460708 Nanoextrusion: A Platform Enabling Comparative Assessment of Nanocomposites Vs. Amorphous Solid Dispersions for Drug Dissolution Enhancement

Tuesday, November 15, 2016: 1:36 PM
Continental 5 (Hilton San Francisco Union Square)
Ecevit Bilgili1, Meng Li2, Nicolas Ioannidis3, Indiana Suriel1 and Costas G. Gogos1,3, (1)Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ, (2)Chemical, Biological, and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ, (3)Polymer Processing Institute, Newark, NJ

A relatively novel nanoextrusion process was used to produce extrudates of griseofulvin (GF), a poorly water-soluble drug, in a polymeric matrix with the goal of enhancing the dissolution rate and thus the bioavailability. Unlike a traditional hot melt extrusion (HME) process, nanoextrusion process (Baumgartner et al., 2014; Khinast et al., 2013) uses a wet-milled suspension of the drug as a feed along with an extrusion polymer and disperses the drug nanoparticles in the polymeric matrix while evaporating water, thus yielding extrudates in the form of nanocomposites. Simply, nanoextrusion process acts as a continuous drier unlike the traditional HME process. Being a continuous process and having the capability to handle viscous drug suspensions, it could be advantageous over various pharmaceutical drying operations in the manufacturing of solid nanoparticle-based formulations. In this study, we propose that as another potential advantage of the nanoextrusion, extrudates with different forms of the drug can be prepared by the same process via use of different extrusion polymers: nanocrystalline drug dispersed in the polymeric matrix (nanocomposites) or amorphous drug molecularly dispersed with the polymer (amorphous solid dispersion, ASD). It is hypothesized that the drug nanocrystals in the nanocomposites dissolve faster than the amorphous drug in the ASD when the drug dose is so low not to cause supersaturation in the dissolution medium (low drug dose). Specifically, hydroxypropyl cellulose (HPC) and Soluplus were used to stabilize wet-milled suspensions and to form the matrix of the extrudates. Feed suspensions of GF were prepared by wet stirred media milling using HPC and Soluplus in the presence of sodium dodecyl sulfate (SDS), an anionic surfactant. The milled suspensions along with additional polymer (HPC/Soluplus) were fed to a co-rotating twin-screw extruder, which dried the suspensions and formed various extrudates. The extrudates were milled into powders via mortar–pestle for further analysis. The effects of drug particle size in the feed suspensions, stability of drug suspensions, and polymeric matrix type–size on the drug dissolution from the milled extrudates were examined. The suspensions were characterized via laser diffraction, while the extrudates and their milled powders were characterized by laser diffraction, SEM, and XRD. Digital microscopy was used to visualize the changes of different polymeric matrices when exposed to water. Statistical analysis with Korsmeyer-Peppas model helped us to identify the drug release mechanisms. By using polymers with different interactions/miscibility with the drug, two different forms of the drug were formed: extrudates with nano/micro-crystalline drug particles dispersed in the HPC matrix as a secondary phase (nanocomposites or microcomposites) and extrudates with amorphous drug molecularly dispersed within the Soluplus matrix (amorphous solid dispersion). In the composites, drug particle size was the dominant factor that affects the dissolution performance, whereas the matrix size appears to play a significant role in the drug dissolution performance in the amorphous solid dispersion. We have demonstrated that for low-dose drugs, e.g. highly potent poorly soluble drugs, drug nanoparticles in the nanocomposites may actually dissolve faster than amorphous form of the drug in an amorphous solid dispersion, depending on the size of the polymeric matrix.

 

References

Baumgartner, R., Eitzlmayr, A., Matsko, N., Tetyczka, C., Khinast, J., Roblegg, E., 2014. Nano-extrusion: A promising tool for continuous manufacturing of solid nano-formulations. Int. J. Pharm. 477, 1‒11.

Khinast, J., Baumgartner, R., Roblegg, E., 2013. Nano-extrusion: a one-step process for manufacturing of solid nanoparticle formulations directly from the liquid phase. AAPS PharmSciTech 14, 601‒604.


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