High-Contrast X-Ray Computed Tomography for Quantifying Amorphous Content in Melt-Quenched Acetaminophen

X-ray computed tomography (XRCT) allows for non-destructive three-dimensional observation and volumetric quantification of samples. It also allows for structural changes monitoring, such as the amorphous-to-crystalline transition in pharmaceuticals, over time. Despite past applications of XRCT to characterize amorphous pharmaceuticals, its quantitative validity has not been systematically verified against established thermal methods. Here, we evaluated laboratory XRCT for monitoring the crystallization behavior of amorphous acetaminophen and validated its accuracy via differential scanning calorimetry (DSC). In XRCT, amorphous content was determined from voxel-based phase segmentation, while DSC estimates were obtained from the specific heat change at the glass transition temperature. Time-dependent crystallization at 30°C was quantified using XRCT followed immediately by DSC, showing strong correlation (R² = 0.990). These results demonstrated that XRCT provides a reliable, voxel-based measure of amorphous fraction, despite the limited precision imposed by the micrometer-scale spatial resolution. XRCT enables continuous monitoring of a single sample-from preparation through near-complete crystallization-and reduces the number of samples required to construct crystallization profiles. In situ XRCT enabled visualization of the initial sites of detectable crystallization and its spatial propagation within the sample, revealing information unattainable from bulk thermal analysis. Herein, phase-retrieval image processing improved phase discrimination, although the processing effect could be influenced by sample type or experimental conditions. The XRCT method is proposed not for precise quantification, but as a practical and efficient tool for rapid screening of physical stability, formulation development, and assessment of storage conditions in early-stage pharmaceutical development.