Process Development for Continuous Extrusion and Pelletization of a Heat and Shear-Sensitive Formulation

Hot-melt extrusion is an emerging technology for pharmaceutical manufacturing. Not only does it offer the possibility to establish amorphous systems to increase bioavailability, but also carries attractive implications process-wise [1]. It is an inherently continuous processes, performs several processing steps in one machine and offers the possibility of continuous monitoring and direct product shaping, e.g. to pellets, strands or films. At the same time, intense shear forces and dissipative heat generation are challenging when using some traditional carrier polymers [2].

In this case an immediate release formulation was developed containing a BCS class II with poor solubility. The formulation consists of the API, Eudragit E and Methocel E5. Methocel E5 was added in order to achieve immediate release from the very dense pellet. Besides the shear and heat sensitivity of Methocel E5, a high pressure drop across the extrusion die is obtained due to the high viscosity and the yield point. Therefore, the extrusion process line consists of (1) a hot-melt extruder with a melt pump, (2) and a strand pelletizer. The strand pelletizer is used to directly produce pellets of small size (x₅₀ = 1000 µm) for subsequent continuous tableting.

The process development focused on the split-feeding unit, the intake zone, the temperature profile, the die plate temperature and the die plate design. After developing a stable process, a screening DoE was performed to investigate content uniformity, dissolution behavior, pellet size and material degradation. Moreover, the residence time distribution was determined.

References:

[1] J. Breitenbach, “Feste Lösungen durch Schmelzextrusion - Ein integriertes Herstellkonzept,” Pharm. Unserer Zeit, vol. 29, no. 1, pp. 46–49, 2000.

[2] A. Meena, T. Parikh, S. S. Gupta, and A. T. M. Serajuddin, “Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion - II : Cellulosic polymers .,” J. Excipients Food Chem., vol. 5, no. 1, pp. 46–55, 2014.