.

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