- Email: [email protected]
The effects of lubrication on roll compaction, ribbon milling and tabletting
Chemical Engineering Science 86 (2013) 9–18
Contents lists available at SciVerse ScienceDirect
Chemical Engineering Science journal homepage: www.elsevier.com/locate/ces
The effects of lubrication on roll compaction, ribbon milling and tabletting Shen Yu a, Michael Adams a, Bindhu Gururajan b, Gavin Reynolds b, Ron Roberts b, Chuan-Yu Wu a,n a b
School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire SK10 2NA, UK
a r t i c l e i n f o
abstract
Article history: Received 3 November 2011 Received in revised form 30 January 2012 Accepted 18 February 2012 Available online 12 March 2012
Lubricants are commonly used in the pharmaceutical industry to prevent adhesion and improve the efficiency of roll compaction and tabletting. The aim of the current work is to develop an improved understanding of the mechanisms involved. Two commonly used pharmaceutical excipients, microcrystalline cellulose (MCC) and di-calcium phosphate dihydrate (DCPD), were selected as the model feed powders with magnesium stearate (MgSt) as the lubricant. An instrumented roll compactor was used, the ribbons were milled using an oscillating mill and the granules were compressed into tablets. The wall and internal friction angles of the feed powders were measured and related to the performance of the roll compaction that was characterised by the nip angle and maximum pressure. The milling performance was related to the fracture energy of the ribbons. The tabletting was assessed by the density and strength of the tablets. A qualitative interpretation of the data was developed and the practical implications of the work are considered. It was also shown that the bulk lubrication results in the reduction in internal friction for MCC but not for DCPD. The wall friction of DCPD is reduced by both bulk and wall lubrication unlike MCC for which the friction coefficient is essentially unchanged. The behaviour of the powders in roll compaction can be ascribed to the variation of the frictional properties due to lubrication. It is found that wall lubrication does not affect either the nip angle or the maximum roll pressure during roll compaction of MCC, but for DCPD the nip angle and maximum pressure are reduced with wall lubrication. In addition, the nip angle and the maximum pressure during roll compaction of MCC and DCPD are reduced with bulk lubrication. Furthermore, bulk lubrication causes reduction in the bonding properties and hence the tensile strength for MCC, but not for DCPD. & 2012 Elsevier Ltd. All rights reserved.
Keywords: Dry granulation Roll compaction Milling Tabletting Lubrication Magnesium stearate
1. Introduction In the pharmaceutical industry, especially for drug development with formulations that are sensitive to heat and moisture, dry granulation is preferred to wet size enlargement processes that require solution or melt binders. Dry granulation generally involves roll compaction in which the feed powders are compressed between counter-rotating rolls to form a coherent ribbon; granules are obtained by milling the ribbons. For most cohesive feed powders, a lubricant is generally required to improve flowability and to prevent adherence to the roll surfaces. Magnesium stearate (MgSt) is widely used as the lubricant for this purpose. It is a common boundary lubricant and such materials reduce solid–solid friction by providing a film with an interfacial shear strength that is smaller than that of the underlying surfaces. The distribution of the lubricant on the surfaces of the particles is a critical factor in controlling the effectiveness when used for powders. A number of
n
Corresponding author. Tel.: þ44121 4145365; fax: þ44121 4145324. E-mail address: [email protected] (C.-Y. Wu).
0009-2509/$ - see front matter & 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.ces.2012.02.026
mechanisms have been proposed on this basis (Bolhuis et al., 1975, 1980; Pintye-Hodi et al., 1981; Tawashi, 1963a, b) as summarised in Table 1. The most commonly accepted mechanism is the formation of Langmuir–Blodgett monolayer of MgSt and the filling of cavities by MgSt (Roblot-Treupel and Puisieux, 1986), especially with prolonged mixing time (Johansson and Nicklasson, 1986). It is probable that the large variations in particle sizes and surface topographies for different feed powders will result in a considerable variation in the performance of the lubricant. There have been a number of studies of roll compaction with MgSt as the lubricant (He et al., 2007; Migue´lez-Mora´n et al., 2008; von Eggelkraut-Gottanka et al., 2002). von Eggelkraut-Gottanka et al. (2002) compacted two different batches of dry herbal extract using a gap width and force controlled roll compactor and investigated the influence of processing parameters and the amount of magnesium stearate using multilinear stepwise regression analysis. It was reported that the disintegration time of the tablets increased with the concentration of MgSt due to an increase in hydrophobicity. They also argued that incorporation of MgSt into the granules (in the internal phase of the tablet) minimised the increase in disintegration time, while preserving its functionality as a lubricant.
