Comparison and Analysis of Theoretical Models for Diffusion-Controlled Dissolution
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- 作者：Yanxing Wang ; Bertil Abrahamsson ; Lennart Lindfors ; James G. Brasseur
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：May 7, 2012
- 年：2012
- 卷：9
- 期：5
- 页码：1052-1066
- 全文大小：558K
- 年卷期：v.9,no.5(May 7, 2012)
- ISSN：1543-8392
文摘
Dissolution models require, at their core, an accurate diffusion model. The accuracy of the model for diffusion-dominated dissolution is particularly important with the trend toward micro- and nanoscale drug particles. Often such models are based on the concept of a 鈥渄iffusion layer.鈥?Here a framework is developed for diffusion-dominated dissolution models, and we discuss the inadequacy of classical models that are based on an unphysical constant diffusion layer thickness assumption, or do not correctly modify dissolution rate due to 鈥渃onfinement effects鈥? (1) the increase in bulk concentration from confinement of the dissolution process, (2) the modification of the flux model (the Sherwood number) by confinement. We derive the exact mathematical solution for a spherical particle in a confined fluid with impermeable boundaries. Using this solution, we analyze the accuracy of a time-dependent 鈥渋nfinite domain model鈥?(IDM) and 鈥渜uasi steady-state model鈥?(QSM), both formally derived for infinite domains but which can be applied in approximate fashion to confined dissolution with proper adjustment of a concentration parameter. We show that dissolution rate is sensitive to the degree of confinement or, equivalently, to the total concentration Ctot. The most practical model, the QSM, is shown to be very accurate for most applications and, consequently, can be used with confidence in design-level dissolution models so long as confinement is accurately treated. The QSM predicts the ratio of diffusion layer thickness to particle radius (the Sherwood number) as a constant plus a correction that depends on the degree of confinement. The QSM also predicts that the time required for complete saturation or dissolution in diffusion-controlled dissolution experiments is singular (i.e., infinite) when total concentration equals the solubility. Using the QSM, we show that measured differences in dissolution rate in a diffusion-controlled dissolution experiment are a result of differences in the degree of confinement on the increase in bulk concentration independent of container geometry and polydisperse vs single particle dissolution. We conclude that the constant diffusion-layer thickness assumption is incorrect in principle and should be replaced by the QSM with accurate treatment of confinement in models of diffusion-controlled dissolution.