Chemical Engineering and Processing: Process Intensification

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1 Chemical Engineering and Processing 48 (2009) Contents lists available at ScienceDirect Chemical Engineering and Processing: Process Intensification journal homepage: Study of the compaction behaviour and compressibility of binary mitures of some pharmaceutical ecipients during direct compression Péter Kása a, János Bajdik a, Zsolt Zsigmond b, Klára Pintye-Hódi a, a Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary b EGIS Pharmaceuticals PLC, H-1106 Budapest, Keresztúri út 30-38, Hungary article info abstract Article history: Received 17 June 2008 Received in revised form 4 September 2008 Accepted 6 November 2008 Available online 17 November 2008 Keywords: Compaction Compressibility Pharmaceutical ecipients Direct compression Energetic parameters Tablets produced in the pharmaceutical industry consist of more than one component. The densification behaviour, the compaction properties of a formulation are strongly influenced by the characteristics of the miture, e.g. the particle size fractions of the components. Direct compression is a well-known and simple method in tablet manufacturing. It has a number of advantages, the greatest of which are the saving of time, labour and cost. It involves only a few processing steps from beginning to end, as compared with up to a dozen steps for wet granulation. However, direct compression also has certain disadvantages: the physical limitations of the drug and the physical properties of the raw materials present become more critical and must be controlled more precisely. We studied the compressibility of some ecipients commonly used in pharmaceutical technology, both alone and in binary mitures. With this aim, we compressed the materials into tablets with a Korsch EK0 instrumented eccentric tablet machine (Emil Korsch Maschinenfabrik, Berlin, Germany). The compression tools were flat-faced bevel-edged punches 8 mm in diameter with a halving line on one side, equipped with strain gauges and a displacement transducer. The binary mitures were compared through the use of compression cycles and energetic parameters Elsevier B.V. All rights reserved. 1. Introduction Compression during tableting is a comple and irreversible dynamic process. Various methods can be used to study compressibility, among them the measurement of force displacement curves [1 5]. Higuchi et al. [6 7] initiated fundamental research on tableting problems in the early 1950s, introducing displacement measurement during a compression process by means of an inductive displacement transducer. A number of authors have reported on the instrumentation of tableting machines [8 11], with which the compression process can be monitored. The compression cycles (force time and force displacement curves) can be studied and different energetic parameters can be calculated. It is well known that the tableting process begins when the upper punch starts to move down in the die filled with a certain quantity of a powder or granulate miture. Particle rearrangement takes place by the particles slipping past each other, reducing the distances of contact between the particles without causing ecessive deformation [12], with energy E 1 being consumed to overcome the friction in this precompression phase (Fig. 1). Corresponding author. Tel.: ; fa: address: klara.hodi@pharm.u-szeged.hu (K. Pintye-Hódi). As the applied stress is increased and the stage is reached at which there is no more room for particle rearrangement, elastic and plastic deformation of the particles occurs (Fig. 1, line A-M), consuming further energy E 2. The effective work E 2 is used for the binding of the particles after the friction work (FW). It is eerted on the die walls in the compression phase, so the useful energy is W use = E 2 FW. After the compression maimum (Fig. 1, point M) the upper punch changes direction and starts to move upwards. A purely plastic material might be epected to follow line M-B. Real materials might be presumed to take up some intermediate position (Fig. 1, curve M-C). (E 1, E 2 and E 3 are calculated by the numerical integration of the areas under the curves.) The friction between the powder or tablet and the die wall is a serious problem during compression and ejection. In the single tablet machine, the force is applied by the upper punch and transmitted aially to the lower punch and also laterally to the die. The transmission of force from the upper to the lower punch depends on the friction between the powder and the die wall. Both the difference in transmitted force, i.e. the upper punch force the lower punch force, and the ratio lower punch force/upper punch force (lubrication coefficient = R value) are used as measures of the die wall friction during compaction [13]. Furthermore, on the basis of the force displacement curve, the movement of the upper punch may also be considered to calculate the friction work [14]. In this /$ see front matter 2008 Elsevier B.V. All rights reserved. doi: /j.cep

