AN EXPERIMENTAL INVESTIGATION OF TEMPERATURE RISE DURING COMPACTION OF PHARMACEUTICAL POWDERS

Alexander Krok1, Andreja Mirtic2, Gavin K. Reynolds2, Serena Schiano1, Ron Roberts2, Chuan-Yu Wu1

1 Department of Chemical and Process Engineering, University of Surrey, Guildford, GU2 7XH, UK 2 Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire, SK10 2NA, UK

Email: a.krok@surrey.ac.uk, c.y.wu@surrey.ac.uk

AbstractDuring pharmaceutical powder compaction, temperature rise in the compressed

powder can affect physiochemical properties of the powder, such as thermal degradation and change in crystallinity. Thus, it is of practical importance to understand the effect of process conditions and material properties on the thermal response of pharmaceutical formulations during compaction. The aim of this study was to examine the temperature rise of pharmaceutical powders during tableting, in particular, to explore how the temperature rise depends on material properties, compression speed and tablet shape. Three grades of microcrystalline cellulose (MCC) were considered: MCC Avicel PH 101, MCC Avicel PH 102 and MCC DG. These powders were compressed using a compaction simulator at various compaction speeds (10 - 500 mm/s). Flat faced, shallow convex and normal convex tablets were produced and temperature distributions on the surface of theses tablets upon ejection were examined using an infrared thermoviewer. It was found that an increase in the compaction speed led to an increase in the average surface temperature. A higher surface temperature was induced when the powder was compressed into a tablet with larger surface curvature. This was primarily due to the increasing degree of powder deformation (i.e. the volume reduction) and the effect of interparticule/wall friction.

KeywordsThermomechanical analysis, Temperature rise, Powder compaction, Tabletting, Microcrystalline cellulose

1. IntroductionPowder compaction is one of the commonly used manufacturing methods in the pharmaceutical industry to produce tablets. It is recognised that, during powder compaction, some mechanical work is converted into heat due to inelastic deformation, particle-particle and particle-wall friction, while part of the generated heat can be quickly dissipated to the surroundings.

Previous studies focused on the understanding of the compaction process in terms of mechanical energy and the heat evolution during the compression of a powder. For instance, Wurster et al. (1995) and Rowlings et al. (1995) quantified the heat generated during compaction for three pharmaceutical powders (Avicel PH 101, anhydrous lactose and Starch 1500). In their study, a hydraulic laboratory press was used. The diameter of the die was 31.75 mm, the compression pressure was approximately 27 MPa, and the time for compaction was 40 s. The weight of the sample was 5 g for each experiment. Two different temperature sensors (tungsten wire sensor and thermistors) were used to determine the temperature rise in the powder. Moreover, with known specific heat capacity of the compacted material and specific heat capacity of the die; the heat that may be generated during the process was calculated. They also designed a control system to allow the

measuring of the force and the temperature of the compacted powders simultaneously. Additionally, greater increases in temperature and better response of measured signal was observed for the sensor positioned in the compacted material. For Avicel PH 101, it was observed that the temperature rose 5.1°C; for anhydrous lactose it was 3.04°C and for Starch 1500 about 2.13°C. It was then concluded that the negative change in internal energy is related to the formation of interparticle bonding in the powder during the process. Overall the net exothermic heat observed with Avicel PH 101 was -19.50 J/g, anhydrous lactose - 9.63 J/g and Starch 1500 -7.20 J/g.

