The NANEX process is a continuous one-step HME process that converts stabilized aqueous nanosuspensions into a solid oral formulation with an increased solubility of poorly soluble drugs. A nanosuspension is fed to the extruder and the solvent is removed via devolatilization. Nanoparticles are embedded in the polymer matrix and solid nano-based pellets can be produced in a single step [1,2]. However, the amount of the active pharmaceutical ingredient (API) in a nanosuspension formulation is restricted to 20-30 % (w/w) making it hard to vary the API loading in the final extrudates.
Therefore, in the current study we focus on evaluating process parameters which impact the maximum amount of water that can be added during hot melt extrusion. Moreover, additional matrix materials that are suitable for incorporation of aqueous suspensions were investigated. Kollidon® VA64, Eudragit® E PO, AQOAT® (hypromellose acetate succinate, HPMCAS; in combination with plasticizer) and poly(ethylene glycol) 20000 (PEG 20000) were used. To assess whether the polymer could be mixed with water during the NANEX process and the added water could be removed completely via devolatilization (vacuum of 200 mbar), liquid (i.e., water) was fed to the hot melt extruder (MICRO 27 GL co-rotating twin-screw extruder, Leistritz Extrusionstechnik GmbH, Nürnberg, Germany) via a micro-angular gear pump in barrel 4, while adding the matrix material in barrel 1 and degassing of the added water in barrel 8. By adding water to the extruder at fixed throughputs and screw speeds, their influence on the maximum amount of water was examined. Clogging of the degassing unit and/or inclusions of moisture within the strands indicated the end-point. Additionally, the mean residence time at fixed process parameters was evaluated and residual moisture contents of the extrudates were measured via Karl Fischer titration.
The results demonstrated that the amount of water fed to the polymer melt is strongly dependent on the filling degree of the screw, which is a function of the throughput and the screw speed. The lower the filling degree was the higher was the maximum amount of added water. Similarly, the longer the residence time, the more water could be added. However, the quantity of added and removed water was not only related to the process parameters but also to the nature of the matrix material. It was found that polymers, which are miscible with water, could be processed via NANEX. For HPMCAS/plasticizer, 110%, and for PEG 20000 and Kollidon® V64 a maximum of 88% water could be added to the molten materials. Results of the Karl Fischer titrations clearly demonstrated that the excess water was removed entirely in the case of Kollidon® VA64 and HPMCAS/plasticizer. However, PEG 20000 extrudates exhibited increased mean residual moisture contents which can be attributed to process temperatures not exceeding 70 °C hampering the devolatilization of water at a vacuum of 200 mbar. To provide a remedy, a further drying step could be performed.
In summary, it was found that via the evaluation of the most important process parameters the API loading of nano-extrudates can be controlled easily and continuously without changing the complex and sensitive formulation of the nano-suspension.
1. Baumgartner, R.; Eitzlmayr, A.; Matsko, N.; Tetyczka, C., Khinast, J. and Roblegg, E. Nano-extrusion: A promising tool for continuous manufacturing of solid nano-formulations. Int J Pharm, 477, 1-11 (2014)
2. Khinast, J.; Baumgartner, R. and Roblegg, E. Nano-extrusion: a one-step process for manufacturing of solid nanoparticle formulations directly from the liquid phase. AAPS PharmSciTech, 14, 601-604 (2013)
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