dry granulation affect the tableting behaviour of inorganic materials?

European Journal of Pharmaceutical Sciences 22 (2004) 325–333

How do roll compaction/dry granulation affect the tableting behaviour of inorganic materials? Microhardness of ribbons and mercury porosimetry measurements of tablets Franziska Freitag a , Katrin Reincke b , Jürgen Runge c , Wolfgang Grellmann b , Peter Kleinebudde d,∗ a

Institute of Pharmaceutics and Biopharmaceutics, School of Pharmacy, Martin-Luther-University (MLU), Halle-Wittenberg, Germany b Department of Engineering Sciences, Institute of Material Sciences, MLU, Halle, Germany c Department of Engineering Sciences, Institute of Mechanical Process Engineering, MLU, Halle, Germany d Institute of Pharmaceutics, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, D-40225 Duesseldorf, Germany Received 13 November 2003; received in revised form 26 March 2004; accepted 3 April 2004 Available online 1 June 2004

Abstract The effect of roll compaction/dry granulation on the ribbon and tablet properties produced using different magnesium carbonates was evaluated. The ribbon microhardness and the pore size distribution of tablets were used as evaluation factors. Increasing the specific compaction force resulted in higher microhardness for ribbons prepared with all four magnesium carbonates accompanied with decreased part of fine. Consequently, the corresponding produced tablets displayed a lower tensile strength. A possible correlation between the particle shape, surface area and the resulting pore structure of tablets produced with the four different types of magnesium carbonate was observed. The tensile strength of tablets prepared using granules was lower than tensile strength of tablets produced using starting materials. The partial loss of compactibility resulted in a demand of low loads during roll compaction. However, the impact of changes in the material properties during the roll compaction depended greatly on the type of magnesium carbonate, the specific compaction force and the tableting pressure applied. © 2004 Elsevier B.V. All rights reserved. Keywords: Roll compaction/dry granulation; Magnesium carbonate; Recompression; Mercury porosimetry; Tablet tensile strength; Microhardness of ribbons

1. Introduction The effects of roll compaction/dry granulation on the particle and bulk material characteristics of different magnesium carbonates were evaluated by Freitag and Kleinebudde (2003). They found that precompaction resulted in a modified material compactibility and tablets with a reduced tensile strength. The loss in tablet strength increased at higher specific compaction force applied during the roll compaction process. Generally, compressing the powder using suitable pressure results in tablets, which consist of solid tableting ma∗ Corresponding author. Tel.: +49-211-811-4220; fax: +49-211-811-4251. E-mail address: [email protected] (P. Kleinebudde).

0928-0987/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2004.04.001

terial with embedded air. The pore structure, which can significantly influence tablet properties (e.g. tensile strength), can be described in terms of total porosity and pore size distribution. It is known from literature that mercury porosimetry can be used for characterisation of tablets produced using granules. The applied load during tableting and the binding mechanism affect greatly the pore size distribution. Vromans et al. (1985) investigated tablets made of different types of lactose with mercury porosimetry. It was found that the pore size distribution depended on the compaction load and the fragmentation behaviour of the materials. Selkirk and Ganderton (1970a) studied tablets of lactose and sucrose and the corresponding granules produced using wet granulation. Tablets made of ungranulated powder depicted a narrow pore size distribution. Granulation resulted in tablets