Thermodynamic properties such as heat, work, or internal energy of the powders during compaction was characterised by Decrosta et al. (2000). Powders (Acetaminophen, Avicel PH 102, Emcompress, Fast Flo Lactose and Starch 1500) were compacted using an instrumented single-station tablet machine. Maximum compaction force was up to 50 kN. The compaction speed for both compression and unloading was 6.7 mm/s for the upper punch and 4.2 mm/s for the lower punch. The speed of ejection was 200 mm/s. The compaction calorimeter was comprised of an aluminum die contained within an acetal resin thermoplastic die and fiberglass flat-faced punches. A thermistor probe was glued with a thermally conductive silver epoxy and drilled in the outside of the die. Additionally, Differential Scanning Calorimetry was employed to determine the specific heat capacity for compacted materials. The compaction work was found to increase more for the plastic materials (Avicel PH 102 and Starch 1500) than for the brittle materials (Emcompress and lactose). Nevertheless, Avicel PH 102 forms more and stronger bonds than lactose and starch. In the case of acetaminophen, which is elastic in nature, it does not allow significant punch penetration compared to the other materials, which is indicative of the lack of strong and numerous bonds. It was believed that the heat generated during compaction is the result of the bonds formed from the applied compaction work, and the compaction is an exothermic process due to bonding, which agrees with previous studies (Wurster et al. (1995) and Rowlings et al. (1995)).

The net heat generated will lead to temperature rise in the compressed powders, which can affect mechanical properties of the powder and have a detrimental effect on pharmaceutical formulations, such as thermal degradation and change in crystallinity. For instance, most of the pharmaceutical and biological powders are very sensitive to temperature as the mobility of the atoms or ions is prone to increase with increasing temperature. Consequently, the increase in temperature can alter the microstructure, mechanical properties and quality of the produced tablets. Roue`che, Serris, Thomas and Périer-Camby (2006) examined the influence of the temperature on the compressibility of an organic powder and showed that, when the temperature increased from 20°C to 80˚C, the tensile strength of the tablets increased significantly even though the porosities of the tablets remained essentially constant, implying that the temperature had a significant impact on the bonding strength of the materials. Cespi, Bonacucina, Casettari and Ronchi (2013) explored the thermomechanical behaviour of both inorganic (dicalcium phosphate dihydrate) and organic (microcrystalline cellulose, ammonia methacrylate copolymer type B and polyethylene oxide) powders using a dynamic mechanical analyser, and found that in the temperature range 20°C ~ 150ºC, the temperature rise significantly affected the storage modulus (which determines the material stiffness) and the tangent of the phase angle (heat transfer during phase transformation) of the organic powders, but had a little effect on thermal transition of the inorganic powder (i.e. dicalcium phosphate).

Both material properties of pharmaceutical formulations and process conditions play an important role in heat generation and subsequent temperature rise. Travers and Merriman (1970) investigated the change in temperature of three different materials (asagran, boric acid and sodium chloride) during compaction using a hydraulic press equipped with a specially modified die in which an embedded thermocouple was fitted. The evolution of the temperature during compression and decompression was measured. It was found that the final temperature of the tablets depended on the material: at a maximum compression pressure of 49 MPa, the temperature change for sodium chloride, asagran and boric acid were 3°C, 7ºC and 10ºC, respectively. This was attributed to the difference in thermal diffusivity and elastic properties of materials. For sodium chloride, a more pronounced decrease in temperature was observed during decompression, when compared with other two materials, because it had a higher thermal diffusivity and a higher Young’s modulus. They also explored the effect of compression pressure on the temperature rise during compaction and found that the increase in temperature was directly proportional to the maximum compression pressure. This was consistent with the experimental observation of Hanus and King (1968) who compacted sodium chloride and calcium carbonate using a Stokes model E flat face single punch tablet machine at speeds from 25 tablet/min. to 140 tablet/min. Bechard and Down (1992) investigated the compression of a binary mixture of MCC Avicel PH 102 and spray-dried lactose using a Korsh PH 106 rotary tablet press at maximum compression forces of 7, 10, 15 and 20 kN, The temperature of the tablets was measured using an infrared (IR) camera. Their results showed that the final temperature of the tablets increased linearly with the compression force. The effect of compression pressure on the change in temperature was also examined by Katolinen, Ilkka and Paronen (1993), who measured the surface temperature of the tablet after ejection using an infrared (IR) camera. They also showed that more significant temperature rise was induced as the maximum compression pressure increased.

