Ellis Scott R, Wright James L
Nektar Therapeutics, 150 Industrial Road, San Carlos, California 94070, USA.
Pharm Res. 2006 Oct;23(10):2441-53. doi: 10.1007/s11095-006-9073-7. Epub 2006 Aug 24.
To demonstrate control of passive diffusion of small molecules through rigid ceramic matrices via manipulation of matrix porosity near the percolation threshold, and to model such control using percolation scaling relationships on both infinite and finite lattices.
Rigid alumina disks of controlled porosity were prepared using standard ceramic casting and sintering techniques. Structural void space distributions in sintered disks were measured by dimensional and volume displacement (pycnometry) methods. The impact of void space on transport was determined by tracking the diffusion of ionized benzoic acid across sintered disks mounted in Stokes diffusion cells. Critical percolation thresholds were estimated by fitting structural and transport-dependent results to percolation scaling relationships. Finite-size scaling studies were performed by adding polymer microspheres of known diameter to the disks to generate artificially large pores.
Nonlinear least squares techniques were used to fit both structural and transport-dependent properties of rigid alumina disks to total disk porosity using percolation scaling relationships. The critical percolation threshold determined from structural properties (0.129) was lower than that determined from benzoic acid transport (0.169). The transport-derived percolation threshold exactly matched that expected for a tetrakaidecahedral (14 sided) lattice. Finite-size scaling was demonstrated through a nonzero effective volume fraction for transport at the percolation threshold.
Manipulation of total disk porosity near the percolation threshold was shown to be a suitable means of controlling the transport rate of a model small molecule, while deliberate enlargement of individual pores was demonstrated to decrease this threshold without increasing total porosity. The lower-than-expected percolation threshold obtained from the structural model was ascribed to limitations of the measurement technique. The threshold determined from the aqueous transport model was concluded to represent the true threshold for this system.
通过在渗流阈值附近操纵基质孔隙率来证明小分子在刚性陶瓷基质中的被动扩散控制，并使用无限和有限晶格上的渗流标度关系对这种控制进行建模。
采用标准陶瓷铸造和烧结技术制备孔隙率可控的刚性氧化铝圆盘。通过尺寸和体积位移（比重瓶法）测量烧结圆盘的结构孔隙空间分布。通过跟踪离子化苯甲酸在安装在斯托克斯扩散池中的烧结圆盘上的扩散来确定孔隙空间对传输的影响。通过将结构和传输相关结果拟合到渗流标度关系来估计临界渗流阈值。通过向圆盘中添加已知直径的聚合物微球以产生人工大孔来进行有限尺寸标度研究。
使用渗流标度关系，采用非线性最小二乘法将刚性氧化铝圆盘的结构和传输相关特性拟合到总圆盘孔隙率。由结构特性确定的临界渗流阈值（0.129）低于由苯甲酸传输确定的阈值（0.169）。传输得出的渗流阈值与十四面体（14 面）晶格预期的阈值完全匹配。通过在渗流阈值处传输的非零有效体积分数证明了有限尺寸标度。
在渗流阈值附近操纵总圆盘孔隙率被证明是控制模型小分子传输速率的合适方法，而故意扩大单个孔隙被证明可降低该阈值而不增加总孔隙率。从结构模型获得的低于预期的渗流阈值归因于测量技术的局限性。得出从水传输模型确定的阈值代表该系统的真实阈值。