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with wide pore size distribution. Large robust granules compressed at low pressures resulted in tablets with a bimodal pore size distribution. Wikberg and Alderborn (1992) noticed similar observation with lactose granules of high and low porosity produced using wet granulation. Granules with high porosity resulted in a narrower pore size distribution and harder tablets. A correlation between median pore size and tablet strength was reported by Juppo (1996) for granulated lactose, glucose and mannitol. The increase in the tablet strength was related to a (1) decreased volume of large pores and (2) shift in the pore size distribution towards smaller pores. Alderborn and Wikberg (1996) described granules as a cluster of discrete particles where the size and shape of the primary particles in the granule are similar to those in the original particles. However, the granules formed by slugging are an exception because the primary particles will go through deformation and fragmentation, which probably occur during the preparation of the granules. The effect of dry granulation by slugging on the consolidation and compaction of ␣-lactose-monohydrate and roller dried ␤-lactose was investigated by Zuurmann et al. (1994). Mercury porosimetry measurements on tablets compacted using granule fractions showed a relationship between the tablet pore diameter and the crushing strength. Generally, the crushing strength decreased at higher tablet pore diameter, Riepma et al. (1993) obtained similar results. Tablets compacted using fine granule size fractions exhibited finer pore sizes and higher strength compared to tablets compacted from coarse size fractions. Mercury porosimetry was used by Selkirk and Ganderton (1970b) and Riepma et al. (1993) for analysing pore size distributions of tablets produced with dry granulated lactose. Both studies showed that slugging pressure influenced the pore structure of tablets produced with granules. Investigating the intermediate products of roll compaction/dry granulation process will lead to better understanding of the granule and tablet properties. The importance of microhardness measurements of tablets was first described by Aulton (1981). He evaluated the changes in mechanical properties across the faces of tablets prepared using a range of materials. It is well known that the porosity in tablets diminishes with increasing tableting force and it removes also in ribbons with increasing specific compaction force (Lammens, 2002). The influence of different specific compaction forces on the microhardness of microcrystalline cellulose ribbons was analysed by Wöll et al. (2000). The aim of this study is to investigate the effects of dry granulation by roll compaction on the pore size distribution of tablets produced using granulated and non granulated magnesium carbonates. Furthermore, the mechanical properties of the tablets should be related to parameters of mercury porosimetry. The method could be used as an additional evidence for the reduced recompression of roll compacted granules. The determination of microhardness of inorganic

ribbons may represent an important key to understand the roll compaction/dry granulation process.

2. Materials and methods 2.1. Materials Four different magnesium carbonates were used as received MC1: magnesium carbonate, heavy, bulk density about 500 g/l, Ph. Eur. lot 113306 MC2: magnesium carbonate, heavy, bulk density about 400 g/l, Ph. Eur. lot 231592 (MC1 and MC2 were received from Dr. Paul Lohmann, GmbH KG, Emmerthal, Germany) MC3: magnesium carbonate, lot 01820199 MC4: magnesium carbonate, heavy, magnesia 182, Ph. Eur. lot 990701 (MC3 and MC4 were received from Magnesia GmbH, Lüneburg, Germany). Magnesium stearate was used as tableting lubricant (lot 93810410, Caelo, Hilden and Bonn, Germany). 2.2. Production of granules and tablets 2.2.1. Roll compaction/dry granulation Ribbons and granules were produced using an instrumented roll compactor (Mini-Pactor, Gerteis, Jona, Switzerland) with smooth rolls of 25 cm diameter × 2.5 cm width. Ribbons of pure magnesium carbonate were prepared using specific compaction forces, i.e. the compaction force per centimetre roll width, of 1, 3, 5 and 7 kN/cm. The gap width was set to 1.5 mm. Ribbons were granulated in an oscillating mode with a pocket mould grooved rotor, sieve 1.25 mm, 50 rpm with an angle of 360◦ in both directions. 2.2.2. Mixing for tableting Granules obtained from dry granulation and powders were blended with 0.5% (w/w) magnesium stearate as lubricant in a drum blender (Erweka, Heusenstamm, Germany) for 10 min at 28 rpm. 2.2.3. Tableting Flat faced tablets (11 mm) of granules and powders were produced using an instrumented single punch machine (EK0, Korsch, Berlin, Germany) at a speed of 10 strokes/min. Forces of 5, 10, 15 and 20 kN were applied, which correspond to tableting pressures of 53, 105, 158 and 210 MPa, respectively. The feed material (350 ± 0.5 mg) was individually weighed on an analytical balance and then manually filled into the die. The machine was connected with an amplifier (DMC-Plus, HBM, Darmstadt, Germany). Time, 780 data sets of force and displacement were recorded for five compaction cycles of every batch. The consolidation behaviour was evaluated by Heckel plots. The slope, k, was