In addition, the effect of compression speed on the temperature rise during compaction has also been explored. Using a thermochromic indicator, Hanus et al. (1968) showed that when the compression rate was 25 tablets/min, the temperature increase was approximately 16.27ºC for calcium carbonate and 2.69ºC for sodium chloride. An increase in the compaction rate to 140 tablets/min resulted in a more significant temperature increase for both materials: for calcium carbonate, the temperature rise was increased to 22.2ºC, while for sodium chloride to 7ºC. They also showed that, at low speeds (say <60 tablet/min), the temperature rise was linearly proportional to the compaction rate; at a very high speed of compaction (say, when more than 140 tablets per minute were produced), the temperature increase became insensitive to the compaction speed. This result indicates that at the high compression speed a limiting value of temperature increase was approached. A hydraulic compaction simulator was used to investigate the effect of compression speed on the change in surface temperature by Zavaliangos, Galen, Cunningham and Winstead (2007), in which MCC Avicel PH 102 was considered and the applied compression speeds were 120 mm/s and 960 mm/s. The surface temperature was measured using an IR camera. It was observed that the surface temperature of the tablets increased from 38ºC to 42ºC as the compression speed increased from 120 mm/s to 960 mm/s. On the contrary, when compressing a binary mixture of MCC Avicel PH 102 and spray-dried lactose at a ratio of 35:65 in weight at different compression speed between 20 rpm and 60 rpm, Bechard and Down, (1992) found that the temperature rise was not affected by the compression speed and the final temperature of compressed tablets fluctuated at 33 ± 1 °C for various compression speeds considered.

Krok et al. (2016) performed a finite element analysis of the thermomechanical behaviour of powders during tableting. They explored the effects of punch shape, compression speed and die wall friction on thermo-mechanical behaviour of powder during compaction. All three stages of compaction process (i.e. compression, decompression and ejection) were modelled, with all the tablets having a diameter of 8 mm and the powder had an initial maximum height of 6 mm. Moreover, the thickness of the final tablets was kept at 2 mm. MCC Avicel PH 102 was used as the model material with the same properties as was reported in Krok et al. (2014). DPC parameters as well as the thermal properties were hence determined as a function of the relative density and implemented into FEM model. To examine the impact of compression speed on the temperature rise, the compression speeds of 12 mm/s; 120 mm/s and 950 mm/s were used. It was shown that as the compression speed increases, the amount of irreversible work increases and consequently a higher temperature is induced. The coefficient of wall friction was chosen in range of 0.1-0.5. When the die wall friction coefficient increases, higher shear stress at the powder-tooling interface were induced, as a result, a higher temperature was induced. The temperature distributions inside of the flat-face (FF); shallow convex (SC) and standard convex (STC) tablets were also investigated. When the radius of the surface curvature decreases (FF>SC>STC), overall degree of powder deformation increases. Consequently, inducing the highest temperatures.

It is clear that the thermal response of the pharmaceutical formulations depends on their physiochemical properties and process conditions. Due to the diversity in formulations and processes involved in pharmaceutical development and manufacturing, the thermomechanical behaviour is not well understood. Although previous studies showed that the compression pressure and compression speed could affect the thermomechanical behaviour of heat-sensitive materials during compaction, in most of these studies powders were compressed using the upper punch only (i.e. single ended compression) into flat-faced tablets. In practical tableting processes, powders were normally compressed with the double-ended compression and convex tablets were commonly manufactured. Furthermore, little attention has been paid on whether the temperature distribution on the surface of the tablet is uniform and whether it is affected by the tablet shape. Such knowledge will be of significant value in formulation and process optimisation in order to produce high quality tablets and avoid thermal degradation.

Therefore, the aim of this study was to systematically examine the influence of the compaction speed and tablet shape on the thermomechanical behaviour of pharmaceutical powders during tableting processes. For this purpose, a wide range of compression speeds (from 10 mm /s to 500 mm/s) were used to mimic the compression speed commonly used in practical tablet manufacturing in the pharmaceutical industries. In addition, the temperature changes during manufacturing of various shaped tablets using different materials were also investigated.

