380058 Fast Dissolving Sub-100 Micron Nanocomposite Drug Powders of Poorly Water-Soluble Drugs Via Fluidized Bed Coating of Geldart Group C Particles

Thursday, November 20, 2014: 12:49 PM
209 (Hilton Atlanta)
Mohammad Azad1, Ecevit Bilgili1 and Rajesh Dave2, (1)Chemical, Biological, and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ, (2)New Jersey Institue of Technology, Newark, NJ

In pharmaceutical industry, many drug molecules exhibit poor bioavailability that originates from their low water-solubility and ensuing slow drug dissolution in gastrointestinal fluids of human body. One general approach to alleviate this issue is to increase the specific surface area of the poorly-water soluble drugs via reduction of crystal size. The most popular methods in pharmaceutical industry to prepare fine drug particles is wet stirred media milling, a.k.a. nanomilling, because highly concentrated drug suspensions can be produced by this solvent-free, scalable, and robust process1. Stable drug nanosuspensions prepared by the wet media milling process are generally used as precursor materials in various drying processes, which convert the nanosuspensions into drug nanocomposite powders. Recently, fluidized bed coating of precursor nanoparticle suspensions onto various carrier particles has gained popularity in the formation of drug nanocomposite powders2. The formation of a core–shell (layer) structure has been demonstrated in nanocomposite microparticles, where the shell contains drug nanoparticles embedded in a polymer or polymer–sugar film (matrix) and the carrier, usually an inactive pharmaceutical excipient such as lactose and microcrystalline cellulose, forms the core. The type, solubility, and concentration of the polymer, as well as the thickness of the coating layer can be varied to modulate the drug release rate.

In this study sub-100 µm freely flowing core–shell nanocomposite particles were prepared using a fluidized-bed coating process to improve the dissolution rate of fenofibrate/ itraconazole, model poorly water-soluble drug. This is in contrast to other fluidized bed coating processes mentioned in literature that utilize carrier particles as large as 850 µm resulting in much larger final nanocomposites. Fenofibrate/Itraconazole particles were wet-milled in a stirred media mill and stabilized via an optimized polymer and surfactant combination. For the coating of nanoparticle suspensions, fine sub-50 micron lactose (Granulac® 200) or potato starch carrier particles were considered. Smaller carrier particles are selected because they can provide a higher specific surface area for coating, thus potentially allowing higher drug loadings in the final dosage form while maintaining a thinner coating layer for fast drug dissolution. Another major advantage is that small particles are typically preferred for orally disintegrating dosage forms to minimize the sensation of a gritty mouth feel and they can also be used for controlled release of the drug through manipulation of the coating polymer(s). However, fluidization and subsequent fluidized-bed processing of such particles, which are Geldart group C powders, is a major technological barrier. It is a significant impediment particularly for the proposed spray coating with drug nanosuspensions, which would normally lead to loss of fluidization and/or significant agglomeration even if the fluidization velocities were adjusted upwards during spray-coating. Fluidization of fine carriers was made possible through dry coating based particle surface modification with hydrophilic nano-silica (M5P) via reduction of cohesion. Their subsequent coating with drug particle nanosuspensions in a fluidized bed was achieved without appreciable agglomeration, which is a major novelty of this work3. The resulting core-shell nanocomposite powders had high bulk densities and were freely flowing, which make them easier to handle than the fine and poorly flowing nanocomposite powders prepared by spray drying. Moreover, they are significantly smaller than nanocomposite particles prepared by conventional fluidized-bed coating that are relatively large (typically > 400 µm). The core–shell nanocomposite powder exhibited significantly faster dissolution in comparison to either as received or micronized/ nano-milled drug along with the same excipients in physical mixtures. The nanocomposite powder is further coated with polymers to eliminate bad taste, which is another major novelty. The resulting final composite powder was fast dissolving, freely flowing sub-100 micron powders without bad taste and less mouth feel. This final composite powder is expected to be advantageous in a variety of solid dosage forms.

Keywords: fine carrier particles, fluidized bed coating, fine nanocomposite drug powders, free flowing powders, poorly water-soluble drugs, fast dissolution


  1. C. Knieke, M. Azad, R. Dave, E. Bilgili, A Study of the Physical Stability of Wet Media-Milled Fenofibrate Suspensions Using Dynamic Equilibrium Curves, Chem. Eng. Res. Des. 91(7) (2013) 1245–1258.
  2. A. Bhakay, M. Azad, E. Bilgili, R. Dave, Redispersible Fast Dissolving Nanocomposite Microparticles of Poorly Water-Soluble Drugs, Int. J. Pharm. Sci. 461(2014) 367–379.
  3. R. Dave, C. Knieke, M. Azad, D. To, E. Bilgili, Pharmaceutical Core-Shell Composite Powder and Process for Making the Same, US Provisional Patent, Application No. 61/725,301, Filed on Nov 13, 2012.

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