2 860 P. Kása et al. / Chemical Engineering and Processing 48 (2009) (E 2 ) and the tensile strength of the tablets can provide more information on the behaviour of the materials after the compression process than the plasticity value [25]: Pr (mass) = = W spec E 2 /m (Pa/Jkg 1 ) (3) where is the tensile strength and W spec is the specific work, which epresses the effective work (E 2 ) invested into the compression of unit mass of substance (m) at a given compression force. The tensile strength ( ) includes the breaking hardness (H), the diameter (d) and the height (h) of the tablet: work this formula was used: FW = S m S 0 { F upper Fig. 1. Force displacement diagram. [ ]} Fupper F lower ds (1) ln(f upper /F lower ) When FW is high, lubricants are necessary in the powder miture to avoid the high friction during tableting. Tablet epansion takes place as a result of elastic recovery in this decompression phase and continues even after tablet ejection [15]. The elastic recovery energy E 3 is a measure of the work generated during the epansion of the tablet. Recovery of the tablet is rather slow and often continues for several hours or days after its ejection from the die [16]. Capping and lamination are attributed to the inability of compacts to relieve localized internal stress without failure [12,17], their incidence depending on the plastic and elastic behaviour of the material used [18]. E 1 depends on the rearrangement of the material. E 2 is the energy needed to form the tablet, and E 3 depends on the degree of elastic springing-back [19]. The ability of formulated powders to form satisfactory tablets depends on their plastic deformation during compression and on their elastic recovery during decompression [20]. Tablets produced in the pharmaceutical industry consist of more than one component. The densification behaviour and the compaction properties are strongly influenced by the characteristics of the miture, e.g. the particle size fractions of the components [20,21 24]. The aim of this work was to evaluate the profile of force displacement curves and the calculated energetic parameters of certain ecipients and mitures of ecipients commonly used in tablet manufacturing. The cycles were obtained from the data collected during the compaction of the mitures. The force displacement curves displayed three steps, the first corresponding to rearrangement and packing (Fig. 1, E 1 ), the second to fragmentation and/or plastic deformation of the particles (E 2 ), and the third to instantaneous elastic recovery when the applied pressure was released (E 3 ). From the E 2 and E 3 values, calculation of the plasticity is possible according to Stamm and Mathis: E 2 Pl = 100 (%) (2) E 2 + E 3 It is well known that the plasticity shows the deformability of the materials during compression. After compression, however, in the case of a larger elastic recovery, the teture of the tablets could undergo change during storage. This change influences the parameters of the tablets (hardness and geometrical parameters), which means that, in spite of high plasticity, the bonds which form during loading break after the compression maimum in the phase of elastic recovery and the tablets show insufficient strength. The new formula of compressibility which involves the deformation energy = 2H (4) dh The compressibility factor allows a better comparison of the tablettability of materials or powder mitures. (Tablettability means the continuous compressibility of powder mitures.) 2. Materials and methods 2.1. Materials Frequently used ecipients were used. Microcrystalline cellulose (Avicel PH 102) (FMC Corp., USA) is a dry binder. Ludipress (BASF, Germany) consists of a solid binder (PVP, 3.5%), a filler ( -Pharmatose monohydrate, 93%) and a disintegrant (PVPP, 3.5%). Tablettose (agglomerated -lactose monohydrate) (Meggle, Germany) and Pharmatose DCL-11 (spray-dried -lactose monohydrate) (DMW International GmbH, The Netherlands) were applied as fillers. 1% of magnesium stearate limits the friction between the running tools during the tableting process. 3. Methods 3.1. Preparation of mitures The binary mitures (Avicel PH 102/Ludipress; Avicel PH 102/Tablettose; and Avicel PH 102/Pharmatose DCL-11) were prepared in ratios of 30/70, 40/60, 50/50 and 60/40 (%, w/w) with a Turbula mier (Willy A Bachofen, Switzerland) at 50 rpm for 8 min, plus 2 min with 1% of magnesium stearate as lubricant. The mass of each powder miture was 200 g Compression procedures The bulk materials and the powder mitures (both with 1% magnesium stearate) were compressed into tablets with a Korsch EK0 instrumented eccentric tablet machine (Emil Korsch Maschinenfabrik, Berlin, Germany). The compression tools were flat-faced bevel-edged punches 8 mm in diameter with a halving line on one side and equipped with strain gauges and a displacement transducer. The strain gauges allowed the pressure forces on the upper and lower punches to be followed with force-measuring equipment, which was calibrated with a Wazau HM-HN-30kN-D cell (Kaliber Ltd., Budapest, Hungary). The displacement transducer (Micropulse, BTL5-A11-M0050-P-532, Balluff, Neuhausen/Filder, Germany) was fitted over the upper punch. The transducer distance accuracy was checked by using five measuring pieces of different accurately known thicknesses (2.0, 5.0, 7.5, 10.0 and 15.0 mm) under zero load (Mitutoyo, Tokyo, Japan). The compression was carried out electrically at 36 rpm, at 24 C air temperature and at 45% relative air humidity. The average mass of the tablets was ± 0.01 g. 10 tablets were compressed at a compression force of 10 kn for each sample (when possible). Lots with relative standard deviations not eceeding 5% were accepted.