2. Materials and methods2.1 MaterialsThree different grades of microcrystalline cellulose (MCC) were used: Avicel PH 101, Avicel PH 102 and Avicel DG (FMC Biopolymer Corporation, USA). MCC DG is composed of 75% MCC and 25% anhydrous calcium phosphate, while MCC PH 101 and 102 are pure microcrystalline cellulose (Rowe, 2009). The true density was measured using a Helium

Pycnometer (AccuPyc II 1340, Micromeritics, UK), while the bulk density was characterised using the graduated cylinder method (World Health Organization, 2012). A particle size analyser (Camsizer XT, Retsch, Germany) was used for particle size characterization of all the materials.

2.2 Powder compactionThe tableting process was performed using a fully instrumented compaction simulator

(ESH, UK) and an analytical balance (METTLER AT 261 DeltaRange, Switzerland) was used to measure the amount of powder used for each compaction experiment as well the weight of tablet. A cylindrical die with a diameter 10 ± 0.01 mm was used. The powder was manually fed into the die before compaction. The diametrical compression test was performed using a tablet hardness tester (Model 8M Bench Top, UK) to measure the breaking force. Equations proposed by Shang. Sinka. Jayraman and Pan (2013) were used to calculate the tensile strength of flat face and convex face tablets.

All compaction experiments were performed using the double-ended compression profile and the corresponding evolutions of the displacements of the upper and lower punches are illustrated in Fig. 1. During compression, the upper punch and the lower punch move towards each other at the same specified speed. During unloading, the upper punch withdraws at the same speed as the compression one while the lower punch stays stationary. During ejection, the lower and upper punches move upward simultaneously. Four different compaction speeds (10 mm/s, 100 mm/s, 300 mm/s and 500 mm/s) were used, and the tablets were compressed into three different shapes: flat face (FF), shallow convex (SC) and normal convex (NC). In this study, the die tool constructed by PharmaGrade Steels (HPG-S) was lubricated with 5% magnesium stearate suspended in acetone and allowed to dry for 2 minutes.

Fig. 1 The double ended compression profile showing the displacements of the upper and lower punches used for the compaction experiments

All powders of MCC used in this study (Avicel PH 101, Avicel PH 102 and Avicel DG) were compressed at various compaction speeds into FF, SC and NC tablets with a

thickness of 3.3 ± 0.01 mm and diameter of 9.9 ± 0.01 mm. Despite the fact, the final relative density of the FF tablets for all of the used materials with various compaction speeds were 0.8 ± 0.05.

The punch depth of SC tablet was 0.776 mm and radius 16.5 mm, while the punch depth of NC tablet was 1.144 mm and radius 11.5mm. In order to ensure the same thickness and diameter for the FF, SC and NC tablets, the amount of MCC powders for these tablets was changed, since the punch separation for tablets with altered curvatures was different. For FF, SC and NC tablets, the weights of all MCC powders are present in Tab. 1. As a result, the relative densities of the final tablets for all used materials were 0.620 for SC and 0.52 for NC.

Table 1 The weights of all MCC powders used for tableting process

Sample Mass (g) FF SC NC

MCC Avicel PH 102 0.325 ± 0.002 0.251 ± 0.009 0.232 ± 0.001MCC Avicel PH 101 0.326 ± 0.002 0.257 ± 0.009 0.234 ± 0.01

MCC Avicel DG 0.367 ± 0.0013 0.279 ± 0.001 0.271 ± 0.002

2.3 Temperature measurements and analysisA portable infrared camera (OPTRIS PI450, Optris GmbH, Germany) was used for

measuring surface temperatures of the tablets after ejection, and the parameters of the calibrated camera were 382×288 pixels, frame rate: 80 Hz, optics: 62° × 49°/ f = 8 mm and thermal sensitivity: 0.04°C. During the experiments, the IR camera was placed approximately 20 cm away from the compression chamber. The Optris PI Connect software was used for data analysis. All experiments were conducted at an ambient temperature of 23.2 ± 1.4°C and repeated three times.

