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Chemical Engineering Science 65 (2010) 19761988

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Chemical Engineering Science


journal homepage: www.elsevier.com/locate/ces

A novel design for hot-melt extrusion pelletizers


Stefan Radl a, Thomas Tritthart b, Johannes G. Khinast a,
a b

Institute for Process and Particle Engineering, Graz University of Technology, A-8010 Graz, Austria mnadis Melt Extrusion Technologies, Austria

a r t i c l e in f o
Article history: Received 8 January 2009 Received in revised form 17 November 2009 Accepted 20 November 2009 Available online 3 December 2009 Keywords: Hot-melt extrusion Pellets Pharmaceuticals Simulation Product processing Non-Newtonian uids

a b s t r a c t
In this work we investigated a novel die design for the scale-up of hot melt extrusion (HME) devices for direct pelletization of pharmaceutics. Therefore we analyzed the temperature distribution in a lab- and production-scale die as well as melt ow through the die. Finally we explored the possibilities of an inner rotating knife for stabilizing melt ow. The work was based on computational uid dynamics for simulating non-Newtonian melt ow and corresponding temperature elds. The results show that a tight temperature control of the die material is necessary to guarantee a safe scale-up of the process. Even in lab-scale applications temperature inhomogeneities have been observed both experimentally as well as in the simulation. These inhomogeneities act as an trigger to destabilize melt ow and hence could lead to a shutdown of the process. The proposed inner rotating knife acts as a pulsating device and consequently is able to enhance process stability. However, due to heat dissipation in the small gap between rotor and stator, this device has to be tted with a separate low-speed drive and cannot be coupled directly to the main extruder shaft. & 2009 Elsevier Ltd. All rights reserved.

1. Introduction Melt extrusion processes have been used in industrial applications for many years, the production of thin lms being only one of the most prominent example. Starting from the polymer and plastic industry, hot-melt extrusion (HME) has also found numerous applications in pharmaceutical manufacturing practice (Breitenbach, 2002; Crowley et al., 2004, 2007; Repka et al., 2007). By use of melt extrusion, various dosage forms can be manufactured, ranging from pellets, over granules to tablets and transdermal drug delivery systems. Compared to other pharmaceutical production processes, HME has the benet of being a solvent free, environmental friendly and cost-efcient technology. Furthermore, by HME it is possible to improve bioavailability of difcult actives by the formation of solid dispersions and solid solutions. This is relevant for poorly-soluble pharmaceutically active substances, frequently encountered among novel active ingredients (Doelker et al., 2005; Klein et al., 2007; Miller et al., 2007). Such benets have led to an increased interest of HME technology in recent years. A typical HME process consists of a feeding system, an extruder with conveying, mixing and melting section, a die section as well as further downstream processing units. A schematic diagram of a HME process is depicted in Fig. 1.

Corresponding author. Tel.: + 43 316 873 7978; fax: + 43 316 873 7963.

E-mail address: khinast@TUGraz.at (J.G. Khinast). 0009-2509/$ - see front matter & 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ces.2009.11.034

The extruder is divided into a feed, transition and metering zone. Pitch and helix angle are different in each of these zones and designed to allow mixing, compression, melting, and plastication of the feed material. Finally, the metering zone ensures a constant ow rate of the melt. Often co-rotating twin-screw extruders are used due to their superior mixing characteristics. In these extruders two parallel mounted shafts are driven by the gearbox and the screw ights are typically fully intermeshing, i.e., each ight wipes both the element on the adjacent shaft and the internal surface of the mixing chamber. This setup eliminates stagnation areas within the extruder and ensures a narrow and well-dened residence time distribution. The residence time is typically in the order of 2 min. Thus, thermal stress of heatsensitive compounds is minimized and heat-sensitive materials can be processes without signicant reduction of drug activity. After forming the melt in the die, the thermoplastic strand is forced between calendar rolls to produce lms, or is fed into another device to form pharmaceuticals directly, e.g. pellets or tablets. The ow of the melt in extruders has been discussed by various authors with experimental, theoretical and computational methods (Bertrand et al., 2003; Carneiro et al., 2004; Khalifeh and Clermont, 2005; Rauwendaal, 2006). Hence, there has been an immense interest in melt ow in the extruder section. Also, there have been numerous studies addressing the details of ow through the die hole and phenomena like die swelling (Carneiro et al., 2001; Tome et al., 2007) or shark skinning (Kulikov and Hornung, 2001; Migler et al., 2002; Molenaar et al., 1998).

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S. Radl et al. / Chemical Engineering Science 65 (2010) 19761988 1977

feeding system

extruder gear, motor and bearing

die downstream processing

Fig. 1. Schematic diagram of a hot melt extrusion system.

