Quantitative Structural and Compositional Elucidation of Real-World Pharmaceutical Tablet Using Large Field-of-View, Correlative Microscopy-Tomography Techniques and AI-Enabled Image Analysis.

Purpose: The purpose of this study is to present a correlative microscopy-tomography approach in conjunction with machine learning-based image segmentation techniques, with the goal of enabling quantitative structural and compositional elucidation of real-world pharmaceutical tablets.

Methods: Specifically, the approach involves three sequential steps: 1) user-oriented tablet constituent identification and characterization using correlative mosaic field-of-view SEM and energy dispersive X-ray spectroscopy techniques, 2) phase contrast synchrotron X-ray micro-computed tomography (SyncCT) characterization of a large, representative volume of the tablet, and 3) constituent segmentation and quantification of the imaging data through user-guided, iterative supervised machine learning and deep learning.

Results: This approach was implemented on a real-world tablet containing 15% API and multiple common excipients. A representative volumetric tablet image was obtained using SyncCT at a 0.36-µm resolution, from which constituent particles and pores were fully segmented and quantified. As validation, the derived tablet formulation composition and porosity agreed with the experimental values, despite the micrometer-scale particle and pore sizes. The approach also revealed the formation of ordered mixture inside the tablet. Notably, the image-derived size distributions of both the agglomerated microcrystalline cellulose and its primary particulate units matched the laser diffraction-based measurements of the as-is material. Key pore attributes including the pore size distribution, spatial anisotropy, and pore interconnectivity were also qualified.

Conclusion: Overall, this study demonstrated that the correlative microscopy-tomography approach, by leveraging phase contrast SyncCT and AI-based image analysis, can deliver new, practically-useful structural and compositional information and facilitate more efficient formulation and process development of tablets.