3. Results 3.1 Material properties

The material properties of the three different grades of microcrystalline cellulose are presented in Table. 2. The bulk densities and the true densities of MCC Avicel PH 101 and Avicel MCC 102 are similar, but their particle sizes are different. MCC Avicel DG is a mixture of microcrystalline cellulose and anhydrous calcium phosphate, and has a larger bulk density and true density compared to MCC Avicel PH 102 and Avicel MCC 101, but it has the smallest particle size among three powders considered.

Table 2 Properties of the different grades of microcrystalline cellulose considered

Avicel PH 101 Avicel PH 102 Avicel DGParticle size d10 (m) 29.73 ± 0.50 33.63 ± 0.45 24.60 ± 0.47Particle size d50 (m) 59.83 ± 1.21 94.67 ± 3.30 52.30 ± 1.27

Particle size d90 (m) 105.50 ± 0.56 185.33 ± 0.04 126.73 ± 5.06Bulk density ρb (kg/m3) 331.00 335.00 399.00

True density ρt (kg/m3) 1,581.00 1,570.30 1,785.60

3.2 Compactor simulatorThe compression can cause deformation of the particles, breach the contact bond and

give rise to relative movement of the contact surfaces, where particles are irreversibly shifting with reduced porosity. The structure of the substance varies and is a function of applied stress that characterizes the intensity of structural changes. Work, for a tablet press, is mechanical energy that is derived from force and displacement measurements. When considering the typ-ical force versus displacement curve (see Fig. 2) as presented in previous studies (DeCrosta et al. 2000; Antikainen & Yliruusi, 2003; Pawar et al. 2016), the compressive work (CW) is the area under the trace region (ABD). When the stress versus displacement plot is reduced to the region between the peak load and the load near zero, the recovery work (RW) during decompression is the area under the trace (CBD). It is known (Ragnarsson, 1985; Molan & Celik, 1996; Vachon et al., 1999; Nokhodchi, 2005) that the compressive work (Fig. 2a) represents the sum of recovery work and net work (NW), whereas the net work for the com-paction process represents apparent work, which is required to form the compact and to over-come the wall friction (Eriksson et. al., 1995, Takeuchi et al. 2004). In addition, the mag-nitude of the net work is related to the deformation properties of the material and to their binding properties. On the other hand, recovery work as an elastic energy is recovered from the material on decompression and ejection.

a) b)Fig. 2 Force-displacement plot illustrating a) the net work and recovery work; b) the friction

work

In terms of energy quantification of the tableting process, the parameters referred as a plasticity ratio and friction work (Kása et al. 2009; Sovány et al. 2013; Kelemen et al. 2015) are used. The plasticity ratio defined by Stamm and Mathis (1976) is equal to the net work (NW) divided by the compressive work (CW). Moreover, the ratio NW/CW indicates how much of energy input is utilized in irreversible deformation of the material. NW/CW can be calculated by Eq. 1. The movement of the upper and lower punch may also be considered to calculate friction work (Fig. 2b), while Eq. 2 was derived by Järvinen and Juslin (1981).

NWCW =

∫UAUC Fupper dU

∫U A

U D FupperdU(1)

FW=∫U A

U D {Fupper−[ Fupper−F lowerln( FupperF lower ) ]}(2)

In this study, compressive work, recovery work and net work were collected from Profile Builder software (Phoenix Calibration, UK) which is one of the applications for the analysis of data from the compaction simulator (ESH, UK). The tensile strength (2.96 ± 0.06 MPa) of a FF tablet with different compaction speeds only slightly varied. It was observed that, as the compaction speed increases, the total compression work needed to deform a ma-terial has been more recovered during the decompression phase and the net work as well the ratio of NW/CW decreased. In particular, it can be seen in Fig. 3a that for the compression speed 10 mm/s, almost 83% of total mechanical work was used to compress the powder into tablets, while for compression speed 500 mm/s it was approximately 24%. Furthermore, it is shown in Fig. 3b, that friction work increased with the compaction speed. The tensile strength of SC tablet was 5.13 MPa and for NC it was 6.62 MPa. Moreover, in the context of the mechanical energy, which was applied on the tablets of various shapes, it was examined that with reducing the curvature of tablets, the friction work increased as well (Fig. 4b).