10
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Table 1 Proposed mechanisms for the lubrication of MgSt based on the nature of the surface coverage. Mechanisms
References
Monomolecular film formation such that the inter-particle surfaces are separated by several molecular layers Uniform mono-particulate continuous layers with the separation between the particles involving a few MgSt particles The cavities on the host particle surfaces filled by MgSt to form smooth surfaces Non-uniform distribution of MgSt on the host particle surfaces
Bolhuis et al. (1975)
Tawashi (1963a, b)
Bolhuis et al. (1980) Pintye-Hodi et al. (1981)
He et al. (2007) roll-compacted MCC (grade Avicel PH 102, 44–75 mm sieve fraction) without lubricant and with 0.5% (w/w) MgSt. Heckel analysis, tablet tensile strength and dynamic indentation measurements were performed in order to evaluate the mechanisms for the loss of re-workability of the feed powder after roll compaction, especially with the addition of MgSt. They concluded that workhardening occurred in the process, and that over-lubrication due to the presence of MgSt appeared to be the major cause for the decrease in mechanical strength of the tablets. Migue´lez-Mora´n et al. (2008) investigated roll compaction with MCC (grade Avicel PH 102) under three conditions: (1) unlubricated, (2) lubricated roll surfaces and (3) lubricated powders, and showed that the most uniform feeding of the powders and the most uniform density of the compacted ribbons were obtained when the powder was lubricated internally with MgSt, while a reduction in the maximum pressure during roll compaction was observed. Their work clearly demonstrated that MgSt can affect the roll compaction of MCC. Despite the previous studies, the relationships between the performance of roll compaction, and the downstream processes of milling and tabletting, and the lubrication mechanisms have not been established. In particular, the influence of the lubricant on the milling behaviour, and the properties of the granules and tablets are not well understood. These were the aims of the current work, in which MCC and DCPD were chosen as the feed powders. They are both commonly used pharmaceutical excipients but with distinctive particle sizes, surface topographies and sensitivities to lubrication with MgSt; it has been reported that the lubrication of DCPD with MgSt is very insensitive to the mixing conditions (Vromans et al., 1988), unlike MCC (Zuurman et al., 1999). 2. Materials MgSt is a white odourless flake-like powder (see Fig. 1). Calipharm D grade DCPD (Rhodia, France) is a brittle crystalline powder with shale-like particles (Fig. 2a). MCC (Avicel grade PH 102, FMC Biopolymer, USA) is a crystalline powder (crystallinity 478%) with needle-shaped particles (see Fig. 2b) that exhibits greater plastic deformation than DCPD, which is relatively brittle. The true densities for MCC and DCPD were measured using a helium pycnometer (AccuPycII 1340, Micromeritics, USA) and are 1569 kg/m3 and 2582 kg/m3, respectively. The mean particle sizes for the two materials are 96.3 mm and 8.1 mm, respectively, measured using a particle size analyser (Model Helos, SympaTec, Germany). Various amounts of MgSt (w/w 0.15–1.5%) were mixed with the two powders using a double-cone blender. Preliminary studies (not presented here) revealed that the frictional and flow properties of the powders did not change for mixing times longer than 5 min, which was the time period finally selected for all the experiments reported here. The surface morphologies of the powders lubricated with 0.75% (w/w) MgSt are shown in Fig. 2c and d.
Fig. 1. Scanning electron micrograph of magnesium stearate.
3. Experimental 3.1. Ring shear cell tests The effective angle of internal friction of the feed powders and milled granules was measured using an RST-XS ring shear cell tester (Dietmar Schulze, Germany) with normal stresses in the range of 4–10 kPa. This instrument was also used to measure the angles of wall friction against a smooth stainless steel plate (surface roughness Ra 0.3 mm) with normal stresses in the range of 1.1–20 kPa. The morphologies of the powders before and after the wall friction measurements were attained using a Scanning electronic microscopy (6060, JEOL, Japan) and are shown in Fig. 2e and f.