However, relatively low attention has been paid to the combined effect of temperature distribution in the die material and the melt (Lin and Jaluria, 1998; Pittman and Sander, 1994). Specically in the area of melt extrusion for pharmaceuticals the literature is very scarce. Up to now, no study exists that focuses on the ow of HME drug products through the extrusion head and the die. For the development of solid dosage forms, the production of spherical pellets via HME is of interest due to their use in controlled-release drug delivery systems. These spherical pellets produced via HME offer additional exibility for further modications, e.g., by coating. Signicant contributions in the area of pelletization have been made by Follonier and co-workers in the mid-90s (Follonier et al., 1994, 1995). A recent report on the production of pellets by HME has been published (Young et al., 2002). Furthermore, various patents for this technology exist (see for example Rein, 2005). Today, pelletization using HME can be seen as a promising technology that may have a commercial breakthrough in the near future. However, compared to the extrusion of polymers, HME in pharmaceutical applications is signicantly more demanding as the dosage forms are a mixture of active pharmaceutical ingredients (API), matrix carriers and other excipients. These ingredients have to be adjusted to give both excellent therapeutic as well as adjustable processing properties of the formulation. Furthermore, the regulatory bodies are increasingly demanding an enhanced process and product understanding, in line with the Quality by Design (QbD) initiative. Hence, along with the knowledge to efciently manufacture a drug product, also insight into the process has to be provided. This paradigm shift from trialand-error methods to an science-based process design provides rational connection of process parameters and product quality attributes. In this study our aim is the rational design of pharmaceutical production processes. Specically, we focus on the design of a novel die including a direct pelletization step.

1.1. Background Rheological data and models relevant to hot melt extrusion can be found in various sources. For example, the effect of drug content changes on the thermophysical and rheological parameters of the formulation has been analyzed recently (Chokshi et al., 2005). In their work they used the Cross model for quantifying the shear thinning effect of their melt. Temperature effects were modeled using the Arrhenius equation. The effect of different polymers (Eudragit EPO, different polyvinylpyrrolidones and Poloxamer 188) on a formulation of indomethacin was studied and they observed a zero-shear viscosity ranging from 5 (formulation with Poloxamer 188 at 60 1C) to over 27,000 Pa s (formulation with Eudragit EPO and 120 1C). The normalized

activation energy Ea/R was in the order of 100010,000 K. In summary, it was found that the zero-shear viscosity is strongly inuenced by the drug-to-polymer ratio. Hence, viscosity within a melt can vary signicantly, if local composition gradients exist, which underlines the need for good mixing of the formulation in HME devices. Rouilly et al., investigated the shear-thinning behavior of thermoplastic sugar beet pulp, a material consisting mainly of polysaccharides (Rouilly et al., 2006). The power law model was used to quantify the melts rheological behavior between 110 and 130 1C and different moisture contents. Grosvenor and Staniforth investigated the effect of molecular weight on the rheological and tensile properties of poly (e-caprolactone) (PCL) (Grosvenor and Staniforth, 1996). This substance has found widespread use in the pharmaceutical industry, e.g., as a release agent. They also used the Arrhenius law to describe the temperature effect of melt viscosity. Viscosity was in the range of 10150 Pa s and the normalized activation energy Ea/R was in the range of 38004700 K. These literature data show that melt viscosity in extrusion processes spans a wide range and that the ow is non-Newtonian. Furthermore, local composition of the mixture signicantly changes the rheological behavior and consequently impacts the ow pattern. Thus, equipment design must take into account these facts. However, only little attention has been devoted to these problems in the literature. Specically, the rational design of dies for HME drug extrusion has not been analyzed critically up to now. The scale-up of HME devices is inuenced by many considerations. Clearly, the temperature distribution in the die and the melt, the mechanical strength of the die and the distribution of the melt within the device may be of central importance. This is especially true for large-scale production systems. Equipment for high-throughput wet mass extruders in the pharmaceutical industry are known for many years (Erkoboni, 2003). In contrast, HME equipment for pellet production is designed nearly exclusively for lab-scale applications, because the quality of the products may be very sensitive to variations in process parameters, e.g., the melt temperature, which is difcult to predict. Clearly, there is a lack of knowledge in the rational design of large-scale HMEs. While transport, mixing and energy dissipation are of central importance for the design of the screw section, the design of the die impacts strongly the quality, shape and uniformity of the pellets. Thus, an optimal design of the extrusion die is extremely important to achieve the desired shape and dimension of the extrudate. The fundamentals of optimal die design can be found in Kostic and Reifschneider (2007), as well as in Ghebre-Sellassie and Martin (2003) or Rauwendaal (2006). Relevant geometries of the die for HME drug extrusion include at dies for the production of lms, as well as prole extrusion dies, e.g. for spaghetti-like products. The ow of the melt through the die will be inuenced by the melts rheological behavior, the channel geometry and the operating conditions, including ow rate and local temperature. For this reasons it is virtually impossible to obtain a ow channel geometry that can be used for a wide range of different products. Consequently adjustment capabilities are build into the extrusion die system. This often includes a variable geometry, e.g. by using so-called choker bars or valves, or a device for controlling the die temperature, e.g., by using cartridge heaters (Rauwendaal, 2006). Referring to the former possibility, uniformity of the melt ow is achieved by the use of choker bars or ex-lips together with a special design of the manifold for melt distribution. These devices for controlling the melt ow are located at numerous points along the width of the die (e.g., in case of a sheet die). The adjustment of these devices is controlled by scanning the thickness of the extrudate in case of lm extrusion.