a) b)

Fig. 3 Evolution of a) NW/CW ratio and b) FW versus the compression speed for FF tablet made of MCC Avicel PH 102

a) b)

Fig. 4 The evolution of a) NW/CW ratio and b) FW versus the various tablet shape made of MCC Avicel PH 102 with compaction speed 100 mm/s

3.3 Effect of compaction speed

The distribution of temperature on the surface of the ejected FF tablets, compressed with MCC PH 102 at various compaction speeds were shown in Fig. 5. It can be seen that both the temperature on the sides of the tablets and on the upper surface increased with the increasing compression speed. In particular, the highest surface temperature was 33.5°C when the powder was compressed at a speed of 10 mm/s, and increased to 41.5 °C when a compression speed of 500 mm/s was used. It is also apparent that the surface temperature dis-tribution is not uniform. The corresponding temperature profiles on the upper surface are shown in Fig 6. On the x-axis, the value x/R = 0 represents the centre of the upper surface, and the value of x/R = 1 represents the edge of the upper surface. It is clear from Fig. 6 that as the compression speed increases, the temperature on the upper surface of the tablets gener-ally increases. In addition, for all compression speeds considered, the highest surface temper-ature was obtained at the centre of the FF tablet (x/R = 0), and this surface temperature mono-tonically decreases towards the edge, i.e. the temperature at the edge of tablet (x/R = 1) is generally lower than that in the centre (x/R = 0).

a) b)

c) d)

Fig. 5 The temperature distributions (measured using the IR camera) on the surfaces of the FF tablets made of MCC Avicel PH 102 at various compression speeds: a) 10 mm/s; b) 100 mm/s; c) 300 mm/s;

d) 500 mm/s.

Fig. 6 Temperature profiles of MCC Avicel PH 102 on the top surface of the FF tablets produced at compaction speeds of 10, 100, 300 and 500 mm/s

Fig. 7 shows the corresponding temperature profiles on the side of the FF tablets produced at different compression speeds. The value of x/δ = 0 on the x-axis represents the bottom edge of the tablet, and the value of x/δ = 1 represents the top edge of the tablet. It can be seen that the surface temperature increases with the increasing compression speed, similar to the surface temperature on the top surface as shown in Fig.6. This is in broad agreement with experimental observations of many others (Hanus et. al., 1968; Bechard et. al., 1992 and Zavaliangos et. al., 2007). Fig. 7 also shows that the temperature near the bottom edge is generally lower than that at the top edge for all compression speeds considered.

Fig. 7 Temperature profile on the side of the FF tablets produced with MCC Avicel PH 102 at compression speeds of 10, 100, 300 and 500 mm/s

Fig. 8 Temperature variations at the top and side of the tablets produced at various compression speeds

It was observed that the temperatures were not uniformly distributed. The temperature variations (the difference between highest and lowest temperatures) at the top and side of the tablets were presented in Fig. 8. It can be seen that this temperature variation at the top surface of the tablets was reduced with the increasing compression speed. Similarly, it was observed that there was temperature variation on the side of the tablets. The compression speed also had some impact on temperature variations on the side: at a compression speed of 10 mm/s, the side temperature variation was ca. 1.5°C, it creased to 5°C when the compression speed is increased to 500 mm/s.

3.4 Effect of tablet shape Immediately after ejection, infrared images of the temperature distribution on the top

surface and sides of the FF, SC and NC tablets were captured using the IR camera, as shown in Fig. 9. It can be seen that the maximum surface temperature increases as the surface curvature of the tablet increases, i.e. the maximum surface temperature of the NC tablets is the highest (40.4oC), while that of the FF tablet is the lowest (i.e. 34.0oC). These data were further analysed to explore the influence of the tablet shape on the temperature distributions as shown in Figs 10 and 11.

a) b) c)

Fig. 9 Temperature distributions recorded with an IR camera for MCC Avicel PH 102 on the surfaces of a) FF; b) SC; c) NC tablets immediately after ejection at a compression speed of 100 mm/s