3 P. Kása et al. / Chemical Engineering and Processing 48 (2009) Fig. 2. Force displacement curve of Avicel PH 102. Fig. 4. Force displacement curve of Ludipress. Force displacement curves were plotted, and the different energy/work relations were calculated from the curves by our software. 4. Results and discussion In this work the compressional behaviour of some important ecipients and their mitures was investigated. The force displacement curve of Avicel PH 102 (Fig. 2) revealed that the degree of friction is very small (0.19 J) and the elastic recovery is also small (0.64 J). The plasticity value calculated according to Stamm and Mathis is 83.76%. The compressional behaviour of Tablettose is similar. The profile of the curve is normal, but it can be seen in Fig. 3 that the friction is somewhat lower and the elastic recovery is about twice that of Avicel PH 102. E 2 is a little smaller than that of Avicel PH 102, so the plasticity is also smaller (70.44%). It is striking in Fig. 4 that the force displacement curve of Ludipress is abnormal: an unequal force effect can be observed, which means that the deformation is hindered because of the friction in the die in the precompression phase. The plasticity is high (89.99%), but the profile of the curve it is clear that it must be left out of consideration. The same situation can be observed for Pharmatose DCL-11 (Fig. 5). The curve of the upper punch revealed high friction in the die during the precompression phase. The reason lies in part in the friction between the particles, and there is also high friction between the forces of the lower and upper punches. In spite of the high plasticity (95.96%), it can be stated that the compressibility of this material is not suitable. It is clear from Figs. 4 and 5 that the maimum pressure forces were smaller than 10 kn. Because of the sticking and capping, it was not possible to increase the pressure forces, and only a few tablets could be compressed. This means that the compression of bulk Ludipress and Pharmatose DCL-11 is not possible without the addition of some other ecipient. Similar results have been presented in the literature for active pharmaceutical ingredients [26]. The small E 1 and higher E 2 of Pharmatose lead us to think that the deformability of this material is very good. However, it is clear that this is illusory when we consider the profile of the force displacement curve. Such a result draws attention directly to the importance of the profile of compressional curves. The compressibility of binary mitures of the above-mentioned ecipients was also studied. In direct compression, it is necessary to use a dry binder in order to achieve the required tablet properties. Accordingly, Avicel PH 102 (as dry binder) was mied with the other ecipients. The binary mitures were compared through the use of compression cycles and some energetic parameters. The use of a lubricant (1% of magnesium stearate) was necessary for the tableting of the mitures. Avicel PH 102 improved the compressibility of Tablettose and Pharmatose DCL-11 at all of the ratios investigated. For Ludipress, the ratio 1:1 was best. The force displacement curves of some mitures demonstrated that the profiles of the curves were normal and similar (Figs. 6 8). No abnormal friction was detected in the profiles. They clearly demonstrated that the compression of the mitures was improved Fig. 3. Force displacement curve of Tablettose. Fig. 5. Force displacement curve of Pharmatose DCL-11.

