(700d) Agglomeration of Fine APIs As a Material Sparing Screening Indicator for Powder Processability

Most of the drugs already marketed or under development are poorly soluble, requiring milling to increase the available surface area for dissolution^1-5. Unfortunately, milling increases interparticle adhesion force or cohesion, arising from van der Waals (vdW) attraction, concerning individual particle’s weight ^6-8. This adversely impacts bulk powder properties and hence poor flow and packing and induces large agglomerate formation while delaying dissolution and unfavorably impacting API blend uniformity^9-15. Excessive cohesion of fine particles could be mitigated through the dry coating of fine powders with nanoparticles such as silica, reducing the extent of agglomeration^2,16. Reduction in the agglomeration has been reported to improve dissolution rate and API blend uniformity ^{13, 14}, and overall powder processability, including flowability and packing enabling direct compaction ^17-19.

Fine API agglomeration, while expected, has not yet been addressed well in the literature. Our recent work has indicated that the agglomerate ratio (mean agglomerate size to mean primary particle size) could provide early indications of inadequate fine powder processability, i.e., flowability, bulk density, dispersibility, and consequently blend uniformity and dissolution. More importantly, our work has also shown that dry coating could significantly help in reducing the powder cohesion, hence reducing agglomeration and enhancing the powder processability. Consequently, a simple assessment of the agglomerate ratio (AR) with and without dry coating could provide a practical guideline during the early formulation development efforts to mitigate the adverse impact of high cohesion on powder processability. Towards that objective, the current work examined the causal relationship between the interparticle cohesion and the bulk powder properties through a particle scale dimensionless parameter, granular Bond number (Bo_g), towards developing a predictive guideline at a reduced need for experimental testing ^{12, 20}.

The dry coating of the model powders (BCS II drugs, three sizes of ibuprofen (d₅₀ ~ 5, 10, 20 µm), fenofibrate (d₅₀ ~10 µm), and griseofulvin (d₅₀ ~10 µm)) was done employing a high-energy vibratory mixer, LabRAM. The examined material properties include primary and agglomerate size distribution using a compressed-air-dispersion-based laser diffraction particle sizer and a gravity dispersion basis dynamic imaging particle sizer, respectively. USP IV method with 12 mM sodium dodecyl sulfate aqueous solution as the dissolution medium was utilized to evaluate dissolution rate, while FT4 was used to assess flowability (FFC) and bulk density (BD). The surface energy of the uncoated and dry coated powders was measured with inverse gas chromatography, iGC-SEA, which operated under the helium environment. Then, normalized agglomerate size was studied as the critical material attribute, and its relationship to Bo_g, FFC, BD, and dissolution rates was found.

As a novel outcome, the prominent role of agglomeration was demonstrated through demonstrating enhanced dissolution of fine poorly water-soluble APIs even when the dry coating was done with hydrophobic silica, R972P. Additional important outcomes include: (1) For all five model powders, dry coating led to enhanced processability. Flowability was enhanced by up to four regimes, while bulk density increased by up to 100 %. (2) The dissolution, expressed as the area under the dissolution curve (AUC) improved by up to 60% due to a 1–2 orders of magnitude reduction in agglomeration. (3) As another major novelty, agglomeration (AR), quicker material sparing measure, was a key indicator of both processability and dissolution of fine APIs. (4) AR and Bo_g exhibited a power-law relationship for fine APIs, removing the explicit need for assessing Bo_g. (5) AR was well-correlated with both FFC and BD, greatly facilitating the determination of dry coating efficacy for processability enhancement and setting AR ≤ 5 as a bar for powder processability. (6) The natural surface roughness of the uncoated particles was shown to play a significant role in bulk properties, and the prevalent recommendation of 200 nm (or size-based estimation²¹) natural surface roughness is inappropriate. (7) For APIs such as ibuprofen, milling would significantly increase surface energy values, further increasing effective powder cohesion, requiring dry coating-based passivation ⁸.

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