Crystal pressure of pharmaceuticals in nanoscale pores

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Montana State University - Bozeman, College of Engineering


Many pharmaceutical compounds are poorly soluble in water. This is problematic because most pharmaceuticals are delivered orally and must dissolve in the gastrointestinal fluid to be absorbed by the body. Drug dissolution rate is proportional to surface area, so a common formulation strategy is to structure drugs as small as possible to maximize surface area. A simple approach to create very small particles is to structure the compounds within the nanoscale pore space of a colloidal packing. The resulting composite undergoes rapid disintegration in water and the exposed drug exhibits dramatically improved dissolution rates. We hypothesize that composite breakup is driven by the growth of nanoscale crystals, which exert a pressure on the walls of the confining pores. To test this hypothesis, we systematically vary the amount of water permitted into the composite and use calorimetry to monitor the evolution of the crystal size distribution as a function of water content. To exert sufficient pressure to overcome the tensile yield stress of the composite, the crystals must be fed by a supersaturated phase. Our results suggest that differences in crystal curvature due to crystal confinement and crystal size polydispersity generate the necessary supersaturation. These results are relevant not just for drug formulations, but for understanding physical processes such as salt damage to buildings and road damage due to frost heave.




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