Fig. 10 shows the temperature profiles of the top surfaces of different shaped tablets. It can be seen that the highest temperature was obtained in the centre of the upper surface for

the FF tablets, while for SC and NC tablets the highest temperature was reached near the edge. The corresponding temperature profiles on the sides of tablets are shown in Fig. 11. It was found that the temperature on the wall increases in the order of FF<SC<NC. As the tablet surface curvature increases and the punch separation is reduced, then a higher temperature on the side is induced. Figure 11 also indicates that a higher temperature on the top edge (x / δ = 1) is induced, compared to the bottom edge (x / δ = 0).

Fig. 10 Temperature profile on the upper surface of FF, SC and NC tablets at a compression speed of 100 mm/s

Fig. 11 Temperature profiles on the sides of FF, SC and NC tablets at a compression speed of 100 mm/s

Fig. 12 Temperature differences at the bottom and the upper edge of FF, SC and NC tablet for compression speed 100 mm/s

It was also found that tablet surface curvature affected the temperature variation on the top surface and on the side of the tablets, as shown in Fig.12. For the FF tablet, the temperature variations on both surfaces were the highest, and the temperature variations decreased as the surface curvature increased.

3.5 Effect of material propertiesThe plasticity ratio NC/CW varied with the compression speed for all MCC powders (Avicel PH 102; Avicel PH 101 and Avicel DG) that have been compressed into tablets of various shapes and are presented in Fig. 13. It was observed that NC/CW decreases for all forms of the tablets with increasing compression speeds. Furthermore, a linear trend was observed with the NC/CW for MCC Avicel DG with increase compression speeds for FF tablets compared to SC or NC tablets, where the trend of NC/CW for MCC Avicel DG was essentially exponential.

a) b)

c)

Fig. 13 NW/CW via compression speed for a) FF; b) SC and c) NC tablets made of different powders

The evolution of friction work at various compression speeds for FF, SC and NC tablets made of different MCC powders used in this study are shown in Fig. 14. It was observed that the work to overcome the wall friction was growing with the increase in compression speed in all of these cases. Further, the greater values of friction work for MCC Avicel PH 102 were achieved at the lower compression speeds (from 10-100 mm/s), whereas at the higher speed (from 300 – 500 mm/s) only MCC Avicel DG reached the higher values of friction work.

a) b)

c)

Fig. 14 FW via compression speed for a) FF; b) SC and c) NC tablets made of different powders

The temperature at the top centre of the FF, SC and NC tablets made of three different materials (MCC Avicel PH 101, MCC Avicel PH 102 and MCC Avicel PH DG) at various compression speeds immediately after ejection are shown in Fig. 15. For all MCC powders used in this study, the temperature increases with the compression speed for various tablet shapes considered. It can also be observed that for tablets of different shapes, the temperatures at the top centre of the MCC Avicel DG tables are the highest.

a)

b)

c)

Fig. 15 Temperatures at the top centre of: a) FF, b) SC, and c) NC tablets made of different powders

