Department of Mechanical Engineering, 10-269 Donadeo Innovation Centre for Engineering, University of Alberta, Edmonton, Alberta, T6G 1H9, Canada.
Pharm Res. 2019 Jan 30;36(3):43. doi: 10.1007/s11095-019-2572-0.
The effects of particle size and particle surface roughness on the colloidal stability of pressurized pharmaceutical suspensions were investigated using monodisperse spray-dried particles.
The colloidal stability of multiple suspensions in the propellant HFA227ea was characterized using a shadowgraphic imaging technique and quantitatively compared using an instability index. Model suspensions of monodisperse spray-dried trehalose particles of narrow distributions (GSD < 1.2) and different sizes (MMAD = 5.98 μm, 10.1 μm, 15.5 μm) were measured first to study the dependence of colloidal stability on particle size. Particles with different surface rugosity were then designed by adding different fractions of trileucine, a shell former, and their suspension stability measured to further study the effects of surface roughness on the colloidal stability of pressurized suspensions.
The colloidal stability significantly improved (p < 0.001) from the suspension with 15.5 μm-particles to the suspension with 5.98 μm-particles as quantified by the decreased instability index from 0.63 ± 0.04 to 0.07 ± 0.01, demonstrating a strongly size-dependent colloidal stability. No significant improvement of suspension stability (p > 0.1) was observed at low trileucine fraction at 0.4 % where particles remained relatively smooth until the surface rugosity of the particles was improved by the higher trileucine fractions at 1.0 % and 5.0 %, which was indicated by the substantially decreased instability index from 0.27 ± 0.02 for the suspensions with trehalose model particles to 0.18 ± 0.01 (p < 0.01) and 0.03 ± 0.01 (p < 0.002) respectively.
Surface modification of particles by adding shell formers like trileucine to the feed solutions of spray drying was demonstrated to be a promising method of improving the colloidal stability of pharmaceutical suspensions in pressurized metered dose inhalers.
使用单分散喷雾干燥颗粒研究粒径和颗粒表面粗糙度对加压药物混悬剂胶体稳定性的影响。
使用阴影成像技术对多种混悬液在推进剂 HFA227ea 中的胶体稳定性进行了表征，并使用不稳定性指数进行了定量比较。首先测量了窄分布（GSD<1.2）和不同粒径（MMAD=5.98μm、10.1μm、15.5μm）的单分散喷雾干燥海藻糖颗粒的模型混悬液，以研究胶体稳定性对粒径的依赖性。然后设计了具有不同粗糙度的颗粒，方法是添加不同比例的三亮氨酸作为壳形成剂，并测量其混悬液稳定性，以进一步研究表面粗糙度对加压混悬液胶体稳定性的影响。
不稳定性指数从 0.63±0.04 降低到 0.07±0.01，表明胶体稳定性显著提高（p<0.001），这表明粒径依赖性的胶体稳定性较强。当三亮氨酸比例较低（0.4%）时，混悬液稳定性没有明显提高（p>0.1），此时颗粒仍然相对光滑，直到颗粒表面粗糙度通过较高的三亮氨酸比例（1.0%和 5.0%）得到改善时，混悬液稳定性才显著提高，不稳定性指数从含有海藻糖模型颗粒的混悬液的 0.27±0.02 分别显著降低到 0.18±0.01（p<0.01）和 0.03±0.01（p<0.002）。
向喷雾干燥的进料溶液中添加壳形成剂（如三亮氨酸）对颗粒表面进行改性，被证明是提高加压计量吸入器中药物混悬剂胶体稳定性的一种有前途的方法。