F. Freitag et al. / European Journal of Pharmaceutical Sciences 22 (2004) 325–333

2.3. Characterisation of powders, granules and tablets For further analysis, adequate granule samples were obtained from a rotary sample divider (PT 100, Retsch, Haan, Germany). Particle size distribution of the granules was evaluated by sieve analysis using an air jet sieve (Alpine 200 LS-N, Hosokawa-Alpine, Augsburg, Germany) with sieves of 32, 63, 90, 125, 250, 355 ␮m. Sieves of 500, 710, 1000 ␮m (Retsch, Haan, Germany) were shaken on a sieve tower (Vibrio, Retsch, Haan, Germany) for 10 min at level 50. The part of fines was set smaller than 90 ␮m. The specific surface area of powders and granules was determined by an areameter (Ströhlein, Viersen, Germany) according to DIN 66132 (Deutsches Institut für Normung, 1975). The apparent particle density of magnesium carbonate powder was determined with a helium pycnometer (AccuPyc 1330, Micromeritics, Norcross, USA). Tensile strength: the crushing strength of tablets was measured using a crushing strength tester (TBH-30, Erweka, Heusenstamm, Germany). The height of the tablets was determined with a micrometer screw (Mitotuyo, Kawasaki, Japan). The tensile strength was calculated according to Fell and Newton (1970). The presented data are the average of at least five compacts. The environmental scanning electron micrographs of the materials were determined using ESEM (XL 30 FEG, Philips, Eindhoven, The Netherlands). 2.4. Microhardness measurements Generally, for a comprehensive hardness measurement of a material, it is necessary to record the indentation load and the penetration depth during the whole experiment (Bierögel et al., 2001). This is possible using an instrumented hardness measurement system, where the force and the penetration depth are measured at all times and so the evaluation of loading and unloading curves is possible. For example, quantification or analysis of the viscoelastic–plastic behaviour of the material can be performed by comparison of the loaded and unloaded states. However, microhardness measurement in principle allows only the analysis of the region near the surface of the material because the maximum load is very small. Generally, microhardness measurements are performed in a load range lower than 2 N. Fig. 1 (Bierögel et al., 2001) shows schematically a measuring cycle for the determination of the load–penetration diagram. Microhardness measurements of ribbons described in this paper were performed using a commercial instrumented Fischerscope H100 microhardness system (Helmut Fischer, Sindelfingen, Germany) with a ball indenter. For

Indenter

h

ht

h (µm)

obtained from linear regression analysis and only the data points giving a straight line with r 2 ≥ 0.999 were used for further evaluation. The apparent mean yield pressure was calculated according to Hersey and Rees (1971).

327

Specimen

t Unloading

Loading Elastic-Plastic Indentation Depth at Maximum Load Plastic Indentation Depth at Minimum Load F (N)

F min

F

max

Fig. 1. Schematic illustration of the load–penetration diagram during a microhardness measurement.

this study, a load range from 0.4 to 1000 mN was applied with 200 measuring steps in 20 s in each direction. The landing of the indenter on the specimen surface and the penetration are controlled by a microprocessor forming part of the measuring system. The resulting penetration depth and the system time are measured simultaneously, as the load increases. After the maximum load has correctly been reached, the penetration depth ht can be obtained. Subsequently, a reduction of the load to the predicted value Fmin is performed automatically by the measuring system. The microhardness is calculated for the last load point, Fmax , by using the indenter ball radius, r, and its indentation depth, ht microhardness =

Fmax (N/mm2 ) 2πrht

2.5. Mercury porosimetry The mercury porosimetry measurements of tablets were performed with Poresizer 9320 (Micromeritics, Norcross, USA). The relationship between intruded volume of mercury and the intrusion pressure was analysed with the software V2.09 (Micromeritics, Norcross, USA). At the beginning of every determination the penetrometer was evacuated up to a pressure of 0.0667 kPa. Then it was filled with mercury under increasing pressure from 3.45 up to 13.8 kPa. The low pressure stage reached up to 69 kPa. Penetration pressures between 0.069 and about 206 MPa were applied in 37 steps in the high pressure stage. The pore sizes corresponding to the intrusion pressures were calculated assuming cylindrical pores, a contact angle of 130◦ and a surface tension for mercury of 485 mN/m. An equilibration time of 10 s was kept for every step. The cumulative pore volume was converted into percent for representing a pore size distribution. Porosimeter tests were carried out in duplicate or triplicate. Relative tablet densities were calculated from porosity.