4 862 P. Kása et al. / Chemical Engineering and Processing 48 (2009) Table 1 Energetic parameters based on compression curves. Ecipients Pressure force (kn) Energetic parameters (J) E 1 E 2 E 3 FW Avicel PH ± Tablettose a 10 ± Ludipress a 8 ± Pharmatose DCL-11 a 4 ± :70 Mitures Avicel PH Tablettose 10 ± Avicel PH Ludipress b 10 ± Avicel PH DCL ± :60 Mitures Avicel PH Tablettose 10 ± Avicel PH Ludipress b 10 ± Avicel PH DCL ± Fig. 6. Force displacement curve of a 1:1 binary miture of Avicel PH 102 and Tablettose with 1% magnesium stearate. 50:50 Mitures Avicel PH Tablettose 10 ± Avicel PH Ludipress 10 ± Avicel PH DCL ± :40 Mitures Avicel PH Tablettose 10 ± Avicel PH Ludipress 10 ± Avicel PH DCL ± a Cannot be compressed continuously. b Not compressible. Fig. 7. Force displacement curve of a 1:1 binary miture of Avicel PH 102 and Ludipress with 1% magnesium stearate. by Avicel PH 102, especially in the cases of Ludipress and Pharmatose DCL-11. The energetic parameters of the curves of the different mitures are listed in Table 1. Comparison of the parameters of the bulk materials alone is not possible because of the different pressure forces which have to be used for their tableting. However, it can be stated that Avicel PH 102 improved their compressibility. The compression of the mitures was successful, and comparison of the energetic parameters of the mitures is therefore possible. Fig. 8. Force displacement curve of a 1:1 binary miture of Avicel PH 102 and Pharmatose DCL-11 with 1% magnesium stearate. It can be seen from Table 1 that 30% and 40% of Avicel PH 102 did not improve the compression of Ludipress. These mitures were not compressible continuously. However, further increase of the Avicel PH 102 content improved the compactibility of the miture. The data on the mitures reveal that E 1 is higher for the Avicel Ludipress miture than for the other mitures. This means that the interparticulate friction during the precompression phase was highest for this miture. The compressibility of the Tablettose mitures with 30%, 40% or 50% Avicel PH 102 was good, but further increase of the quantity of Avicel PH 102 was not advantageous: E 1 increased and E 2 decreased. In the case of Pharmatose DCL-11, the 1:1 miture yielded the best data. On increase of the Avicel PH 102 content, E 1 also increased. The data in Table 1 additionally demonstrate that there are only small differences in the values of E 3. As regards FW, it can be stated that the friction of the mitures in the postcompression phase was generally not too high. Data on the plasticity and compressibility factor of the powder mitures are to be seen in Table 2. We can make practically any difference between the mitures in regard of plasticity. However, considering the compressibility factor, there are higher differences; the influence of Avicel is evident, the compressibility factor increasing with increasing Avicel amount. Finally, it may be concluded that, besides calculation of the energetic parameters, it is also necessary to consider the shape of the compressional curves, because they indicate when some problem is to be epected during compression. The other important finding is that at every ratio eamined Avicel PH 102 improved the compressional behaviour of Tablettose and Pharmatose DCL- 11, but the ratio 1:1 was best for achievement of a suitable tablet quality. For Ludipress, only a high amount of Avicel PH 102 improved the compressibility. Furthermore, we suggest the use of the compressional factor in the comparison of the compressibility of different materials or powder mitures. These results indicate that more detailed eaminations of the ecipient ratio may possibly lead to an improved efficiency of the manufacturing process.

5 P. Kása et al. / Chemical Engineering and Processing 48 (2009) Table 2 Plasticity and compressibility values of tablets compressed with 10 kn compression force. Plasticity Compressibility factor 30:70 Mitures Avicel PH Tablettose ± ± 3.21 Avicel PH Ludipress Avicel PH DCL ± ± :60 Mitures Avicel PH Tablettose ± ± 3.90 Avicel PH Ludipress Avicel PH DCL ± ± :50 Mitures Avicel PH Tablettose ± ± Avicel PH Ludipress ± ± 4.01 Avicel PH DCL ± ± :40 Mitures Avicel PH Tablettose ± ± 9.91 Avicel PH Ludipress ± ± 5.42 Avicel PH DCL ± ± Conclusions The role of the ecipients is important in the composition of a tablet. They must ensure that the tableting operation (tablettability) can run satisfactorily and that tablets of good quality are prepared. In order to form tablets of a size suitable for handling, a lower limit in terms of powder volume and mass is required. A low dose of active pharmaceutical ingredient requires some filler (diluent). In direct compression dry binders are also very important. In practice, these ecipients are frequently used in different ratios, which influences the tableting operation. The present results reveal that a knowledge of deformability (the profile and shape of the curves), the energetic parameters of the materials and the compressibility factors is necessary for the manufacturing of tablets. To make tablets by direct compression from a material with poor compressional behaviour, it is necessary to improve the compressibility and to enhance the binding. Appendi A. Nomenclature E 1 E 2 E 3 R FW W use Pl Pr lost energy deformation energy (effective work) elastic recovery energy lubrication coefficient friction work useful energy plasticity compressibility factor tensile strength References [1] A. Stamm, C. Mathis, Verpressbarkeit von festen Hilfstoffen für Direkttablettierung, Acta Pharm. Technol. 22 (1976) [2] T.M. 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