4. Discussion

When pharmaceutical powders are compressed in a die, total mechanical work generated by the punches during compression represents the total energy applied to the system, which is the sum of the recovered work during decompression, the energy used to deform the compact (Ragnarsson et. al., 1985), the energy dissipated and converted into heat. Heat in the compressed material is generated primarily due to 1) irreversible particle deformation, 2) interparticle friction and 3) die-wall friction. The generation of heat due to interparticle friction and particle deformation mainly takes place during compression (Hanus et. al., 1968; Travers et. al., 1970; Fuhrer et. al., 1977; Cespi et. al., 2013; Zavaliangos, 2007) , while the die-wall friction affects the generation of heat during whole compaction process (i.e. compression and decompression). Moreover, the heat generated due to die-wall friction is proportional to the compression speed (Klinzing, 2010). The average load force, the thickness and the relative density of FF tablets were practically unchanged with increasing of the compaction speed. Hence seems clear that the tensile strength of a FF tablet with different compaction speeds only slightly varied. In fact, similar observation have been explored by Maarshalk et al. (1996) and Tye at al. (2004), where they found that the tensile strength as a function of tablet porosity was independent of compression speed. Thus, it can be concluded that actually there is no correlation between temperature rise of tablets and its tensile strength. As the compaction speed increases, the time to compacted powder is reduced and the compression work is more recovered. Therefore, it was explored that the NW/CW ratio decreased with compaction speed (Fig. 3a and 13). However, as the compression speed increases, the amount of heat generated due to interparticle friction and die-wall friction increases (Fig. 3b and 14), but the heat transferred/dissipated into the surrounding media and the tooling decreases (i.e. the heat transfer time decreases). As a consequence, a higher temperature is induced, as shown in Figs 5 and 15. Furthermore, heat will be generated not only from irreversible plastic deformation and interparticle friction, but also from the die wall friction. At the same time, some generated heat will be transferred and dissipated into the die wall, which depends on the heat transfer rate and the transfer time. At a low compression speed, the compressed powder bed has a long contact time with the die wall, so the heat transfer time increases and the amount of heat transferred/dissipated will increase (Abdel-Hamid, 2011; Sun, 2015). As the compression speed increase, the amount of the heat lost will be reduced. Hence, comparing to the powder in the centre of the tablet, the net heat acquired by the powder close to die wall will be lower (see Figs 6 and 10). Furthermore, as the compression speed increases, the temperature difference in the centre of the tablet and at the edge decreases (Figs 8 and 12). During ejection, the lower surface of the tablet is in contact with the lower punch and some heat will transfer to the lower punch. Hence, compared to the powder at the top edge of the compressed tablet, which is in contact with the die wall during the ejection, the amount of net heat acquired near the lower edge is smaller than that at the top edge. As a result, the temperature at the bottom edge is generally lower than that at the top edge (Figs 7 and 11). While the average load force only slightly varied for all tablets of different shape, and also the volume in order to FF>SC>NC was reduced, thus degree of powder deformation increased and the tensile strength increased. This is in broad agreement with observation published by Pitt et al. (1989) and Davies et al. (2007). They clearly indicates that, as either the cylinder length ratio (minimum separation / diameter of

tablet) or face-curvature ratio (diameter of tablet / radius of face curvature) increases, then the fracture load increases. The heat generated due to irreversible plastic deformation depends upon the extend of the deformation during compaction. A greater amount of heat is generated when deformation is larger. For various tablet shapes considered in this study, as the tablet surface curvature increases, the radius of the surface curvature and punch separation decreases (FF>SC>STC), overall die wall friction and degree of deformation increases (Fig. 4a and 4b) and more heat is generated, consequently a higher temperature is induced (Fig.9). Despite the fact that the diameter and thickness of the tablets, the curvatures of tablets as well as range of the compaction speed were different compared to the previous study Krok et al. (2016), it can be reported that the results collected in this study are in broad agreement with the numerical observation of authors’ previous publication.

5. ConclusionsA systematic study of the temperature increase during the tabletting process was

performed. A compaction simulator was used to produce different shaped tablets at various compression speeds and an IR camera was used for measuring the surface temperature. It was found that an increase in the compression speed has a significant effect on the temperature rise in the tablet: the temperature generally increases as the compaction speed increases. For flat faced tablets, the temperature at the centre of the top surface is generally higher than that at the edge, while the highest temperature for convex tablets appears in the region close to the edge. It was also observed that the temperature on the side of a tablet was not uniform, and a higher temperature was observed near the top edge than that at the bottom edge.

ACKNOWLEDGEMENTS

This work was supported by the Marie Curie Intra-European Fellowships with acronym ThermoPC, funded through the People Programme (Marie Curie Actions) of the European Union's Seventh FP7 under REA grant agreement No. 622874. This work also was supported by the IPROCOM Marie Curie Initial Training Network, funded through the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7 under REA grant agreement No. 316555. The authors would also like to thank FMC Chemicals sprl, Brussels, Belgium, for providing the MCC powders.

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