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4 MC1

MC1

MC2

30

tensile strength [N/mm² ]

microhardness [N/mm² ]

MC2 MC3 MC4 20

10

3

MC3 MC4

2

1

0 -1

1

3

5

7

9

specific compaction force [kN/cm]

0 0

10

20

30

40

microhardness [N/mm²]

Fig. 2. Microhardness of ribbons for different types of magnesium carbonate produced using roll compaction.

3. Results and discussion 3.1. Microhardness of ribbons As mentioned before, ribbons of the different magnesium carbonates (MC1, MC2, MC3 and MC4) were produced at four specific compaction forces (1, 3, 5 and 7 kN/cm). The microhardness of the ribbons for all four materials rose with increasing specific compaction force (Fig. 2). The weakest ribbons were produced at the lowest specific compaction force. MC4 showed the lowest hardness over the whole range, followed by MC2, whereas MC1 was comparable to MC3 within the scope of standard deviation. For ribbons of magnesium carbonate it has been found earlier that the length of ribbons diminished by using higher specific compaction forces (Freitag and Kleinebudde, 2002). It was difficult to determine the microhardness of small ribbons because of their high brittleness and small area. Using ribbons with higher hardness value resulted in tablets with lower tensile strength for all four materials (Fig. 3). In addition, the weakest ribbons of each material resulted in tablets with the best mechanical properties. It can be generally supposed that a diminished ribbon densification and strength due to a low specific compaction force is advantageously. Although the microhardness of ribbons produced at 1 kN/cm did not differ very much, the tensile strength of tablets changed from 0.8 N/mm2 for MC4 up to 2.9 N/mm2 for MC2. It can be assumed that roll compaction at 1 kN/cm did not densify the materials too much, so the ribbon properties of the four materials are similar at 1 kN/cm. The tableting step with additional compression emphasised the differences in material properties of the four magnesium carbonates. For MC4, both microhardness of ribbons and tensile strength of tablets were low (∼7 to 16.5 N/mm2 , and ∼0.85 to 0.69 N/mm2 , respectively). However, big differences in microhardness of ribbons resulted in small differences in tablet tensile strength for all materials. The particle size distribution, the outer

Fig. 3. Tensile strength of tablets and microhardness of the corresponding ribbons using different types of magnesium carbonate: 158 MPa tableting pressure (mean ± S.D. in x- and y-direction).

surface area of the four starting materials, and the resulting granules differed significantly (Freitag and Kleinebudde, 2002). Since the amount of the lubricant magnesium stearate was kept constant at 0.5% for all tablets the ability of magnesium stearate to form a film on the accessible surface may lead to films with different thickness. Large granules with a small outer specific surface area may carry a thicker film of magnesium stearate compared to the starting material. This can be compensated by the propensity of granules to break during tableting providing new unlubricated surfaces. The apparent mean yield pressure of tablets determined from Heckel plot is an indication of fragmentation and deformation intensity of the materials. The higher the values of the apparent mean yield pressure the more fragmentation could determine the bonding mechanism (Duberg and Nyström, 1986). In an earlier investigation, it was shown that higher specific compaction force for magnesium carbonate was accompanied with higher apparent mean yield pressure of tablets made of magnesium carbonate (Freitag and Kleinebudde, 2003). A correlation can be found between the apparent mean yield pressure of tablets and the microhardness of ribbons (Fig. 4). Increasing specific compaction force resulted in higher hardness and also higher apparent mean yield pressure for each magnesium carbonate. MC4 displayed low microhardness values whereas the resulting tablets possessed a low deformation propensity due to the high values of the apparent mean yield pressure. In contrast, the values of the apparent mean yield pressure of MC2 were low in comparison to the other materials. This may be related to special compaction behaviour as explained by York (1992), where a plastic flow at contact points was postulated. The granule properties of magnesium carbonate were improved with roll compaction/dry granulation. The flowability and the relative density were increased (Freitag and Kleinebudde, 2003). It can be assumed that the ribbons

F. Freitag et al. / European Journal of Pharmaceutical Sciences 22 (2004) 325–333

apparent mean yield pressure [MPa]

