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Stabilization of Amorphous Drugs by Polymers: The Role of C*

By Prof. Ronald Siegel,
Professor and Department Head, Department of Pharmaceutics,
University of Minnesota, Minneapolis, MN 55455

For many low solubility drugs, the crystalline form is unfavorable due to poor bioavailability. The amorphous form has higher free energy and hence increased solubility and bioavailability, but at the cost of reduced stability and tendency to revert to the crystalline form. Amorphous solid dispersions (ASDs), in which the drug is admixed with a suitable polymer, are used to slow or prevent crystallization. A question that arises is, how much polymer needs to be added? Too little polymer is insufficient to adequately retard crystallization, while too much polymer increases the overall volume and hence the pill burden. Recently, we have shown that the minimum required polymer loading is given by the so-called overlap concentration, C*, of the polymer, as determined by rheological measurements of polymer-in-drug solutions prepared in the molten state, followed by quenching below the glass transition temperature, Tg. The parameter C* decreases with increasing polymer molecular weight and increasing attractive interactions between the drug and the polymer. In this presentation, we will introduce the C* concept and show how it successfully predicts the kinetic stability of ASDs consisting of a variety of drugs and polymers, using DSC and PXR
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