Disparities of Single-Particle Growth Rates in Buried Versus Exposed Ritonavir Crystals within Amorphous Solid Dispersions
Disparities of Single-Particle Growth Rates in Buried Versus Exposed Ritonavir Crystals within Amorphous Solid Dispersions
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DOI：
10.1021/acs.molpharmaceut.0c00744
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发表时间：
2020-12-07
影响因子：
4.9
通讯作者：
Simpson, Garth J.
中科院分区：
文献类型：
--
作者：
Griffin, Scott R.;Takanti, Nita;Simpson, Garth J.
通过单粒子跟踪二次谐波发生 (SHG) 显微镜评估了共聚维酮中利托那韦晶种在 75% 相对湿度 (RH) 和 50 摄氏度下的生长速率，发现表面微晶的生长速度比本体的微晶慢 3 倍。含有无定形固体分散体 (ASD) 的最终剂型的保质期通常取决于活性药物成分结晶的速率。当暴露于较高的相对湿度时，ASD 表面附近预期的较高含水量有可能显着影响相对于本体的成核和生长动力学。然而，由于在整体平均测量中区分两种贡献（过饱和度和分子迁移率）相关的挑战，对这些增长率差异的定量评估变得复杂。在本研究中，制备了“三明治”材料，其中稀疏的利托那韦单晶晶种被压在两个相似的 ASD 薄膜之间，以评估整体结晶速率。将这些夹层材料与类似制备的没有封盖膜的“开放面”样品进行比较和对比，以评估表面结晶速率。原位结晶过程中通过 SHG 显微镜时间序列进行的单颗粒分析显示，块状柱状晶体的平均生长速率为 3.8 μm/h，颗粒间标准偏差为 0.9 μm/h。另外，测得表面颗粒的柱状晶体生长速率为1.3μm/h，测得表面颗粒的辐射晶体生长速率为1.0μm/h，两者的颗粒间偏差均为0.4μm/h。在表面接种时观察到的辐射晶体的出现归因于界面处水吸附时利托那韦溶解度降低，导致晶体生长中的缺陷密度更高。尽管晶体习性存在显着差异，但根据几何效应将表面生长速率校正为 4 倍，导致两个局部环境的生长动力学存在相对较小但具有统计显着性的差异。这些结果是一致的，粘度是吸水率的相对较弱的函数，加上主要是扩散限制的生长动力学。
Seeded growth rates of ritonavir in copovidone at 75% relative humidity (RH) and 50 degrees C were evaluated by single-particle tracking second harmonic generation (SHG) microscopy and found to be similar to 3-fold slower for crystallites at the surface compared to the bulk. The shelf lives of final dosage forms containing amorphous solid dispersions (ASDs) are often dictated by the rates of active pharmaceutical ingredient crystallization. Upon exposure to elevated RH, the higher anticipated water content near the surfaces of ASDs has the potential to substantially impact nucleation and growth kinetics relative to the bulk. However, quantitative assessment of these differences in growth rates is complicated by challenges associated with discrimination of the two contributions (supersaturation and molecular mobility) in ensemble-averaged measurements. In the present study, "sandwich" materials were prepared, in which sparse populations of ritonavir single-crystalline seeds were pressed between two similar ASD films to assess bulk crystallization rates. These sandwich materials were compared and contrasted with analogously prepared "open-faced" samples, without the capping film, to assess the surface crystallization rates. Single-particle analysis by SHG microscopy time-series during in situ crystallization produced average growth rates of 3.8 mu m/h for bulk columnar crystals with a particle-to-particle standard deviation of 0.9 mu m/h. In addition, columnar crystal growth rates for surface particles were measured to be 1.3 mu m/h and radiating crystal growth rates for surface particles were measured to be 1.0 mu m/h, both with a particle-to-particle deviation of 0.4 mu m/h. The observed appearance of radiating crystals upon surface seeding is attributed to reduced ritonavir solubility upon water adsorption at the interface, leading to higher defect densities in crystal growth. Despite substantial differences in crystal habit, correction of the surface growth rates by a factor of 4 from geometric effects resulted in relatively minor but statistically significant differences in the growth kinetics for the two local environments. These results are consistent, with viscosity being a relatively weak function of water absorption coupled with primarily diffusion-limited growth kinetics.