Chen Yinshan, Baviriseaty Sruthika, Thool Prajwal, Zhu Aiden, Sluga Kellie, Yawman Phillip D, Zhang Shawn, Mao Chen
Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA 94080, United States.
digiM Solution LLC., 500 West Cummings Park, Suite 3650, Woburn, MA 01801, United States.
J Pharm Sci. 2025 Aug 16:103955. doi: 10.1016/j.xphs.2025.103955.
In low-dose tablet formulations, achieving content uniformity is of utmost importance. Conventional bulk characterization methods, such as blend uniformity testing, lack the ability to capture the structural and compositional characteristics of API within tablets. To fill this gap, we employed a correlative imaging and analysis workflow that integrates synchrotron X-ray micro-computed tomography (SyncCT), mosaic field-of-view scanning electron microscopy (mSEM), and energy-dispersive X-ray spectroscopy (EDX) methods, combined with AI-enabled image segmentation algorithms. This workflow was utilized to investigate the effect of ordered mixing, introduced by conical screening milling (comilling), on API distribution in two real-world tablets. Specifically, two tablets with identical formulations were prepared; one incorporating comilling and the other without it. The tablets were then subjected to the imaging workflow. The results showed that the comilling process significantly improved the uniformity of API distribution in the tablet through ordered mixing, as evidenced by mSEM-EDX and SyncCT imaging. Furthermore, the API uniformity was achieved without altering the microstructural characteristics, as evidenced by consistent pore size distribution and tortuosity values between the comilled and non-comilled tablets. Overall, this study demonstrated the potential of advanced imaging and AI-based image analysis in facilitating formulation development for low-dose tablets.
在低剂量片剂配方中，实现含量均匀性至关重要。传统的整体表征方法，如混合均匀度测试，无法捕捉片剂中活性药物成分（API）的结构和组成特征。为了填补这一空白，我们采用了一种相关成像和分析工作流程，该流程整合了同步加速器X射线显微计算机断层扫描（SyncCT）、镶嵌视野扫描电子显微镜（mSEM）和能量色散X射线光谱（EDX）方法，并结合了人工智能驱动的图像分割算法。该工作流程用于研究锥形筛分研磨（共研磨）引入的有序混合对两种实际片剂中API分布的影响。具体而言，制备了两种配方相同的片剂；一种采用共研磨，另一种不采用。然后对这些片剂进行成像工作流程。结果表明，共研磨过程通过有序混合显著提高了片剂中API分布的均匀性，mSEM-EDX和SyncCT成像证明了这一点。此外，共研磨片剂和未共研磨片剂之间的孔径分布和曲折度值一致，证明在不改变微观结构特征的情况下实现了API均匀性。总体而言，本研究证明了先进成像和基于人工智能的图像分析在促进低剂量片剂配方开发方面的潜力。