3.2. Roll compaction The powders were compacted using a laboratory scale instrumented roll compactor developed at the University of Birmingham (Bindhumadhavan et al., 2005; Migue´lez-Mora´n et al., 2008; Patel et al., 2010). It consists of two stainless steel rolls of 46 mm in width and 100 mm in radius. Gravity powder feeding was employed, which involved an initial constant volume of powder in a hopper with a rectangular cross-section that was filled manually, and the excess was levelled gently. In the current study, the minimum roll gap, S, and the roll speed, u, were fixed at 1.0 mm and 1 rpm, respectively. The angular position, y, was measured from the minimum roll gap, and the corresponding radial roll pressure, p was measured using a piezoelectric pressure sensor (PCB 105C33, Techni-Measure, Studley, UK), which fitted in the centre of one roll, allowed the roll pressure distributions to be obtained. The influence of bulk and wall lubrication was investigated. In the case of wall lubrication, the metal roll surfaces were lubricated with ethanol suspensions of MgSt having concentrations of 0.25% and 1%. The dimensions (i.e. length, width and thickness) of the ribbons were measured using a digital calliper (Mitutoyo, Hampshire, UK) to determine their volumes, from which the bulk densities were obtained. The fracture energies of the ribbons were measured by 3-point bending configuration using a universal mechanical testing machine (Instron, High Wycombe, UK). This involved integrating the force–displacement data to determine the total work to fracture. The fracture energy was obtained as the ratio of the work and the area of the fracture surface.
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
11
Fig. 2. Scanning electron micrographs of DCPD and MCC powders with and without MgSt. (a) Unlubricated DCPD; (b) unlubricated MCC; (c) bulk lubricated DCPD (0.75% w/w MgSt); (d) Bulk lubricated MCC (0.75% w/w MgSt); (e) bulk lubricated DCPD after ring shear cell tests; (f) lubricated MCC after ring shear cell tests.
3.3. Milling Segments of ribbons (100 g) were cut to specific dimensions (approximately 22 22 mm) in order to minimise the effects of variations due to different shapes and sizes. An oscillating mill (Fig. 3, Coeply, AR 401) was used for the milling with a screen size of 630 mm, and a milling speed of 200 rpm. The mass throughput of granules as a function of time was measured using a computerised balance. 3.4. Uniaxial compression The feed powders and granules obtained from the milling process were compressed uniaxially into tablets in a stainless steel die with an internal diameter of 13.0 mm (Specac, UK) using a universal material testing machine (Z030, Zwick Roell, Germany). The compression speed was 0.5 mm/s, which is comparable to the
effective uniaxial component (i.e. the horizontal speed) in the roll compactor. The masses of MCC and DCPD powders and granules that were fed into the die were 0.8 and 1.1 g, respectively. The corresponding initial powder heights at a pre-compression load of 5 N were 15.05 and 9.43 mm for MCC and DCPD, respectively. The samples were then compressed with uniaxial strains of 0.66 and 0.53 in order to produce tablets of similar thickness (ca. 5 mm). Compressibility factors were determined from the stress–strain relationships in uniaxial compression using the same multi-variate fitting approach as proposed by Patel et al. (2010). Three cases were considered for the uniaxial compression of the feed powders: (1) unlubricated, (2) lubricated powder and (3) lubricated inner wall of the die. Once the tablets were ejected, the dimensions (i.e. diameter, thickness) and masses were measured so that the bulk densities could be determined. The tablets were then compressed diametrically to determine their tensile strength using the universal material testing machine.
12
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Screen Mesh
143 mm
Blade Mesh
136 mm 40 mm Blade
Fig. 3. (a) Photograph of the oscillating mill showing the blades and screen; (b) schematic diagram of the cross-sectional geometry.
