Determinants of simulated dissolution profile similarity (f2): Interactions of Z-factor, particle size, dose, solubility, and diffusivity.

Particle size frequently varies during development and is a common critical material attribute for oral drug products. In this work, we investigated how particle size effects on dissolution similarity depend on dose, intrinsic solubility, and dissolution surfactant micelle diffusivity. Dissolution profiles were simulated using a mechanistic Z-factor model for spherical particles across a factorial design: initial particle radius (10-50 µm), dose (50-200 mg), solubility (0.083-8.35 mg/mL), and diffusivity (3 × 10⁻⁶-3 × 10⁻⁴ cm²/min) in a dissolution volume of 900 mL. Simulated profiles were compared to a 30 µm particle radius reference using the similarity factor f2, except when both profiles exceeded 85% dissolution within 15 min. Overall, a substantial fraction of comparisons failed f2, demonstrating that particle-size similarity cannot be interpreted in isolation: higher dose tended to amplify differences; higher solubility and higher diffusivity tended to promote similarity, while incomplete dissolution could also yield high f2 values. These findings emphasize that particle size specifications should be evaluated in the context of biorelevant dissolution conditions when dose, solubility, and diffusivity impact on dissolution profile sameness.