Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.
AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois 60064, United States.
Mol Pharm. 2020 Dec 7;17(12):4564-4571. doi: 10.1021/acs.molpharmaceut.0c00744. Epub 2020 Nov 5.
Seeded growth rates of ritonavir in copovidone at 75% relative humidity (RH) and 50 °C were evaluated by single-particle tracking second harmonic generation (SHG) microscopy and found to be ∼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 crystallization produced average growth rates of 3.8 μm/h for bulk columnar crystals with a particle-to-particle standard deviation of 0.9 μm/h. In addition, columnar crystal growth rates for surface particles were measured to be 1.3 μm/h and radiating crystal growth rates for surface particles were measured to be 1.0 μm/h, both with a particle-to-particle deviation of 0.4 μm/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.
在 75%相对湿度（RH）和 50°C 下，通过单粒子跟踪二次谐波产生（SHG）显微镜评估利托那韦在共聚维酮中的成核速率，发现与体相相比，表面处的结晶颗粒的成核速率慢约 3 倍。含有无定形固体分散体（ASD）的最终剂型的货架寿命通常取决于活性药物成分结晶的速率。在暴露于高 RH 时，ASD 表面附近预期的较高含水量有可能对成核和生长动力学产生实质性影响，与体相相比。然而，由于在平均测量中难以区分两种贡献（过饱和度和分子迁移率），因此定量评估这些生长速率的差异很复杂。在本研究中，制备了“三明治”材料，其中利托那韦单晶种子的稀疏种群被压在两个类似的 ASD 膜之间，以评估体相结晶速率。这些三明治材料与没有盖帽膜的类似制备的“开口面”样品进行了比较和对比，以评估表面结晶速率。通过 SHG 显微镜时间序列进行的单粒子分析在结晶过程中产生了平均生长速率为 3.8μm/h 的柱状晶体，其颗粒间标准偏差为 0.9μm/h。此外，测量到表面颗粒的柱状晶体生长速率为 1.3μm/h，表面颗粒的放射状晶体生长速率为 1.0μm/h，两者的颗粒间偏差均为 0.4μm/h。在表面播种时观察到放射状晶体的出现归因于界面处水吸附导致利托那韦溶解度降低，从而导致晶体生长中的缺陷密度增加。尽管晶体习性存在显著差异，但通过几何效应将表面生长速率校正为 4 倍后，两种局部环境的生长动力学差异相对较小，但具有统计学意义。这些结果与以下事实一致：粘度是水吸收的相对较弱的函数，并且主要是扩散限制的生长动力学。