4. Results
position data to the following equations given by Johanson (1965):
4.1. Ring shear cell tests
ds 4ðp=2yvÞtan fe ¼ s dx D=2½1 þ S=Dcos y½cotðAmÞcotðA þ mÞ
ð1Þ
ds kð2 cos y1S=DÞtan y ¼ s dx D=2½ð1 þS=Dcos yÞcos y
ð2Þ
Fig. 4 shows the wall shear stress as a function of the normal stress for the feed powders mixed with different amounts of MgSt; the gradients are equal to the coefficients of friction. In the case of the unlubricated powders, the gradients for DCPD and MCC are 0.5 and 0.09, respectively which for DCPD reduces to 0.1 when 0.75% (w/w) MgSt was added to the bulk, while for MCC the values are unaffected by the addition of the lubricant. The influence of the amount of lubricant on the wall friction in terms of the angle of wall friction, fw, is shown in Fig. 5, together with the corresponding effective angles of friction, fe. The value of fe for unlubricated DCPD is only slightly greater than for MCC and it does not decrease with increasing MgSt unlike MCC. The values of fe and fw of the granules produced by milling as a function of the amount of MgSt added to the feed powders are presented in Fig. 6. Only slight differences in the values of fe are observed between those for the granules (Fig. 6) and powders (Fig. 5). The wall friction for granules produced from unlubricated MCC is greater than the feed powder while lubrication leads to a reduction in the wall friction. For DCPD, the effect of MgSt on the wall friction for granules is not significant.
4.2. Roll compaction A simplified model of roll compaction was developed by Johanson (1965), who divided the space between the two counterrotating rolls into three different regions, termed the slip, nip and release regions. The slip region corresponds to the zone where the powders are fed into the compactor. They slip along the roll surfaces and rearrange in this region, and only small roll pressures are developed. The location where the velocity of the powder flow is equal to that of the roll surfaces is defined as the boundary of the nip region. In this zone, the powders are dragged to the smallest gap and compressed by the increasing pressure developed during the process. Powder densification primarily takes place in this region. The compacts then enter the release region after passing the smallest gap. Elastic recovery of the compacts occurs in this region. The maximum pressure and nip angle are two major parameters determining the performance of a roll compactor. A typical pressure distribution measured in the current work is shown in Fig. 7; the maximum pressure is 100 MPa and the nip angle is 81. The nip angles, which are a measure of the size of the compaction region, were determined from the measured roll pressure distributions using the method presented by Yu et al. (in press), which involves fitting the measured pressure gradient–angular
where the x coordinate corresponds to the centre of the gap between the rolls with an origin at the minimum roll gap such that positive values are against the direction of flow and D is the diameter of the rolls. k is the compressibility factor of the powder obtained from uniaxial compression experiments. The parameters n and A are functions of fe and fw as defined by the following expressions: 1 sin fw v¼ parcsin fw ð3Þ 2 sin fe A¼
y þv þ p=2 2
ð4Þ
where s is the pressure in an orthogonal direction to the roll surfaces at an angular position y with y ¼0 being the minimum roll gap, S. The data in the slip region were fitted to Eq. (1) and those in the nip region were fitted to Eq. (2) as exemplified in Fig. 8. The fitting parameters for Eq. (1) (i.e. slip region) were fe and fw, while that for Eq. (2) was k. The nip angle corresponds to the intersection of the two equations. The maximum roll pressures and nip angles are shown in Figs. 9 and 10. For MCC, the maximum pressure and nip angle were unaffected when the roll surfaces were lubricated but they were reduced by bulk lubrication. For DCPD, both roll and bulk lubrication resulted in reductions in the nip angle and maximum pressure. However, the maximum pressure and nip angle reach constant values at 0.25% w/w MgSt. Provided that there is sufficient MgSt to induce the maximum possible lubrication, the reduction in the nip angle and maximum pressure is similar.
4.3. Milling The solid fraction and fracture energies of the ribbons are given in Table 2. Solid fraction is used in order to compare the level of densification for the tablets. Bulk lubrication causes a large reduction in the values of solid fraction and fracture energy for MCC, but wall lubrication leads to a much smaller reduction. At the same roll compaction conditions (i.e. roll gap and roll speed), the solid fractions of the DCPD ribbons were smaller than those for MCC and the values were reduced by both wall and bulk lubrication. They were too fragile for measuring the fracture energies.
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
13
Fig. 4. Variation of the wall shear stress with normal stress for (a) DCPD and (b) MCC, with various amounts of MgSt in bulk.