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In addition to mechanical design strategies, there have been several efforts to prevent extrusion dies from freezing using controlled heat transfer. In underwater pelletization of polymers the die has been insulated on the exit side to reduce heat transfer to the liquid media (Jackson et al., 2007). Alternatively, the liquid media can be heated. However, this has the drawback of increased energy consumption. Furthermore, the melt temperature can be controlled using different die metals (Bertolotti, 1989). In summary, an ideal die design will: (Kostic and Reifschneider, 2007)

 The design must allow a tight temperature control of the die


material.

 Pressure loss across the die should be minimized to allow 


a high throughput, i.e., the thickness of the die should be minimized. The residence time in the extrusion device should be short (12 min) and the residence time distribution should be narrow.

 balance the melt ow to provide a uniform exit velocity across


the entire die exit,

 achieve a minimal pressure drop,  avoid abrupt changes that may cause stagnation areas and
thermal degradation,

 allow adjustment during production by inclusion of owcontrol devices for optimization of the ow distribution,

This paper is structured as follows: rst we provide some background information on the computational method used in this work. The available rheological models and data for pharmaceutically relevant melts are highlighted. In the results section we rst discuss the temperature distribution in a lab-scale and the novel production-scale extrusion device. Finally, we focus on the production scale extruder and investigate the effect of a knife rotating inside the extrusion die.

 have a modular design for better manufacturability, assembly,


cleaning and convenient modication and

2. Materials and methods 2.1. Materials The polyol D-Mannitol (CPharmMannidex 16700), sorbitol (CPharmSorbidex S 16606) and the polysaccharide maltodextrin (CPharmDry 01980 Maltodextrin DE 8) were purchased from Cerestar Austria Handelsgesellschaft m.b.H. Glucono-d-lactone (F2500) was supplied by Jungbunzlauer Austria AG. 2.2. Model substance The model substance used within this work consisted of 37 w% D-Mannitol, 38 w% Glucono-d-Lactone, 20 w% maltodextrin and 5 w% sorbitol. The rheological behavior of the melt was determined at different temperatures using a high-pressure capillary rheometer (Rheograph 2002, Gottfert GmbH, Germany) according to DIN 53014. The density of the melt was measured using a PVT-100 (SWO Polymertechnik GmbH, Germany). The heat conductivity was determined with a K-System II (Advanced CAE Technology Inc., USA) according to ASTM D5930-97. All measurements were performed at the University of Leoben (Schuschnigg et al., 2007). The models used for the description of the melt rheology as well as the numerical values for the physical properties of the melt are described at the end of Section 2.3 of this paper. 2.3. Computational method In order to compute the time-dependent velocity and temperature distribution of the melt, the nite volume method was used to solve the underlying equations for mass, momentum and energy conservation. Assuming an incompressible media, the continuity equation can be written as:

 have a so-called die land, i.e., a region upstream of the die,


which has a length of at least 10 times the product thickness in order to facilitate polymer melt stress relaxation. A wide range of designs for extrusion dies can be found in literature. However, their application to pharmaceutical manufacturing processes is limited. 1.2. Objectives The objective of this study is to develop a method to computationally assess the feasibility of different complex die designs, which we will apply to a new HME drug extrusion process with direct granulation. Direct granulation refers to a novel process, where the hot, still molten extrudate, is cut directly after exiting the die. Cutting of the molten strand is achieved with a rapidly rotating cutter knife. By doing so, the granules will form perfectly shaped pellets (micro pellets) immediately due to the action of surface tension and the shrinkage due to solidication. Hence, there is no need for a subsequent spheronization step. This process has the advantage of not requiring a further melting of the product, thus lowering equipment costs and reducing energy demand. It also allows effective integration in a continuous manufacturing environment. In order to study in detail the ow characteristics in the extrusion die device, a computational tool has been developed. The momentum and mass conservation equations, as well as the energy equation, have been solved to calculate the velocity, pressure and temperature eld in the melt as well as in the extrusion die. Melt rheology was described by a shear-rate and temperature-dependent viscosity. Viscoelastic effects have been excluded from this work. The die design studied in this work is based on a cylindrical shape of the extrusion device, i.e., the melt is entering the die in axial direction and exiting in radial direction. To facilitate melt ow, the effect of an additional rotor that is located inside the extrusion die was investigated. This rotor works as a pulsation device to clear plugged die holes. Consequently, the robustness of the process can be increased and a continuous operation can be ensured. Requirements for the process design include:

r ~ 0: u

where ~ denotes the velocity vector. The momentum equation u can be written as @r ~ u T x ~ rr~ rp r m~ r~ r ~: u u u u @t 2

 Melt pressure and temperature have to be constant for each


individual die hole to ensure a uniform melt distribution and pellet diameter.

