(681b) Nano-Extrusion: A Novel One-Step Process for the Manufacturing of Solid Drug Nanoparticle-Formulations

Given the increasing number of poorly soluble active pharmaceutical ingredients (APIs), pharmaceutical scientists increasingly focus on innovative formulation platforms for such molecules. The emerging field of nanoscience, in particular the application of nanosuspensions, offers novel possibilities (1). However, nanosuspensions suffer from stability problems, such as agglomeration. Hence, stabilizers must be used to cover the particle surfaces. Moreover, they are typically delivered parenterally, which is an undesired and invasive delivery route. Thus, it would be beneficial to transform the nanosuspensions into solid oral dosage forms. However, the manufacturing of solid-nanoparticle formulations requires several challenging steps. Five products (Rapamune®, Emend®, TriCor®, Megace®ES and Triglide™) produced via nanoparticle technology are currently available on the market, of which four are based on the media milling technique (Elan NanoCrystal® technology). The remaining one (Triglide™) is manufactured using high-pressure homogenization (DissoCubes®, SkyePharma PLC) and requires several steps, including freeze drying, spray drying, spray coating and pelletizing or granulation, to  convert the nano-particles in a solid powder for compaction into tablets or filling into capsules (2). Since these complex processes are time-consuming and cost-intensive, new technologies are needed to transfer a nano-suspension into a solid application form while avoiding any agglomeration. In the present study, a one-step nano-extrusion process is presented where the nanosuspension is directly fed to a hot-melt extruder. The goal was to obtain extrudates that contain homogenously distributed and de-aggregated embedded API nano-crystals in a polymer matrix (3). Using this novel technique, the drug release rate of the poor soluble drug was significantly enhanced.

Phenytoin, a poorly soluble antiepileptic drug with a melting temperature above 280°C was used as model drug. Stable aqueous nanosuspensions of Phenytoin were produced via high-pressure homogenization by adding appropriate stabilizers (i.e., Tween® 20 and Kolliphor® EL) in accordance to the physicochemical characteristics of the API. Next, the nanosuspension was fed to the extruder via a liquid side feeding device, while using Soluplus® as matrix-material (glass transition temperature 70°C). The solvent was removed continuously via devolatilization, which is standard procedure during extrusion of solvent-containing drug-excipient mixtures. The obtained extrudates were investigated via TEM and EDX to visualize and verify the embedded nanocrystals. Furthermore, dissolution studies were conducted to evaluate the drug release profile.

The addition of both stabilizers to Phenytoin-dispersions results in stable nanosuspensions, which were added into the molten polymer via side feeding of a hot melt extruder. TEM- and EDX data of the obtained extrudates confirmed that the nanocrystals were embedded in the matrix in a de-aggregated form. Furthermore, the dissolution studies displayed an improvement of Phenytoin release from the solid nanoparticle-formulation in comparison to the untreated Phenytoin-powder.

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 dosage form. Furthermore, the embedded drug nanocrystals allow an improvement of the dissolution properties of poorly soluble and therefore poorly bioavailable APIs.

1.        Müller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future. Adv Drug Deliv Rev. 2001; 47(1): 3–19.

2.        Van Eerdenbrugh B, Van den Mooter G, Augustijns P. Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm. 2008; 364(1): 64–75.

3.        Khinast J, Baumgartner R, Roblegg E. Nano-extrusion: a One-Step Process for Manufacturing of Solid Nanoparticle Formulations Directly from the Liquid Phase. AAPS PharmSciTech. 2013; published online: March 06