Fig. 5. Frictional angles of MCC and DCPD as a function of amount of MgSt.
Fig. 6. Frictional angles of MCC and DCPD granules as a function of amount of MgSt.
14
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Fig. 11 shows the typical variation of the mass throughput with the number of milling cycles. The mass throughput increases with the number of cycles, but the rate decreases. It is possible to
describe the data using first order kinetics: dm ¼ kn ðm1 mÞ dN
ð5Þ
where N is the number of cycles, and m and mN are the mass of granules for N ¼N and N ¼N, respectively. Integrating subject to m¼0 at N ¼0 yields m1 m N ¼ exp ð6Þ m1 Nc where Nc is the characteristic number of milling cycles at which m¼ 1 e 1. Thus smaller values of this parameter correspond to more rapid breakdown of the ribbons. Eq. (6) can be re-arranged as N m ¼ m1 1exp ð7Þ Nc
Fig. 7. Typical pressure profile in roll compaction.
The values of Nc for the ribbons made from the unlubricated feed powders and those with wall and bulk lubrication are given in Table 2. It is clear that values for MCC are reduced by lubrication and are much greater than the values for DCPD, while for DCPD, the value of Nc is not sensitive to lubrication. Both the solid fraction and fracture energy for MCC decrease significantly when lubrication is applied, and hence so does the value of Nc. However, the solid fraction and Nc for DCPD are not affected by the lubrication. 4.4. Uniaxial compression
Fig. 8. Determination of nip angle from the pressure gradient data for MCC (S¼ 1.0 mm, u¼ 1.0 rpm).
The solid fraction and tensile strength of the tablets made from the feed powders and granules with and without lubrication are given in Table 3. The solid fractions for each of the powders and granules are approximately constant, which should be the case given the way that the experimental procedure was carried out. It can be seen that the solid fraction for MCC powder and granules are not affected when lubricated, while the values for the granules are smaller than those for the powders due to the loss of tabletability. At the same time, the tensile strength of the tablets decreases significantly when the amount of MgSt is increased. In contrast, the solid fractions for DCPD are not affected by lubrication, and the values for the powders and granules are comparable. With an increasing amount of MgSt, a small increase in the tensile strength is observed. The overall variation of the tablet strength with the amount of MgSt is shown in Fig. 12. The strength of the unlubricated MCC tablets (i.e. when the concentration of MgSt is zero) is about a factor of 6 greater than the corresponding DCPD tablets.
Fig. 9. Effects of lubrication on the maximum roll pressures.
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
15
Fig. 10. Effects of lubrication on nip angle in roll compaction.
Table 2 Effects of lubrication on the bulk density and fracture energy of the ribbons and the characteristic number of milling cycles. MCC
No lubrication Lubricated roll surface 0.25% MgSt (bulk lubrication) 1% of MgSt (bulk lubrication) a
DCPD 2
Solid fraction
Fracture energy (J/m )
Nc
Solid fraction
Fracture energy of the ribbon (J/m2)
Nc
0.683 7 0.035 0.644 7 0.024 0.537 7 0.013 0.475 7 0.000
112 7 3 1097 3 697 1 527 3
951 872 536 306
0.498 7 0.016 0.436 7 0.008 0.470 7 0.011 0.448 7 0.023
a
15 13 13 13
a a a
Ribbons are too fragile for 3-point bend measurement.
case, 0.5% (w/w) MgSt was applied for the bulk lubrication. Fig. 13 shows the data produced from the granules and powders under various lubrication conditions for DCPD and MCC. It is clear that the strength of DCPD tablets is not significantly affected by lubrication and granulation since all the data superimpose onto a single master curve (Fig. 13a). In contrast, in the case of bulk lubrication, a reduction of 30% in tensile strength is observed for MCC (Fig. 13b). The tablets made from granules are weaker than those made from the feed powders, which is consistent with results reported in the literature (Herting and Kleinebudde, 2008). The Ryshkewitch–Duckworth equation (Duckworth, 1953) was employed to fit the experimental data
st ¼ sekð1fÞ
Fig. 11. Typical milling results for roll compacted ribbons made from unlubricated MCC powders at the roll gap of 1.0 mm, roll speed of 1.0 rpm.