600

500

400 MC1 MC2 300

MC3 MC4

200 0

10

20

30

40

microhardness [N/mm²]

Fig. 4. Apparent mean yield pressure of tablets and microhardness of the corresponding ribbons for different types of magnesium carbonate; 158 MPa tableting pressure (mean ± S.D. in x- and y-direction).

properties and the corresponding granules are correlated. The part of fines of the granules decreased at higher microhardness values (Fig. 5). Generally, the harder the ribbons are the lower the parts of fines will be. As shown in Fig. 3, it is obvious that the strength of the tablets decreased with increasing the ribbons hardness. However, there were differences between the investigated materials. The part of fines of MC3 was nearly independent of the microhardness and had a value lower than 10%. In contrast, for the part of fine of MC1, MC2 and MC4 decreased at higher microhardness values (but not below 20%). 3.2. Pore structure of tablets: investigation with mercury porosimetry and electron microscopy The measurements were carried out using tablets prepared using powdered starting material as well as granules obtained from ribbons compacted at 7 kN/cm. 80 MC1 MC2

part of fines [%]

60

MC3 MC4 40

20

0 0

10

20

30

40

microhardness [N/mm²]

Fig. 5. Part of fines of granules vs. microhardness of the corresponding ribbons for different types of magnesium carbonate.

329

The scanning electron micrographs (Fig. 6) display clear differences between the materials. The initial particles of the four magnesium carbonates (shown on the left side) differ in size and shape. MC3 has the smallest and more pin-like particles of an irregular shape, whereas MC1 and MC4 depict more spherical agglomerates and MC2 consists of larger and less structured particles. The particle shape of MC1 and MC4 is similar, but both substances differ in their particle surface texture, as shown in part one (Freitag and Kleinebudde, 2003). Moreover, only MC4 shows some indentations at the surface. The surface of tablets made of granules seems to be more irregular in comparison to the surface of tablets made of powder (with the exception of MC4). The particle shape can influence the kind of binding in the tablet. The extent of the mechanical interlocking of particles depends on the particle shape and surface characteristics. It expected to be manifested in the case of needle-shaped and fibrous particles (Leuenberger and Rohera, 1986). At high compression pressure, the powder particles in a compact are forced into contact, and extensive areas of true contact between particles will form. This contact area between the particles is strongly dependent upon the shape and compressibility of the particles. MC4 and MC1 have more spherical starting particles and, consequently, the tablet tensile strength is lower compared to MC2 and MC3. However, MC3 has the bigger surface area and more needle-like structure than MC2. Mattson and Nyström (2000) investigated tablets of calcium carbonate using mercury porosimetry. They found a narrow pore size distribution in comparison to the plastically deforming sodium bicarbonate. The large number of binding points that are established during volume reduction of the fragmenting material will keep the tablet porosity relatively high. Thus, the pore size distributions of magnesium carbonate tablets, shown in Fig. 7, may give an indication of fragmentation as the main volume reduction mechanism. It can be proposed that there is a connection between particle shape, surface area and the resulting pore structure of the tablet. MC3 and MC2 showed the smallest pores, presented as cumulative volume curve followed by MC1 and finally MC4, which showed the highest value. The tablets produced using granules showed smaller pores than the tablets prepared using starting materials, which can be attributed to the double compaction of the materials. Hence, a connection between relative tap density and relative tablet density can be assumed, described as degree of densification for the four magnesium carbonates (Freitag and Kleinebudde, 2003). Higher the degree of densification of the investigated starting materials will lead to bigger capacity to form strong bindings which will result in smaller pores. For the four materials, the tensile strength are ranked the same order. The specific surface area of MC4 increased during roll compaction/dry granulation from 7.6 for the powder up to 8.5 m2 /g for granules. MC1 and MC2 showed a similar behaviour. The specific surface area for MC1 and MC2 increased from 11.9 up to 13.5 m2 /g and 14.1 up to 17.5 m2 /g, respectively. The specific surface area of MC3 decreased

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Fig. 6. Environmental scanning electron micrographs of different magnesium carbonates in descending order regarding the specific surface area of powders (left row powder particles, middle row tablet surface made from powder and right row tablet surface made from granules): (a–c) MC3, (d–f) MC2, (g–i) MC1, (j–l) MC4.

