Nanoextrusion: A Promising Strategy for the Oral Drug Delivery MarketR. Baumgartner1, J. Khinast1,2, E. Roblegg1,3

1 Research Center Pharmaceutical Engineering, Graz, Austria2 Graz University of Technology, Institute for Process and Particle Engineering, Austria 3 Karl-Franzens University Graz, Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, Austria

INTRODUCTION

METHODS AND MATERIALSI. Physicochemical characterization of bulk Phenytoin

� Small- and Wide-Angle X-ray Scattering (SWAXS)

� Dissolution studies (apparent solubility)

� Differential scanning calorimetry (DSC)

� Contact angle measurements/ Log P (shake flask method)

� Transmission electron microscopy (TEM)

I. Physicochemical characterization of bulk Phenytoin

RESULTS

Structure:

C15H12N2O25,5-diphenylimidazolidine-2,4-dione

Melting point (Tm): 298.6 ± 0.4 °C

Log P: 2.95 ± 0.5

Wettability: 79.5 ± 2.7 °

Apparent solubility: 11.4 ± 0.4 µg/ml

Crystal structure: Crystalline TEM Image:

Given the high number of poorly soluble active pharmaceutical ingredients (APIs), scientists increasingly focus on innovative formulation platforms for such molecules.Thereby, the emerging field of nanoscience, in particular the application of nanosuspensions, offers novel possibilities. However, nanosuspensions suffer from stabilityproblems. Moreover, they are typically delivered parenterally, which is an invasive and painful route for patients. Thus, it would be beneficial to transform nanosuspensionsinto solid oral dosage forms. However, the manufacturing of solid-nanoparticle formulations requires several challenging steps. In the present study, a one-step nano-extrusion process was developed where a stable nanosuspension of Phenytoin (as a model API) is directly fed to a hot-melt extruder. The goal was to obtain extrudates thatcomprise homogenously distributed and de-aggregated embedded API nano-crystals in a polymer matrix.

II. Preparation of a stable aqueous Phenytoin nanosuspensi on

IV. Nano-extrusion process

III. Characterization of prepared nanosuspensions

� Photon correlation spectroscopy (PCS) and Laser Doppler electrophoreses (LDE)

� Differential scanning calorimetry (DSC)

� Transmission electron microscopy (TEM)

� Small- and Wide-Angle X-ray Scattering (SWAXS)

� Dissolution studies (apparent solubility)

B) Media Milling (MM, 24h, 200 rpm)

24 h

Milling bowlCounter-weight

Supporting disc

Stabilizer Phenytoin Zirconium oxide beads (0.5 mm)

A) High Pressure Homogenization(HPH,15 cycles of 5 min at 1000 bar)

* *

* Tested stabilizers: Tween® 20 and 80 and Kolliphor® EL, RH40, P407, P188, TPGS and IR

II-V. Characterization of the Phenytoin nanosuspensions an d nano-extrudates

The addition of Tween® 80 to Phenytoin suspensions prepared via media milling resultedin stable nanosuspensions with smallest particles (Z-average = 335 ± 6 nm).Tween® 80-stabilized Phenytoin nanosuspensions were used for hot-melt extrusionexperiments.

TEM-images of Tween® 80-stabilized Phenytoin nanocrystals prepared via media milling.

WAXS spectra of pure Phenytoin and air-driednanosuspension. Comparing the Bragg peaks ofthe pure powder with the air-dried nanosuspensionshowed the same peak positions which indicatesthat during nanosizing no melting or amorphizationof the API occurs

DSC thermograms of pure untreated Phenytoin(melting endotherms at 298.6 ± 0.4 °C) andSoluplus® (glass transition at 77.3 ± 1.3 °C;degradation at 317.7 ± 0.1 °C),nanosuspension ( melting endotherms at 291.7± 0.4 °C) and nano-extrudate (glass transitionof Soluplus® at 79.5 ± 1.6 °C; degradation ofSoluplus® at and above 300 °C; characteristicmelting peak of Phenytoin with an onset at300.1 ± 3.0 °C).

K1 Competence Center - Initiated by the Federal Ministry of Transport, Innovation & Technology (BMVIT) and the Federal Ministry of Economics & Labour (BMWA). Funded

by FFG, Land Steiermark and Steirische Wirtschaftsförderung (SFG)

23rd Scientific Congress of the Austrian Pharmaceutical Soci ety (ÖPhG)23rd -25th April 2014, Graz

V. Characterization of obtained nano-extrudates

� Transmission electron microscopy (TEM), Atomic force microscopy (AFM) and Energy dispersive X-ray spectroscopy (EDX)

� Differential scanning calorimetry (DSC)

� Dissolution studies (apparent solubility)

CONCLUSION

TEM image and EDX spectra of Tween® 80-stabilized Phenytoin nanocrystals embeded in the Soluplus® matrix..

AFM images (B is the magnification of A) ofTween® 80-stabilized Phenytoin nanocrystalswith a size of 115 nm and 135 nm embeded inthe Soluplus® matrix in de-aggregated form.

Dissolution studies:the Increase in solubility was on the one hand due to solubilizing properties of Soluplus®. On the other hand enhanced solubility of nano-crystalline Phenytoin compared to the bulk material was also verified.

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. doi:10.1208/s12249-013-9946-0

The current study demonstrates that this novel process based on hot-melt extrusion of a nanosuspension is an appropriate continuous technology for producing solid nano-formulations. This one-step process helps to eliminate problems associated with stabilization of nanosuspensions and the conversion of nanoparticles into a solid dosageform. Furthermore, the embedded drug nanocrystals allow an improvement of the dissolution properties of poorly soluble and therefore poorly bioavailable APIs

REFERENCES