Daniel To

Simultaneous micronization and surface modification for improvement of flow and dissolution of drug particles.

Simultaneous micronization and surface modification of drug particles is considered in order to mitigate disadvantages of micronization, e.g., agglomeration, poor flowability, marginal increase in surface area and low bulk density. Particles of ibuprofen (102 μm), a model drug, pre-blended with hydrophilic nano-silica, are micronized down to 10 and 5 μm in a continuous fluid energy mill (FEM) to obtain fine surface modified particles. The solid feeding rate and the grinding pressure are shown as critical parameters for achieving the desired particle size and size distribution. The powder properties were characterized via SEM, laser scattering, powder rheometer with shear-cell, and dissolution test. Significant improvement in flow properties and dissolution rate was observed when micronization accompanied surface modification. Additionally, co-grinding with water-soluble polymer during micronization led to further increase in bulk density and more enhanced dissolution rate improvement, which is attributed to improved wettability. XRD, DSC and Raman were used to examine crystallinity, indicating minimal detectable physical transformation with FEM processed ibuprofen. The surface modified, micronized powders also showed improved dispersion, higher bulk densities (>0.4 g/ml), reduced electrostatic, and higher flowability (FFC ≥ 6) compared to just micronized powder (0.19 g/ml, FFC=1.0), indicating they may be used in high drug loaded formulations amenable to direct compression.

Passivation of High-Surface-Energy Sites of Milled Ibuprofen Crystals via Dry Coating for Reduced Cohesion and Improved Flowability

Ibuprofen micronization with dry coating is investigated to examine its influence on passivation/stabilization of high-surface-energy sites and reduced cohesion. A fluid energy mill was used to micronize ibuprofen particles down to 5-28 μm with or without simultaneous nanosilica coating. Powder flow property and dispersibility were characterized using FT4 powder tester and Rodos/Helos laser diffraction particle sizer. Surface energy was characterized using a next generation inverse gas chromatography instrument. Uncoated micronized ibuprofen showed an increased Lifshitz-van der Waals (LW) dispersion component of surface energy with increasing milling intensity. In contrast, dry-coated milled powders showed a significant reduction in the LW component, whereas physical mixture of uncoated micronized ibuprofen and silica exhibited no reduction in surface energy, indicating that dry coating is necessary for the passivation of high-energy sites of ibuprofen created during micronization. Surface energy of pure micronized ibuprofen was highly heterogeneous, whereas dry-coated ibuprofen had greatly reduced heterogeneity. Micronization with dry coating also improved flowability and bulk density as compared with pure active pharmaceutical ingredient micronization without coating, or just blending with silica. Overall, dry coating leads to decreased cohesion and improved flowability because of reduced LW dispersive component of surface energy and creating nanoscale surface roughness.

Preparation of concentrated stable fenofibrate suspensions via liquid antisolvent precipitation

Abstract A major challenge in achieving size stability for relatively high concentration of fine particles from poorly water-soluble drug fenofibrate (FNB) is addressed through T-mixing based liquid antisolvent precipitation in the presence of ultrasonication and judicious use of stabilizers. Multiple stabilizers were screened in a batch mode prior to their continuous formation via T-mixing. In both cases, the stable suspensions maintained their size after 2 days of storage at room temperature, with the smallest particle size of d50: ∼1.2 µm was achieved through a combination of HPMC with SDS or PF-68. The influence of processing parameters, such as sonication energy, sonication probe insert depth and solvent/antisolvent flow rate, on the particle size distribution (PSD) in T-mixing were investigated, to identify optimum processing conditions. Optimal operating and formulation conditions also allowed increase in the drug loading from 0.32% to 4% (w/v), while keeping the median size 2.5 µm. Interestingly, the primary particles observed in the SEM were spherical and under 100 nm in diameter, indicating agglomeration. It was shown that the stabilized particles could be centrifuged and did not show size growth upon resuspension, allowing for increase in the drug loading up to 27% (w/v), which is a significant novel outcome.