Here m denotes the dynamic viscosity that depends on the shear rate and the local temperature. r is the density and p is the pressure. In our study a rotating knife has been considered within the cylindrical die. Therefore, it was necessary to introduce as second, rotating reference frame. In this rotating reference frame,

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S. Radl et al. / Chemical Engineering Science 65 (2010) 19761988 1979

~ characterized by the angular velocity vector O , the centrifugal ~ ~ r force Fcent r O O ~ and the Coriolis force Fcor 2 r ~ u O ~ have to be considered. In this case, the momentum equation can be written as: (Brenn, 2004) @r ~ u ~ x ~ rr~ rp r m~ r~ rT ~r O u u u u @t ~ r ~ u O ~2 r O ~;

_ on the local viscosity, i.e., m mg ; T, i.e., _ _ mg ; T aT m0 minf 1 B aT g C D1=C ; 8

where the dimensionless quantity aT is the temperature correction function dened as    Ea 1 1 : 9 aT exp R T T0 Eq. (9) is based on the Arrhenius equation with the normalized activation energy Ea/R. The constants describing the uid under investigation where given as:

By making this equation dimensionless the relative impact of these additional forces becomes apparent:   @~ u 1 2 ~ ~ r ~ rp r ~ u u O Re u @t Ek Ro Re ~ ~ r O ~ 2 O ~ ; u 4 Ro where Ro = U/(O L) is the Rossby number (i.e., inertial to Coriolis forces). Ek= m/(r O L2) is the Ekmann number (i.e., viscous to Coriolis forces). In the current framework Re will be very small, Ro will be O(1), because U will be in the order of O L (note that the rotating motion is fast compared to the axial uid ow in the extrusion head). The Ekmann number will be in the order of 1/Re, i.e., it will be high. Hence, centrifugal and Coriolis forces can be safely neglected in the current work. This allows a more efcient implementation in the simulation software. Following Bird et al., the energy equation for an incompressible uid with constant heat capacity cp and thermal conductivity l is: (Bird et al., 2002)

m0 = 1680 Pa s minf = 0 Pa s
B = 2.50 10 3 s C = 3.88 D= 9.9 10 2 Ea/R= 2.13 104 K T0 = 378.15 K As simulation software the open-source CFD package OpenFOAM has been used. This software enables easy modication of the governing equations and is numerically efcient. For mesh generation OpenFOAMs internal mesh generator blockMesh as well as CUBIT have been used (Blacker, 2007). The computational mesh was designed such that the ow eld and the temperature gradients were captured well. To obtain a mesh independent solution, the mesh has been locally rened. The largest meshes (for 3D simulations) consisted of approximately 280,000 cells, whereas for the 2D simulations the maximum cell number was around 60,000 cells. The solver has been veried against an analytical solution for isothermal non-Newtonian ow. For this case the solution for the steady-state ow of a uid in a straight pipe with circular cross section can be evaluated from: (Bohme, 2000) 3 Z tw p d _ t2 g t dt 10 Q 3 8 tw 0 In Eq. (10) Q denotes the ow rate (m3/s), d is the pipe diameter _ (m), tw is the wall shear stress (Pa) and g t is the inverse

@h l u r2 ht : r~: r ~ rh u cp @t

u In Eq. (5) the term t : r~ denotes the heat of dissipation, where t is the stress tensor. The enthalpy h is related to the temperature eld, i.e., h cp TT0 : 6

In Eq. (5) the stress tensor t can be calculated from the rheological properties of the melt and the velocity eld. In the solid domain (we solve both for the die material and the die ow) the velocity vector ~ in Eq. (5) was set to zero, which resulted in the Laplace u equation in case of the steady-state cases. The enthalpy equation was solved simultaneously with the uid dynamics, as the rheology is strongly dependent on the temperature. As the temperature eld in the uid and solid domain was calculated separately, an iterative technique was employed to couple these two regions. This was done by imposing the calculated temperature boundary eld from the solid domain on the uid domain. To guarantee the heat balance at the boundary, the heat uxes in the uid and solid domain must be equal, i.e.

ls

@Tf @Ts lf ; @~ n @~ n

where the index s stands for the solid domain, f refers to the uid domain and ~ is the unit normal vector of the boundary. With n these boundary conditions the temperature eld in the uid domain can be calculated. Subsequently, the temperature boundary conditions were updated in the solid region and the cycle was repeated until the difference in the calculated heat uxes was below a certain threshold. The thermal conductivity of the melt was assumed to be constant at lf = 0.205 W/mK, which was supported by the measurements. The density was measured to be approximately constant and 1480 kg/m3. The heat capacity was estimated to be 1260 J/kg K= m2/s2/K and was based on that of saccharose at room temperature. A modication of the Carreau model was used to _ account for the effect of shear rate g 1=s and temperature T (K)

Fig. 2. Results for isothermal non-Newtonian pipe ow (line: analytical solution, symbols: numerical solution; 1 mm pipe diameter, 3 mm pipe length, 378.15 K melt temperature, viscosity according to Eqs. (8) and (9)).

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viscosity function, i.e., the function describing the rheological behavior of the uid as given by Eq. (8). The wall shear stress tw depends linearly on the pressure drop Dp over a pipe with length Dl and hence is known. A simple force balance yields:

3.2. Temperature distribution in a lab-scale die First, the temperature distribution in the planar lab-scale die plate (refer to Fig. 4) was analyzed. The die plate consists of a cone that acts as a distributor for the melt (Fig. 4 right) and a planar plate with 16 die holes. To reduce pressure drop, the die holes consist of a 5 mm diameter pilot bore and a 1 mm diameter exit bore. The die plate is mounted directly to the extruder head via six bolts (Fig. 4 left) and is in thermal contact with the extruder, which was temperature controlled (386.15 K). An isometric view that shows the die plate assembled with the extruder head and the melt ow is presented in Fig. 5. Because of the symmetry of the plate, only 1/6 of the plate was modeled and subsequently simulated. Since the extruder head, the die plate and the melt are in thermal contact, it is important to understand the heat exchange between these three regions. Hence, it was necessary to simulate heat and melt ow simultaneously. Furthermore, the rotating cutter knife causes a turbulent air ow at the front side of the die plate. Hence, it is essential to take into account the convective heat transfer from the die plate to the surrounding air. Thus, the boundary conditions for this situation were chosen as:

tw

Dp d : Dl 4

11

The comparison of the simulation results with the analytical solution is presented in Fig. 2. As can be seen, an excellent agreement is obtained.