during roll compaction/dry granulation from 21.9 down to 20.3 m2 /g. The studies of Selkirk and Ganderton (1970b), Wikberg and Alderborn (1992) and Juppo (1996) focused on materials with lower fragmentation propensity compared to magnesium carbonate. It can be suggested that the described widening of pore size distributions with increasing particle size during tableting must be attributed to the change in the inter-

particular distance. Van der Zwan and Siskens (1982) studied the volume reduction characteristics of granules of a ceramic and mineral using scanning electron microscopy of the upper surface and fracture surface of the compacts. For compacts produced at low pressures, individual granules could be clearly distinguished in the compacts but they seemed to be locally deformed at the intergranular contact points. It was also argued that the intergranular pore space had

F. Freitag et al. / European Journal of Pharmaceutical Sciences 22 (2004) 325–333

apparent mean yield pressure [MPa]

600

75

MC1 MC2 MC3 MC4 MC1 MC2 MC3 MC4

50

25

0 0.01

0.1

1

11.9 m²/g 14.1 m²/g 21.9 m²/g 7.6 m²/g 13.5 m²/g 17.5 m²/g 20.3 m²/g 8.5 m²/g

MC1 MC2 500

MC3 MC4 MC1

400

MC2 MC3 MC4

300

200 0.35 10

pore diameter [µm]

Fig. 7. Pore size distribution of tablets determined by mercury porosimetry at tableting pressure of 105 MPa; (full symbols) powders, (open symbols) granules 7 kN/cm together with their corresponding specific surface area of powder and granules, respectively.

already reached a low value at low compaction pressures. Hence, further compression of the mass was associated with reduction in the porosity of the granules. With increased pressure, it became difficult to distinguish individual granules in the compact. However, with increased compaction pressure, the integrity of the granules will be progressively lost when granules are deformed and fragmented and the intergranular separation distance approaches the distance between the primary particles. The volume reduction mechanism seems to be dependent on the kind of investigated material. Carstensen and Hou (1985) studied tablet pore size distribution from granules of tricalcium phosphate at different compaction pressures. They suggested that the reduction in total tablet porosity, with the subsequent increase in compact strength, was mainly due to the deformation of the granules. They argued that the intragranular pore space seemed to be more-or-less unaffected by the compression procedure. However, the granule production process was not described. It can be supposed that, if strongly fragmenting materials like the investigated magnesium carbonates and their granules are compacted, the intraparticular and interparticular pore space is filled with fragments due to increasing specific compaction and tableting pressure. The distinction between intraparticular and interparticular pore in the pore size distribution becomes difficult. The apparent mean yield pressure and the relative densities of magnesium carbonate were lower for powder tablets compared to granule tablets. The compression step of roll compaction/dry granulation resulted in higher values for the apparent mean yield pressure of the granule tablets. As shown in Fig. 8, large granule particles of one substance are less deformable during the tableting process than smaller powder particles. MC4 has the highest relative density and apparent mean yield pressure values, followed by MC1,

0.45

0.55

0.65

relative tablet density (mercury porosimetry)

Fig. 8. Apparent mean yield pressure of tablets and their relative density determined by mercury porosimetry at three tableting pressures (53, 105 and 158 MPa); (full symbols) powder, (open symbols) granules 7 kN/cm.

MC3 and MC2. This is consistent with the results depicted in Fig. 3. Relative density (determined by mercury porosimetry) increased by increasing tableting pressure and specific compaction force (Fig. 9). Tablets from the powder displayed higher tensile strength than the tablets produced from granules at 7 kN/cm. The additional compression during tableting did not solidify the resulting tablets. Hüttenrauch (1978) postulated a connection of tableting pressure, volume dilatation and hardness of compacts. The pressure sensitivity and hardness of compacts decreased with repeated compression because the activating breaking and friction events are missed. Furthermore, small particles showed a greater surface area than bigger ones and, therefore, more potential for activating breaking and friction events. The order and values differ slightly to the relative tablet density from part one due to the method of determination by mercury porosimetry and 4

MC1 MC2 MC3

tensile strength [N/mm ² ]

cumulative volume [%]

100

331

3

MC4 MC1 MC2

2

MC3 MC4

1

0 0.35

0.45

0.55

0.65

relative tablet density (mercury porosimetry)

Fig. 9. Tensile strength and relative density of tablets determined by mercury porosimetry at three tableting pressures (53, 105 and 158 MPa); (full symbols) powder, (open symbols) granules 7 kN/cm.

