Particle engineering of a needle-like active pharmaceutical ingredient into size controlled agglomerates: Part II. Evaluating direct compression manufacturability, microstructure and product performance

Spherical agglomeration presents a promising particle engineering strategy for converting crystalline active pharmaceutical ingredients (APIs) with challenging bulk powder properties into manufacturable drug products. However, a critical gap remains in understanding their downstream processability via direct compression and the resulting drug release performance. This study provides a comprehensive assessment of how a successfully spherical agglomerated API, prepared at controlled particle sizes, influences tablet mechanical behaviour, microstructure arrangement, and dissolution performance. Three agglomerate size fractions (35 µm, 88 µm, and 143 µm), together with the original un-agglomerated API, were each formulated at a fixed 20% w/w drug load using an identical direct compression excipient blend (FastFlo 316, Avicel PH-101, AcDiSol, Ligamed MF-2 V) and evaluated alongside a benchmark wet granulated formulation. Compactability and compressibility modelling demonstrated systematic trends in tablet strength and densification across all formulations, with agglomerate size exerting only a minor influence on compactability. Advanced Raman imaging and nano-CT, integrated with data-driven tablet microstructure analysis, revealed that smaller agglomerates and un-agglomerated particles promoted more homogeneous API distributions, whereas larger agglomerates formed more localized clusters within the tablet matrix. Post-compression in-tablet particle and pore size distributions showed agglomerate domains were largely preserved during compaction. In-vitro dissolution studies further showed that all spherical agglomerate formulations achieved rapid drug release, meeting the label requirement of Q = 75% within 45 min, with a modest particle size dependence observed under biorelevant dissolution conditions across gastric, duodenal, and jejunal compartments. Overall, the results demonstrate that under the tested particle sizes, spherical agglomerates were suitable for direct compression solid dosage form manufacturing.