3. Results In order to asses the novel concept for the die, numerous simulations of the non-isothermal melt ow in the novel cylindrical die were performed. 3.1. Flow through the die hole The simulations of the non-isothermal melt ow through the die hole showed a local temperature maximum near the wall. This is a phenomena well known in the literature (Ghebre-Sellassie and Martin, 2003) and will not be discussed in more detail. The pressure drop over the nal die hole (diameter=1 mm, length= 3 mm) was in the order of 120 bar at the design melt temperature of 95 1C and a ow rate of 0.25 kg/h. The maximum temperature rise was about 7 K. A typical result for the temperature distribution is shown in Fig. 3.

 Convective heat transfer from the front side (melt exit, light
region in Fig. 6) of the die plate to the surrounding air (T= 293.15 K). The heat transfer coefcient a to the surrounding air was obtained from an idealized assumption of air ow over a at plate. This analysis showed that a is in the range between 50 and 80 W/m2 K under operating conditions. The surfaces in contact with the screws have the temperature of the extruder head (dark region in Fig. 6). The melt entering the extrusion device has the same temperature as the extruder head (368 K). The extruder head surface temperature is constant on the full length up to the die plate.

  

Fig. 3. Temperature distribution in a capillary die hole (ow is entering from the top, 1 mm hole diameter, 3 mm length).

The results for the temperature distribution are shown in Fig. 7 for both heat transfer coefcients of 50 (left) and 80 W/m2 K (right). The gure shows an axial cross section through the extrusion head, the melt region and the die plate. As can be seen, the temperature distribution especially in the die plate is very inhomogeneous. This is true for both heat transfer coefcients studied, but is more pronounced in the case of a =80 W/m2 K as expected. Clearly, the die plate is virtually insulated from the extrusion head by the melt channel. Consequently, heat ow to the conical distributor of the die is limited and this part is signicantly cooler. As the ow rate of the melt is relatively low (in our case 2 kg/h), the hot melt cannot heat the conical distributor. In the contrary, the melt is cooled to some extend at the inner surface of the channel. These results are in good agreement with experimental observations that showed signicantly lower temperatures at the center of the die plate (Tritthart, 2007, personal communication). The thermal situation also affects the ow in the melt channel, i.e., the velocity prole in the melt distributor. This is due to lower melt velocities at the cooler side of the channel, which is the consequence of the higher melt viscosity (results not shown). Also the pressure drop in the melt distributor was increased by 34% (!) as the heat transfer coefcient was changed from 50 to 80 W/m2 K. Hence, a small change in the external heat transfer to the surrounding air causes signicant variability in the melt ow, indicating the sensitivity of the process to environmental characteristics. Above mentioned computations are rather expensive, as the grid resolution in the uid region (the melt) must be ne to

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Fig. 4. Area in contact with the melt for the lab-scale planar extrusion head (left: view onto the outlet side; right: view in melt ow direction).

die hole

extrusion head melt channel

die plate

melt inflow from extruder

Fig. 5. Schematics of the die plate, the extruder head and the melt (isometric view).

capture the details of the temperature eld. Therefore, we have also tested what happens when we treat the melt as a static insulation layer. The extrusion head temperature for this situation was assumed to be constant on the outer side of the melt channel, which is in fairly good agreement with the fully coupled simulation (see Fig. 7). With these boundary conditions, we have calculated the temperature eld in the die plate only. In Fig. 8 we show the results for this simplied case. Clearly, we observe the same characteristics of the temperature distribution as in the fully coupled simulation. Due to the assumption of a constant extrusion head temperature the minimal temperature for the simplied case is 34 K higher. This is usually an acceptable deviation, as the uncertainty introduced by the assumed heat transfer coefcient is also signicant.

Fig. 6. Boundary conditions at the front side of the die plate, black: constant temperature (melt temperature), grey: convective heat transfer to the surrounding air.

3.3. Temperature distribution in a production-scale die In this chapter we focus on a new design of a HME device for use at the production scale. Specically, we are rst interested in the temperature distribution in such a device. Fig. 9

shows an exploded view of this new design consisting of a cylindrical die together with an inner rotor. This rotor has the function to create a pressure pulse that facilitates melt ow through the die holes (a detailed discussion on this is provided in the next chapter). As the investigations related to the lab-scale die showed that a homogenous die temperature is critical, we rst focused on the effect of heating channels in the die. These channels consist of axial bores in the die (see Fig. 9) which are thermo-regulated by means of liquid ow through the bores. The ow rate through the channels was designed such that the wall temperature of the axial bores can be assumed as constant. Consequently, the only factor that effects the die temperature is the number and arrangement of the channels in the die. In Fig. 10 temperature contour plots for two different arrangements of the heating channels are shown. It was

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extrusion head

melt

die plate

flow direction

flow direction

Fig. 7. Temperature distribution in the die plate and the extrusion head (coupled simulation; left: a = 50 W/m2 K, right: a = 80 W/m2 K, temperature contour lines are separated by 0.5 K).

