Yuan Zhihui, Li Zunhua, Luo Jie, Nawaz Asad, Zhang Bowen, Dessie Wubliker
College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou 425199, China.
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
Molecules. 2024 May 18;29(10):2379. doi: 10.3390/molecules29102379.
The amorphous form of poorly soluble drugs is physically unstable and prone to crystallization, resulting in decreased solubility and bioavailability. However, the conventional accelerated stability test for amorphous drugs is time-consuming and inaccurate. Therefore, there is an urgent need to develop rapid and accurate stability assessment technology. This study used the antitumor drug nilotinib free base as a model drug. The degree of disorder and physical stability in the amorphous form was assessed by applying the pair distribution function (PDF) and principal component analysis (PCA) methods based on powder X-ray diffraction (PXRD) data. Specifically, the assessment conditions, such as the PDF interatomic distance range, PXRD detector type, and PXRD diffraction angle range were also optimized. The results showed that more reliable PCA data could be obtained when the PDF interatomic distance range was 0-15 Å. When the PXRD detector was a semiconductor-type detector, the PDF data obtained were more accurate than other detectors. When the PXRD diffraction angle range was 5-40°, the intermolecular arrangement of the amorphous drugs could be accurately predicted. Finally, the accelerated stability test also showed that under the above-optimized conditions, this method could accurately and rapidly assess the degree of disorder and physical stability in the amorphous form of drugs, which has obvious advantages compared with the accelerated stability test.
难溶性药物的无定形形式物理性质不稳定，易于结晶，导致溶解度和生物利用度降低。然而，传统的无定形药物加速稳定性试验耗时且不准确。因此，迫切需要开发快速准确的稳定性评估技术。本研究以抗肿瘤药物尼罗替尼游离碱为模型药物。基于粉末X射线衍射（PXRD）数据，应用对分布函数（PDF）和主成分分析（PCA）方法评估无定形形式的无序程度和物理稳定性。具体而言，还优化了评估条件，如PDF原子间距离范围、PXRD探测器类型和PXRD衍射角范围。结果表明，当PDF原子间距离范围为0-15 Å时，可以获得更可靠的PCA数据。当PXRD探测器为半导体型探测器时，获得的PDF数据比其他探测器更准确。当PXRD衍射角范围为5-40°时，可以准确预测无定形药物的分子间排列。最后，加速稳定性试验还表明，在上述优化条件下，该方法可以准确快速地评估药物无定形形式的无序程度和物理稳定性，与加速稳定性试验相比具有明显优势。
