Turbidimetric measurement and prediction of dissolution rates of poorly soluble drug nanocrystals

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Abstract

Rapid dissolution rates of nanocrystal suspensions of the poorly water-soluble drugs, danazol and itraconazole were measured continuously by in-situ turbidimetry. For pre-wetted suspensions of 300 nm particles, dissolution half-lives as short as a few seconds were determined upon adding surfactant to initiate dissolution. A mass transfer model is presented to determine the particle size distribution and dissolution rate in terms of two steps: interfacial reaction, consisting of micelle uptake and desorption, followed by diffusion of the drug-loaded micelles. The interfacial reaction rate constant, kS, regressed from turbidity versus time data, in conjunction with the Mie theory of light scattering, was independent of particle size. Therefore, dissolution rate data for micron-sized drug particles, which are widely available, may be used to predict the behavior for submicron particle sizes down to 100 nm. The micellar solubility and kS are significantly smaller for itraconazole than danazol, consistent with itraconazole's larger molecular size. For particles smaller than 1 μm, the interfacial reaction resistance was dominant. Since this resistance has received little attention in previous studies, further emphasis on the design of drug nanoparticles with more rapid interfacial reaction offers the possibility of improvements in dissolution rates.

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