(511d) What Is More Important for Improved Drug Dissolution: Agglomerate Size Reduction or Enhancing Particle Surface Wettability?

A prevalent challenge with fine powders, especially those below 30μm, is high cohesion that leads to flow and handling problems and more importantly, causes significant particle agglomeration that delays their dissolution rate^1,2. Dry coating of fine powders with silica nanoparticles has been shown to be very effective in reducing cohesion and consequently may reduce the extent of agglomeration^3,4. For poorly water-soluble particles, the reduction in agglomeration greatly enhances the available surface area, which could have a positive impact on their dissolution. However, a major concern with the dry coating is that usually hydrophobic silica particles have been found to be more effective in reducing cohesion and particle agglomeration^3,5,6,7. An interesting question arises as to how effective the hydrophilic silica coating for agglomerate size reduction is. Even more interesting question is if the use of hydrophobic silica may lead to a greater extent of cohesion reduction, what is the adverse impact on dissolution is of the extent of increased surface hydrophobicity of drug particles that may be hydrophobic, to begin with. These two questions have largely been ignored in the bulk of the literature on dry coating. Fortunately, in a recent work, Kim et al. 2021 explored the competing relationship between those two impacts on the dissolution rate of dry coated poorly water-soluble and cohesive Active Pharmaceutical ingredients (API)⁸. Quantification of the agglomerate size and surface hydrophobicity of cohesive and micronized poorly water-soluble APIs before and after dry coating was examined in detail. As a positive surprise, the outcomes demonstrated that when the reduction in agglomerate size is effective, the dissolution is not solely dominated by the surface hydrophobicity, but it was the result of the competition between surface hydrophobicity and reduction in agglomerate size. As a corollary, when the reduction in agglomeration or the interparticle cohesion force is not sufficient, surface hydrophobicity was the main driver in the dissolution process⁸. Thus, important insights in understanding a complex phenomenon were gained, opening additional questions such as the reported observation holds for drug materials that have even higher hydrophobicity and even lower solubility in water. Higher hydrophobicity could have confounding effects in various aspects of the dissolution of agglomerated particles. For example, the study of instantization of granulated milk powders in water has pointed out multiple interacting phenomena, such as the surface wetting, sinking, penetration in the pores, agglomeration dispersion, and particle dissolution all affected by the particle’s inherent solubility, its surface properties, and its size⁹.

In the extended work that is the subject of the poster presentation, three different drug materials were considered while keeping their sizes comparable. To better analyze the effect of disparate water solubility, a small amount of wetting agent was added to the dissolution buffer as is the common practice for in vitro dissolution testing. Specifically, 0.012M of sodium dodecyl sulfate (SDS) solution¹⁰ was added and the extent of agglomerate sizes, as well as surface wettability and dissolution rate of uncoated and dry coated model APIs, were evaluated^11,12. The model APIs are all BCS II drugs, which were ibuprofen, griseofulvin, and fenofibrate, all having 10 microns in d₅₀ were considered. In addition, for the sake of comparison with previous work^3,8, for ibuprofen, another size of 20 microns d₅₀, was also included in this study. These model APIs were dry coated with either hydrophilic (A200), or hydrophobic (R972P) fumed silica via a high energy mixer, LabRAM, at varying ranges of theoretical surface area coverage (SAC) by silica. Agglomerated and primary particle sizes were evaluated by two different particle sizers, a gravity-driven dispersion method, and a compressed air dispersion method, respectively. Following USP <711> protocol, USP IV dissolution testing was conducted in 0.012M SDS solution. Surface hydrophilicity was measured via the modified Washburn method^11,12. The results further verified the observation reported in the earlier work by demonstrating that irrespective of the chemical nature or log P value of the targeted poorly water-soluble API, it is the extent of deagglomeration that has larger influence on how the dissolution process takes its course. In fact, that also explains why dissolution improves in certain cases of fine APIs dry coated with hydrophobic silica. In summary, this innovative study helps answer the question if and when even hydrophobic silica coating can help improve the dissolution rate of poorly water-soluble drugs based on a better understanding of the relative impacts of the surface hydrophobicity and the agglomerate size.

References

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