Fig. 8. Temperature distribution for the simplied case (left: a = 50 W/m2 K, right: a = 80 W/m2 K, temperature contour lines are separated by 0.5 K).

melt discharge heating channels

rotor

melt inlet

cylindrical die

The calculations show that heating channels are necessary next to each row of die holes to allow a tight control of the temperature (Fig. 10, right). As can be seen from Fig. 10 (right) the lowest temperature in this case is located near the outlet of the melt. Here the die temperature has a local minimum that is about 1.5 K below the melt temperature. A more precise temperature control does not seem feasible due to limited manufacturability and the fact that the cylinder cannot be insulated to the surrounding air. If an insufcient number of heating channels is used and the end plate is not temperature controlled (Fig. 10, left), a signicant temperature gradient over the die exit is observed. This could lead to partial solidication as observed during the lab-scale experiments.

Fig. 9. 3D view of the cylindrical die with inner rotating knife.

3.4. Pressure distribution around an inner rotating knife The new cylindrical design for a HME device incorporates a rotating knife that aids melt ow through the die holes. This is realized by means of a pressure pulse that periodically increases the pressure in front of certain die holes. Consequently the ow

assumed that the rotor is in thermal contact with the cylindrical die. Hence, this can lead to an unwanted cooling of the melt, as can be seen in Fig. 10 (left).

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temperature-controlled end plate

cylindrical die rotor contact line

Fig. 10. Temperature distribution in the production-scale die with one heating channel per two die row (left) as well as one heating channel per die row and a temperature-controlled end plate (right). Rotor and cylindrical die have been assumed to be in thermal contact along the full contact line.

Fig. 12. Pressure variation versus angular position for different gap widths (2D simulation, 601 knife angle, 80 mm rotor diameter, 60 min 1).

Fig. 11. Geometry of the rotor, the knife and the cylindrical die for the 2D simulations.

Table 1 Geometrical parameters for the 2D simulations. Gap (distance knifecylinder) Knife angle Rotor diameter Stator diameter 13 mm 30901 8095 mm 100 mm

through these holes will be higher for a short period, thus spilling unwanted accumulations from the system. The rotor itself consists of a cylinder and multiple straight knives located on the perimeter of the cylinder, covering the full axial length. A two-dimensional sketch of the rotor geometry is provided in Fig. 11. To asses the impact of the rotors geometry, simulations have been conduced. Here the main focus was the pressure prole of the pulsating stream induced by the rotor. In the simulations the ow in slices perpendicular to the cylinder axis was analyzed. The

Fig. 13. Pressure variation versus angular position for different gap widths (2D simulation, 601 knife angle, 95 mm rotor diameter, 60 min 1).

geometrical parameters are summarized in Table 1. The boundary conditions were chosen to mimic a die that has a constant temperature. Because the simulations were conducted in 2D only,

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the effects of temperature build-up along the cylinder axis could not be investigated. Hence, the 2D simulations mimic a situation where only radial heat transfer can take place. The rotational speed was varied between 20 and 60 min 1. The rotor and stator diameter, the knife angle and the gap as well as the angular position relative to the knifes edge are shown in Fig. 11. Results for a knife angle of 601 are shown in Figs. 12 and 13 for two different rotor diameters. In these gures the pressure variation refers to the difference between the pressure at the inner shell of the cylindrical die and the mean pressure in the die. The four curves in Figs. 12 and 13 indicate four different rotorto-stator gaps. The angular position is relative to the knife edge in circumferential direction (see Fig. 11). As can be seen from Fig. 12, when the gap decreases, the pressure peak becomes more and more localized. Hence, only the die hole near the knife edge will

experience a short pressure variation while all others are nearly unaffected by the rotating knife. This is benecial, since the pellet size distribution will be more uniform in this case with only a few slightly larger particles. A simple analysis of the simulated pressure curve shows, that when the pressure varies as in Figs. 12 and 13, the maximal deviation from the mean pellet diameter is 73% for all gap sizes investigated. In case the inner rotor diameter is increased while all other geometrical parameters are held constant, this situation changes. As can be seen from Fig. 13 the shape of the pressure prole changes to a more at one. This is because the height of the rotor knife relative to the rotor-to-stator gap is decreasing with an increasing rotor inner diameter. In this situation there will be no sharp pressure peak and all die holes on the perimeter will be inuenced by the rotating knife. In addition, for the cases of a

Fig. 14. Temperature (left, with streamlines) and pressure (right) distribution near the knife (2D simulation, 601 knife angle, 80 mm rotor diameter, 0.75 mm knife gap, 60 min 1).

Fig. 15. Temperature (left, with streamlines) and pressure (right) distribution near the knife (2D simulation, 601 knife angle, 95 mm rotor diameter, top: 1 mm knife gap, bottom: 1.75 mm knife gap, 60 min 1).

