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Eur J Pharm Sci. 2020 Jan 1;141:105113. doi: 10.1016/j.ejps.2019.105113. Epub 2019 Oct 23.

Incorporation of HPMCAS during loading of glibenclamide onto mesoporous silica improves dissolution and inhibits precipitation.

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Merck KGaA, Darmstadt, Germany; Institute of Pharmaceutical Technology, Goethe University, Frankfurt, Germany. Electronic address:
Merck KGaA, Darmstadt, Germany.
Institute for Biophysical Chemistry & Centre for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.
University of Arts and Applied Sciences Northwestern Switzerland, Basel, Switzerland.
Institute of Pharmaceutical Technology, Goethe University, Frankfurt, Germany.
Merck KGaA, Darmstadt, Germany. Electronic address:


Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.


Mechanistic; Mesoporous silica; Precipitation inhibition; Solid dispersion; Supersaturation


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