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The study focuses on understanding the material changes that occur in the micronized drug during annealing, in relation to its use for DPI (Dry Powder Inhaler) formulations. The process-induced amorphous fraction can transform into a solvate or a metastable crystalline form. At the particle level, some undesirable changes like particle growth, aggregation, and/or reduction in specific surface area (SSA) can occur. The annealing process can extend from a few hours to several months, making it difficult to predict the optimal time requirement. From a manufacturing perspective, it is desirable to accelerate the annealing process to minimize the hold time between unit operations and shorten the overall manufacturing time.
The study investigates the molecular- and particle-level changes that occur in a non hygroscopic crystalline drug during post micronization annealing under varied temperature and humidity conditions, for intended use in a DPI formulation. The study demonstrates the use of Surface Free Energy (SFE) to monitor drug material changes during annealing. Complementary techniques are used to monitor changes in the micronized drug, with emphasis on characterization of SFE as a descriptor for surface-specific information. The obtained SFE trends were related to the solid-state disorder determined by RH perfusion microcalorimetry and the changes in interparticle interaction forces measured using atomic force microscopy (AFM).
The study identifies tools for characterizing postmicronization material changes that can help develop materials with consistent quality. The SFE descriptor was used to elucidate the relative differences in the extent of mechanical activation when the drug is co-micronized with magnesium stearate (MgSt).
