AN experimental investigationof 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, GU27XH, UK
2 Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire, SK10 2NA, UK
Email: ,
Abstract
During pharmaceutical powder compaction, temperature rise in the compressed powder can affect physiochemical properties of the powder, such as thermal degradationand 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).Flatfaced, shallow convex and normal convex tablets were produced and temperature distributions on the surface of theses tabletsupon 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 temperaturewas induced when the powder was compressed into a tablet with larger surface curvature. This was primarily due to the increasing degree ofpowder deformation (i.e. the volume reduction)and the effect of interparticule/wall friction.
Keywords
Thermomechanical analysis,Temperaturerise, Powder compaction,Tabletting, Microcrystalline cellulose
1. Introduction
Powdercompactionis one of thecommonly used manufacturing methods in the pharmaceutical industry to produce tablets. It is recognised that, during powder compaction,some mechanical work is converted into heatdue to inelastic deformation, particle-particle and particle-wall friction, while part of the generated heat can be quickly dissipated to the surroundings.
Previous studiesfocused onthe 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 40s. 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 50kN. The compaction speed for both compression and unloading was 6.7mm/s for the upper punch and 4.2 mm/s for the lower punch. The speed of ejection was 200mm/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 athermally 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 powderandshowed 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, CasettariandRonchi (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 whichan embedded thermocouple was fitted. The evolution of the temperature during compression and decompression was measured. It wasfound 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 tothe difference in thermal diffusivity and elastic properties of materials. For sodium chloride, a more pronounced decreaseintemperature was observed during decompression, when compared with other two materials,because it had a higher thermal diffusivity anda higher Young’s modulus. They also explored theeffect of compression pressure on the temperature rise during compactionand foundthat the increase in temperature was directly proportional to the maximum compression pressure. This was consistent with the experimental observation ofHanus and King (1968)who compactedsodium 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 lactoseusing a Korsh PH 106 rotary tablet pressat 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 minutewere 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 thatthe temperature rise was not affected by the compression speedand the final temperature of compressed tablets fluctuated at 33 ± 1 °Cfor 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 wereused. 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 frictionwas 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 pressureandcompression 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 werenormally 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 500mm/s) wereusedto mimic the compression speed commonly used in practical tablet manufacturing in the pharmaceutical industries.In addition, the temperature changes during manufacturing of various shapedtablets using different materials were also investigated.
2. Materials and methods
2.1 Materials
Three 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 wasmeasured 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 compaction
The tableting process was performedusing a fully instrumented compaction simulator (ESH, UK) andan analytical balance (METTLER AT 261 DeltaRange, Switzerland) was usedto 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 compressedat various compaction speeds into FF, SC and NC tablets with a thickness of 3.3 ± 0.01 mm and diameterof 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 amountof 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 ± 0.001
MCC 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
2.3Temperature measurements and analysis
A portable infrared camera (OPTRIS PI450, Optris GmbH, Germany) wasused for measuring surface temperatures of the tablets after ejection, and the parameters of the calibrated camerawere 382×288pixels,frame rate: 80Hz, 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 conductedat 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 102are 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 ± 0.47
Particle 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 ± 5.06
Bulk 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 simulator
The 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 typical 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 compaction process represents apparent work, which is required to form the compact and to overcome the wall friction (Eriksson et. al., 1995, Takeuchi et al. 2004). In addition, the magnitude 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.