Tuesday, 07 May 2013 08:46

Pellet Production by Hot Melt Extrusion and Die Face Pelletising

Written by Daniel Treffer and Simone Schrank
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Process chain for the production of dosage forms via hot melt extrusion [Internal RCPE Report] Process chain for the production of dosage forms via hot melt extrusion [Internal RCPE Report]

Introduction

The production and manufacturing of solid pharmaceutical products is in need of new technologies to ensure a safe and efficient medical therapy. Hot melt extrusion (HME) is a new and innovative technology in the field of pharmaceutics, which aids to overcome numerous limitations of traditional manufacturing techniques. The benefit of HME is three-fold: First, the bioavailability of poorly soluble drugs is significantly increased due to the conversion of the drug from the crystalline into its amorphous state [1]. Recent work showed that HME is even capable of converting a liquid nanosuspension into a solid formulation in a one-step process [2], thereby avoiding aggregation of nanocrystals. Second, drug release profiles can be specifically tailored (in most cases retarded release of water soluble drugs) via the application of a proper matrix carrier in combination with plasticisers [3]. Third, drug abuse can be prevented due to superior mechanical properties of the final product [4].

However, there are still challenges, which need to be overcome during the development of a hot melt extruded product. During formulation design a suitable combination of carrier and additives must be identified to achieve the desired final dosage form properties. Here, it is especially important to guarantee dosage form stability over shelf life. During process development the melt extrusion process and downstream processing need to be optimised. The downstream is chosen on basis of the target dosage form; commonly, extrudates are milled prior to compression into tablets. However, several alternatives are available, including die face pelletising, shaping calander, strand cutting, etc. We focus on the development/establishment of die face pelletising, as it can shorten the process chain and leads to superior extrudate properties. The die faced pellets or granules are further filled into capsules or processed into tablets via conventional compaction devices and/or injection moulding. (Figure 1).

Die Face Pelletising

The extruder produces homogeneous material, i.e., extrudates, which is shaped into the intermediate/product during downstream processing. A good overview of different pelletising processes is given by [5]. In the case of die face pelletising the molten material emerges from the extruder die plate as small strands, which are immediately cut into small particles, i.e., pellets, by a rotating knife. The outstanding advantage of die face pelletising is the production of spherical pellets with narrow particle size distributions. The spherical shape is due to the fact that the cutting takes place above the softening point of the material, where viscous forces allow the particles to contract and get spherical.

Sphero®-THA

The Sphero®-THA (Figure 2)  is a novel die face pelletising system, which was developed by the project partner Automatik Plastics Machinery in close cooperation with the RCPE. It is designed to fulfil the GMP requirements and offers better processibility of sticky materials compared to conventional die face pelletisers.

A sectional view of our die face pelletizer is illustrated in Figure 3. The cutting chamber is penetrated by cooling air, which on the one hand cools the pellets and on the other hand conveys them into a product container or to a subsequent product handling step. The two main advantages of our system in comparison to conventional systems are the design of the knife and the increased cooling capacity. The knives are pressed on die plate and thus, smearing and film formation on the plate are prevented. The cooling capacity is increased due to adiabatic expansion of the cooling air at the entrance into the cutting chamber. The combined effects of knife design and cooling capacity enable cuttability of certain sticky materials. Figure 4 gives a few examples of materials that were processed via the Sphero®-THA, including (1) 80% calcium stearate 20% paracetamol [3], (2) ethylene vinyl actetate [6], (3) Kollidon VA64 and (4) 80% Eudragit EPO and 20% Talcum. The latter two materials show high stickiness and tend to agglomerate at the outlet, which makes die face pelletising complicating. However, due to the high cooling capacity of the Sphero-THA these obstacles can be overcome.

Pellet Properties

In addition to material properties the flowability is a strong function of the pellet shape, i.e., pellet sphericity. When using a die face pelletising system, the mean pellet size is determined by the number of knives and their rotational speed, and by the material throughput and die plate configuration. Figure 5.1 shows the size distributions (generated from the circle equivalent pellet diameter with QICPIC, Sympatec) of pellets that were either processed by a strand cutter or by the Sphero®-THA. Clearly, the Sphero®-THA produces pellets with a narrow size distribution, whereas after strand cutting the distribution is broadened. However, the major advantage of the Sphero®-THA is that the sphericity can be improved significantly. The deformation to a sphere after the cutting process depends on the rheology and surface tension. A good process parameter set can lead to almost spherical pellets. An example of pellets produced via the Sphero®-THA are close to one (Figure 5.2), indicating an almost spherical shape resulting in excellent flowability. A visual comparison the investigated pellets is shown in Figure 6.

Figure 7 shows the surface morphology of pellets with a diameter of approximately 1 mm produced by the Sphero®-THA. Despite some cracks that were probably generated due to comparatively rapid cooling and/or the material properties the surface is rather smooth and regular.

Outlook

A mechanistic understanding of the pellet formation process is the focus of our work and is based on detailed material and process characterisation, such as viscosity and melt behaviour, miscibility, thermal behaviour and power input, just to mention some examples. Additionally, mechanistic models will be established and used in the future to allow a prediction of processibility by die face pelletising.

References

[1] Breitenbach, J. (2002). Melt extrusion: from process to drug delivery technology European Journal of Pharmaceutics and Biopharmaceutics, 54 (2), 107-117 DOI: 10.1016/S0939-6411(02)00061-9

[2] 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, 1-4 DOI: 10.1208/s12249-013-9946-0

[3] Roblegg, E., Jäger, E., Hodzic, A., Koscher, G., Mohr, S., Zimmer, A., & Khinast, J. (2011). Development of sustained-release lipophilic calcium stearate pellets via hot melt extrusion European Journal of Pharmaceutics and Biopharmaceutics, 79 (3), 635-645 DOI: 10.1016/j.ejpb.2011.07.004

[4] Bartholomaeus, J., Arkenau-Marić, E., & Galia, E. (2012). Opioid extended-release tablets with improved tamper-resistant properties Expert Opinion on Drug Delivery, 9 (8), 879-891 DOI: 10.1517/17425247.2012.698606

[5] Mürb, R. (2012). Kunststoff granulieren und/oder pelletieren? Chemie Ingenieur Technik, 84 (11), 1885-1893 DOI: 10.1002/cite.201200014

[6] Daniel Treffer, et al., Continuous Pharmaceutical Hot-Melt Extrusion and Hot-Die Face Pelletizing, Aiche Annual Meeting 2012 Conference Proceedings

PSSRC Facilities

The area “Pharmaceutical Engineering and Particle Technology” at the institute of process and particle engineering has developed from a group of researchers around Prof. Johannes Khinast in autumn 2005. Initially focused on catalysis and direct numerical simulations of bubbly flows, Prof. Khinast’s group has formed three sub-groups dedicated to research in the fields of applied chemistry and continuous processing, manufacturing processes for the pharmaceutical industry, and simulation science. In a highly interdisciplinary environment, our area is eager to gain a more fundamental understanding of

  • transport process in (bio-)reactors,
  • the production of heterogeneous catalysts and (nano-)particles,
  • (chromatographic) separation processes,
  • hot melt extrusion
  • multiphase and granular flows, as well as
  • transport processes in complex fluids.

A main focus with respect to teaching is the training of students in the area of pharmaceutical engineering, transport phenomena and particle technology. Our research complements that of our sister organisation “Research Center Pharmaceutical Engineering GmbH”, and is tightly connected to leading national and international research institutions. This makes our area an attractive partner for industry, and brings us into the position to apply and win Austrian and European wide research grants.

Please find further information on: http://ippt.tugraz.at and www.rcpe.at

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