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rotor-to-stator gap of 1.5 and 1.75 mm and a rotor diameter of 95 mm, we observe that the pressure is negative in front and behind the blade (see Fig. 13). This is because in both cases, the high pressure zone is localized near the knife edge and the zone near the cylindrical die is nearly unaffected by the knifes movement (see Fig. 15). The pressure build-up in circumferential direction is very small and the maximum (positive) pressure is observed between two consecutive knifes at the perimeter (i.e., at an angular position of 901 in case of two knifes, data not shown). This peculiar behavior is caused by the extremely small height of the rotor knife relative to the rotor-to-stator gap. In Figs. 14 and 15 we compare the temperature and pressure distribution in the two-dimensional plane for different rotor diameters and knife gaps. In addition, we show the effect of the rotor-to-stator gap on the ow eld in Fig. 15. As can be seen in all of these gures, the maximal melt temperature is about 30 K above the wall temperature. Also in the case of a larger rotor diameter, i.e., 95 mm, the temperature rise is signicant and above 20 K. Hence a signicant amount of heat is generated at the relevant rotational speed, which cannot be removed with the proposed rotor diameters. In Fig. 14 it can be seen that if the gap is sufciently small, a local pressure peak is built up in the vicinity of the knife. However, for a given gap size this localized pressure peak vanishes if the rotor diameter is increased, while the overall pressure drop over the knife is similar to the case of a smaller rotor diameter (compare Figs. 14 and 15). Furthermore, if we increase the rotor-to-stator gap (see Fig. 15), the ow pattern changes and the recirculation zone near the knife edge is no longer observed. Thus, the melt ow is relatively unaffected by the knife and is not pushed against the cylindrical die. Such an arrangement causes a very localized pressure near the knife edge but not at the cylindrical die. Hence, excessively large rotor-tostator gaps are ineffective for the generation of the desired pressure pulse.

3.5. 3D simulation results The results of the two-dimensional simulations showed that a knife angle of 601 and a rotor-to-stator gap smaller than 1 mm is necessary to create the desired pressure peak needed to remove plugs from the die hole and to ensure smooth and continuous operation. However, to assess the temperature distribution of the melt in axial direction, full three-dimensional simulations are necessary. The parameters for these 3D simulations are summarized in Table 2. As an additional parameter for the geometry of the internal rotor, the pitch p of a helically-shaped knife has been studied. The pitch is the axial distance of a (hypothetical) point traveled during a single revolution of a helix. p is inversely proportional to the angle f between the axis of the cylindrical device and the knife edge. The relationship between pitch and the axis-knife-edge angle is cotf p

pD

12

Table 2 Geometrical parameters for the 3D simulations. Gap (distance knifecylinder) Knife angle Die diameter Pitch mm 1 mm 30 1C 45100 mm 1000 to + 3000 mm

where D is the outer knife edge diameter. The boundary conditions for the 3D simulations consist of a uniform pressure and temperature at the melt inlet. The velocity gradient has been set to zero at the inlet. While the melt ow has been specied to be normal to the cylindrical outlet surface, the velocities in tangential and axial direction at this surface have been set to zero. At all other surfaces the no-slip boundary condition has been applied. This is supported by our experimental results that showed generally smooth surfaces of the product, that indicate that a stick-slip transition has not occurred in the die. Also, uniform wall temperatures have been used in the simulations. The results for a rotor speed of 60 min 1 are shown in Fig. 16 for a straight knife. As can be seen, the velocity vectors of the melt (Fig. 16, left) are essentially perpendicular to the knife, i.e., the main ow consists of a circular motion. This is because the mean ow velocity in axial direction is very slow. Only at the inlet of the melt, where a uniform pressure boundary condition has been used in the simulation, the local pressure before the knife leads to an outow. At the backside of the knife melt is locally sucked into the extrusion device. The temperature distribution (Fig. 16, middle) shows a signicant temperature gradient in axial direction. The maximal

Fig. 16. Results for straight knife at 60 rpm (left: velocity vectors and pressure contour, middle: temperature, right: pressure).

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temperature is more than 10 K below the prediction of the twodimensional simulation (see Fig. 15). However, the temperature heterogeneities inside the device are still signicant and would lead to considerable differences of melt outlet velocity. Also, the temperature maximum is now closer to the wall compared with the two-dimensional case. This is because there is an additional convective energy transport in radial direction that was not included in the 2D simulation. Furthermore, the pressure distribution (see Fig. 16, right) indicates that the pressure loss in axial direction is negligible. In the vicinity of the knife we observe that the local pressure maximum is becoming smaller in axial direction. This is due to the change in melt viscosity as a consequence of the increasing temperature. Thus, the higher temperature leads to a lower melt viscosity and a lower pressure build up near the knife edge. Furthermore, the ow and temperature distribution has been investigated at a lower rotor speed of 20 min 1 for a pitched knife (Fig. 17). The results show that the temperature difference over the full length for this situation is about 11 K. As can be seen from Fig. 17 (right), this has the positive effect of a more uniform distribution of the pressure maximum in front of the knife. Interestingly, the pressure maximum is nearly the same as for a rotor speed of 60 min 1. The inuence of the knife pitch has been investigated for the case of a rotor speed of 20 min 1. However, the simulations showed that the differences in general are small. The only observation that can be made is that for the smallest pitch (Fig. 17) the peak pressure is more uniform along the axis. The disadvantage in this case is the increasing in- and outow at the melt inlet that may lead to an unwanted oscillatory uid motion in the inlet channel upstream of the extrusion device. The power drawn by the melt and the torque needed to turn the rotor have been investigated as a function of rotor speed and pitch. As can be seen from Table 3 the differences in the torque requirements between the two rotor speeds are small, i.e., a lower rotor speed does not decrease the torque accordingly. This is due to the shear-thinning behavior of the melt. The inuence of the pitch is small ( o5%) for a rotor speed of 20 min 1 and higher ( o50%) for 60 min 1 because axial pumping increases with rotor speed. An alternative design of the rotor has been studied with a smaller diameter of 60 mm and a rotor speed of 120 min 1 (see Fig. 18). The main idea for this design is to mount the rotor