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measurement with micrometer screw, analytical balance and helium pycnometer. MC3 and MC2 are switched (Fig. 9) in comparison to part one which can be explained with their different particle shape and tablet surface structure. 4. Conclusion The measurement of ribbon microhardness and the investigation of tablet pore size with mercury porosimetry give crucial information to understand the roll compaction/dry granulation process. The four investigated magnesium carbonates differed during processing and, therefore, several parameters were used to describe the properties of starting materials, ribbons, granules and tablets. The magnesium carbonate with the lowest specific surface area, MC4, has the lowest degree of densification and the biggest tablet pores. This arrangement of properties results in tablets with the lowest tensile strength. MC1 has a higher specific surface area. The degree of densification is rising, tablet pores are diminishing and tablet tensile strength increases. The materials with the highest specific surface area, MC2 and MC3 have the highest degree of densification, the smallest pores and the highest tablet tensile strength. It could be shown that some material properties are preferable to produce granules and tablets using magnesium carbonate powder. High specific surface area, e.g. MC3, indicates a good compactibility of the starting material and leads to ribbons with a high microhardness and low part of fines. In regard to the microhardness, the materials showed a similar behaviour at low specific compaction forces, but exhibited marked differences at high specific compaction forces and at the tableting step. For MC1, MC2 and MC3, in the case of producing ribbons with higher specific compaction forces, e.g. with 7 kN/cm, the differences in microhardness of ribbons were considerable. In contrast, only little differences were noticed in tablet tensile strength at higher specific compaction forces compared to lower specific compaction forces. However, MC4 showed low values of microhardness as well as low values of tablet tensile strength. For ribbons prepared with all four magnesium carbonates increasing specific compaction force resulted in higher microhardness and, simultaneously, the part of fines diminished. In addition, the tensile strength of the corresponding tablets decreased. Hence, it can be suggested that low specific compaction forces are favourable in order to obtain tablets with good quality using magnesium carbonate materials. This is consistent and supportive to our previous finding (Freitag and Kleinebudde, 2003) which indicated that the materials should only be exposed to low loads in order to obtain good granule flowability. Acknowledgements The authors would like to thank Dr. Shlieout and Mr. Schenk, Magnesia GmbH, Germany and Mr. Fischer, Dr.

Paul Lohmann, GmbH KG for the supply of the magnesium carbonates. We also thank Mr. Syrowatka for taking the scanning electron micrographs, Ms. Schwarz for measuring BET-surface, Ms. Sachse for determining the microhardness, and Ms. Füssel and Mr. Benesch for doing the mercury porosity measurements. The authors are grateful to Mr. Augsten for excellent experimental assistance. Our research was supported by the Department of Culture and Education, Saxony-Anhalt (FKZ: 3081A/0029B).

