Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta, Canada.
School of Chemistry, University of Bristol, Bristol, United Kingdom.
Int J Pharm. 2021 Jan 5;592:120102. doi: 10.1016/j.ijpharm.2020.120102. Epub 2020 Nov 21.
The particle formation of L-leucine, a dispersibility-enhancing amino acid used in the spray drying of inhalable pharmaceutical aerosols, was extensively studied using three experimental methods, and the results were interpreted with the aid of theory. A comparative-kinetics electrodynamic balance was used to study the shell formation behavior in single evaporating microdroplets containing leucine and trehalose. Different concentration thresholds of solidification and shell formation were determined for trehalose and leucine, which were then used in the particle formation model to predict the properties of spray-dried particles. Furthermore, a droplet chain instrument was used to study the particle morphologies and particle densities that were not accessible in the single particle experiments. Lab-scale spray drying was also used to produce powders typical for actual pharmaceutical applications. Raman spectroscopy confirmed that a glass former, such as trehalose, can inhibit the crystallization of leucine. The surface compositions of these spray-dried powders were analyzed via time-of-flight secondary ion mass spectrometry. The leucine surface coverage in a polydisperse powder was determined to be a function of the particle size or the initial droplet diameter of each respective particle. This observation confirms the important role of leucine crystallization kinetics in its shell-forming capabilities. A critical supersaturation ratio of 3.5 was also calculated for leucine, at which it is assumed to instantaneously nucleate out of solution. This ratio was used as the threshold for the initiation of crystallization. Crystallinity predictions for the leucine-trehalose particles based on this supersaturation ratio were in good agreement with the solid-state characterizations obtained by Raman spectroscopy. This study improves the fundamental understanding of the particle formation process of leucine-containing formulations, which can apply to other crystallizing systems and potentially facilitate the rational design of such formulations with reduced experimental effort.
L-亮氨酸是一种可提高分散性的氨基酸，用于吸入式药物气溶胶的喷雾干燥，本文广泛研究了其颗粒形成过程，使用了三种实验方法，并借助理论进行了解释。采用比较动力学电动平衡法研究了含有亮氨酸和海藻糖的单蒸发微液滴中的壳层形成行为。确定了海藻糖和亮氨酸的固化和壳层形成的不同浓度阈值，然后将其用于颗粒形成模型，以预测喷雾干燥颗粒的性质。此外，还使用液滴链仪器研究了单颗粒实验中无法获得的颗粒形态和颗粒密度。实验室规模的喷雾干燥也用于生产典型的实际药物应用的粉末。拉曼光谱证实，玻璃形成剂（如海藻糖）可以抑制亮氨酸的结晶。通过飞行时间二次离子质谱法分析了这些喷雾干燥粉末的表面成分。通过拉曼光谱证实，多分散粉末中亮氨酸的表面覆盖率是每个颗粒的粒径或初始液滴直径的函数。这一观察结果证实了亮氨酸结晶动力学在其成壳能力中的重要作用。还计算了亮氨酸的临界过饱和度比为 3.5，假定其会从溶液中瞬间成核。该比值用作结晶起始的阈值。基于该过饱和度比对亮氨酸-海藻糖颗粒的结晶度预测与拉曼光谱获得的固态特性非常吻合。这项研究提高了对含亮氨酸制剂颗粒形成过程的基本认识，这可以应用于其他结晶体系，并可能通过减少实验工作量来促进此类制剂的合理设计。