directly to the extruder, i.e., the rotor does not necessarily need a separate drive. To keep the throughput identical to the large stator diameter of 100 mm, the cylindrical die has to be designed longer. The results show that under this conditions the melt is heated signicantly (about 20 K), which is unacceptable to guarantee a uniform temperature along the cylinder axis. The results for a stator diameter of 45 mm are shown in Fig. 19. The torque requirement for this setup was 45 Nm, the power demand is 565 W. Also for this design heat-up of the melt is signicant (18 K) along the axis. Hence, it is not possible to mount the rotor directly to the extruder, even if the diameter of the cylinder is reduced.

4. Discussion Pelletization via hot melt extrusion has a signicant potential for becoming one of the primary production process for solid dosage forms. However, the process scale-up (in addition to challenges like cleaning in place, CIP) is one of the most important problems that impedes a breakthrough of this technology. Within this work the importance of a proper temperature control of extrusion dies has been highlighted. It could be shown that in the lab-scale setup the low thermal conductivity of the melt as well as the heat transfer from the die plate lead to an undesired thermal situation. This can lead to a partial solidication of the melt which may result in an unstable ow through individual die holes. Observations during lab-scale tests supported this speculation. Furthermore, the temperature
Table 3 Torque requirements for 100 mm stator diameter. Case 60 rpm, 60 rpm, 60 rpm, 60 rpm, 60 rpm, 20 rpm, 20 rpm, 20 rpm, 20 rpm, 20 rpm, straight pitch+ 1000 mm pitch+ 2000 mm pitch+ 3000 mm pitch 3000 mm straight pitch+ 1000 mm pitch+ 2000 mm pitch+ 3000 mm pitch 3000 mm Power demand (W) 499 631 593 594 730 202 195 198 198 204 Torque (Nm) 79 100 94 95 116 96 93 95 95 97

Fig. 17. Results for pitched knife (p = +1000 mm) at 20 rpm (left: velocity vectors and pressure contour, middle: temperature, right: pressure).

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Fig. 18. Temperature distribution for straight knife at 120 rpm (60 mm stator diameter, left: 1 mm gap, right: 2 mm gap).

Fig. 19. Temperature distribution for straight knife at 120 rpm (45 mm stator diameter, 1 mm gap).

dr ds D Ea Ek g h l ~ n p p q Q R Re Ro t T T0 ~ u U

rotor diameter, m stator diameter, m parameter of the Carreau viscosity model activation energy, J/mol Ekmann number radial gap, m specic enthalpy, J/kg length, m unit normal vector, m pressure, Pa pitch, m heat ux, W/m2 volumetric ow rate, m3/s gas constant, J/mol K Reynolds number Rossby number time, s temperature, K reference temperature, K velocity vector, m/s reference velocity, m/s

Greek letters distribution in the die material might become even worse during scale-up. This is a critical point, since melt rheology is very sensitive to temperature changes. The investigation of the concept of a cylindrical die has shown that this design is a feasible option for increasing the throughput for highly viscous HME formulations. An inner rotating knife can be used as a pulsating device for improving melt ow and consequently for increasing process stability. However, there are some limitations. Viscous dissipation heats up the melt along the axis of the cylinder. This can have the effect of worsening the melt distribution among the die holes. Hence, the rotor speed has to be decoupled from the speed of the extruder. Second, a proper stator diameter has to be chosen. This decision is mainly inuenced by considerations on the manufacturability of the die.

a a
b
_ g

m m0 minf r t tw
f
~ O

knife angle heat transfer coefcient, W/m2 K angular position shear rate, s 1 heat conductivity, W/m K viscosity, Pa s viscosity at zero shear rate, Pa s viscosity at innite shear rate, Pa s density, kg/m3 stress tensor, Pa wall shear stress, Pa angle between the axis of the cylindrical device and the knife edge angular velocity vector, s 1

Notation aT B cp C d parameter of the Carreau viscosity model parameter of the Carreau viscosity model, s specic heat capacity, J/kg K parameter of the Carreau viscosity model diameter, m Acknowledgments JGK acknowledges partial funding of this work through the EU Marie Curie Chair program MEXC-CT-2004-006767. Furthermore, we acknowledge the nancial support by mnadis Melt Extrusion Technologies.

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1988 S. Radl et al. / Chemical Engineering Science 65 (2010) 19761988

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