References Alderborn, G., Wikberg, M., 1996. Granule properties. In: Alderborn, G., Nyström, C. (Eds.), Pharmaceutical Powder Compaction Technology. Marcel Dekker, New York, pp. 77–97. Aulton, M.E., 1981. Indentation hardness profiles across the faces of some compressed tablets. Pharm. Acta Helv. 56 (4–5), 133–136. Bierögel, C., Bethge, I., Grellmann W., Haberland, E.-J., 2001. Deformation behaviour of voice prostheses—sensitivity of mechanical test methods. In: Grellmann, W., Seidler, S. (Eds.), Deformation and Fracture Behaviour of Polymers. Springer, Berlin Heidelberg, pp. 471– 476. Carstensen, J.T., Hou, X.-P., 1985. The Athy–Heckel equation applied to granular agglomerates of basic tricalcium phosphate [3Ca3 PO4 )2 · Ca(OH)2 ]. Powder Technol. 42, 153–157. Deutsches Institut für Normung, 1975. DIN 66132: Bestimmung der spezifischen Oberfläche von Feststoffen durch Stickstoffadsorption (Einpunkt-Differenzverfahren nach Haul und Dümbgen), Beuth Verlag GmbH. Duberg, M., Nyström, C., 1986. Studies on direct compression of tablets XVII. Porosity–pressure curves for the characterisation of volume reduction mechanisms in powder compression. Powder Technol. 46, 67–75. Fell, J.T., Newton, J.M., 1970. Determination of tablet strength by the diametral-compression test. J. Pharm. Sci. 59, 688–691. Freitag, F., Kleinebudde, P., 2002. Effect of dry granulation on the tabletting behaviour of inorganic materials: magnesium carbonate. In: Proceedings of the Fourth World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Florence. 8–11 April 2002, pp. 235–236. Freitag, F., Kleinebudde, P., 2003. How do roll compaction/dry granulation affect the tableting behaviour of inorganic materials? Comparison of four magnesium carbonates. Eur. J. Pharm. Sci. 19, 281–289. Hersey, J.A., Rees, J.E., 1971. Deformation of particles during briqueting. Nat. Phys. Sci. 230 (12), 96. Hüttenrauch, R., 1978. Molekulargalenik als Grundlage moderner Arzneiforschung. Acta Pharm. Technol. Suppl. 6, 55–127. Juppo, A.M., 1996. Relationship between breaking force and pore structure of lactose, glucose and mannitol tablets. Int. J. Pharm. 127, 95–102. Lammens, R.F., 2002. Roll compactor instrumentation: key to rationalistic development, reproducible manufacturing, adequate trouble shooting. In: Proceedings of the Fourth World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Florence. 8–11 April 2002, pp. 29–30. Leuenberger, H., Rohera, B.D., 1986. Fundamentals of powder compression. I. The compactibility and compressibility of pharmaceutical powders. Pharm. Res. 3 (1), 12–22. Mattson, S., Nyström, C., 2000. Evaluation of strength-enhancing factors of a ductile binder in direct compression of sodium bicarbonate and calcium carbonate powders. Eur. J. Pharm. Sci. 10, 53–66. Riepma, K.A., Vromans, H., Zuurman, K., Lerk, C.F., 1993. The effect of dry granulation on the consolidation and compaction of crystalline lactose. Int. J. Pharm. 97, 29–38.

F. Freitag et al. / European Journal of Pharmaceutical Sciences 22 (2004) 325–333 Selkirk, A.B., Ganderton, D., 1970a. An investigation of the pore structure of tablets of sucrose and lactose by mercury porosimetry. J. Pharm. Pharmacol. Suppl. 22, 79S–85S. Selkirk, A.B., Ganderton, D., 1970b. The influence of wet and dry granulation methods on the pore structure of lactose tablets. J. Pharm. Pharmacol. Suppl. 22, 86S–94S. Vromans, H., De Boer, A.H., Bolhuis, G.K., Lerk, C.F., Kussendrager, K.D., Bosch, H., 1985. Studies on tableting properties of lactose. Part 2. Consolidation and compaction of different types of crystalline lactose. Pharm. Weekblad Sci. 7, 186–193. Wikberg, M., Alderborn, G., 1992. Compression characteristics of granulated materials. VI. Pore size distributions, assessed by mercury penetration, of compacts of two lactose granulations with different fragmentation propensities. Int. J. Pharm. 84, 191–195.

333

Wöll, F., Shlieout, G., Kleinebudde, P., 2000. Influence of production mode and compaction force of roller compactor on the properties of ribbons and tablets. In: Proceedings of the Third World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Berlin. 3–6 April 2000, pp. 81–82. York, P., 1992. Crystal engineering and particle design for the powder compaction process. Drug Dev. Ind. Pharm. 18 (6–7), 677– 721. Zuurmann, K., Riepma, K.A., Bolhuis, G.K., Vromans, H., Lerk, C.F., 1994. The relationship between bulk density and compactibility of lactose granulations. Int. J. Pharm. 102, 1–9. van der Zwan, J., Siskens, C.A.M., 1982. The compaction and mechanical properties of agglomerated materials. Powder Technol. 33, 43– 54.