Deconstructing Annealing Phenomena in Modified Release Lipid Multiparticulates.

This work investigates annealing-induced changes in modified release lipid multiparticulates composed of glyceryl behenate and poloxamer 407. Multiparticulates were manufactured using multiple lots of excipients and then annealed at 3 different temperatures across 45-50 °C (75% RH) until kinetically stable dissolution profiles were achieved. Throughout annealing, multiparticulates were analyzed using powder X-ray diffraction, scanning electron microscopy, quantitative ¹H NMR, Raman spectroscopy, and novel flow-NMR dissolution techniques. Supporting nonlinear mixed effects models helped systematically link these orthogonal tools to dissolution, altogether providing strong evidence of concurrent glyceryl behenate crystal refinement with phase separation and migration of the poloxamer 407 from glyceryl behenate as the drivers for changes in dissolution with annealing. These findings demonstrate the importance of annealing glyceryl behenate-poloxamer 407 multiparticulates to achieve the complex matrix needed for modified release.