The strengths of the MCC tablets are reduced by bulk lubrication but not by wall lubrication whereas lubrication has little effect on the strength of DCPD tablets. For both MCC and DCPD, the tablets made from granules possess lower tensile strength compared to those made directly from the feed powders. In order to explore the correlation between the solid fraction and tensile strength of the tablets, additional experiments were carried out. Powders and granules were compressed with compression pressures in a range of 52.7–165.7 MPa with an interval of 22.6 MPa to produce tablets with various solid fractions. In this
ð8Þ
where st is the tensile strength of the compacts at a solid fraction of f, s is the tensile strength for the same material at zero porosity, k is a constant representing the bonding capacity of the material with a larger value of k indicating weaker bonding capacity. Typical data fitting are shown in Fig. 13, and the values of the fitting parameters are listed in Table 4. For DCPD, the values of s and k for the various cases considered are essentially identical. For MCC, granulation and lubrication lead to a reduction in the value of s, but an increase in the value of k, indicating a reduction in bonding capacity.
5. Discussion The coefficient of wall friction for unlubricated DCPD is about a factor of 5 greater than that for MCC (Fig. 5). This arises from the smaller interfacial shear strength of organic compared with
16
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Table 3 Effects of lubrication on the solid fractions and tensile strength of the tablets. MCC feed powder
No lubrication Lubricated roll surface Lubricated die wall 0.25% MgSt 1% of MgSt
MCC granules
Solid fraction
Tensile strength (kPa)
Solid fraction
Tensile strength (kPa)
0.7127 0.005 – 0.7067 0.004 0.7007 0.003 0.6937 0.004
5690 7 12 – 5673 7 4 3871 7 13 3113 7 14
0.6387 0.005 0.6357 0.004 – 0.6427 0.003 0.6467 0.003
4221 7 17 4263 7 21 – 2940 7 12 2203 7 6
DCPD feed powder
No lubrication Lubricated roll surface Lubricated die wall 0.25% MgSt 1% of MgSt
DCPD granules
Solid fraction
Tensile strength (kPa)
Solid fraction
Tensile strength (kPa)
0.5897 0.002 – 0.5957 0.001 0.5917 0.003 0.5887 0.005
951 7 2 – 952 7 4 960 73 983 7 4
0.5847 0.003 0.5917 0.005 – 0.5947 0.004 0.5967 0.002
789 7 3 796 7 5 – 799 7 8 792 7 8
Fig. 12. Effects of lubrication on the tablet strength, the data points on the vertical dash line (x¼ 0) present the values for unlubricated cases.
inorganic materials. Boundary lubricants provide a weak interfacial layer with coefficients of friction being typically 0.1 (Bowden and Tabor, 1950), which represents the minimum value that can generally be achieved. This is similar to that measured for unlubricated MCC and consequently boundary lubrication was ineffective at reducing friction. Organic polymers are generally difficult to boundary lubricate since they typically have similar interfacial shear strengths to boundary lubricants being both organic in nature. However, the coefficient of friction for unlubricated DCPD was 0.5 and therefore it could be effectively reduced by the application of MgSt to the observed minimum value of 0.1. There is clearly a minimum amount of MgSt required to achieve a uniform and robust surface layer. The coefficient of wall friction for unlubricated MCC increases after granulation, while the value for DCPD decreases (Fig. 6). This may be ascribed to the size enlargement and changes in the surface morphology. For the granules produced from feed powders with bulk lubrication, boundary lubrication is only effective for MCC. There is likely to be at least two contributory factors to the wall friction for DCPD granules being practically unchanged by the addition of MgSt. Firstly, in the milling process, some of the particles are lost because of their small size ( 8 mm) and, because of their relatively large surface-to-volume ratio, this causes a disproportional loss of the adhered MgSt. Secondly, even if DCPD granules are initially well-lubricated on the surface, fragmentation
Fig. 13. Tensile strength as a function of solid fraction of the tablets produced under various lubricating conditions for (a) DCPD and (b) MCC, the solid line presents the fitting results to Eq. (8).
Table 4 The value of fitting parameters in Eq. (8) obtained from multivariate fitting to experimental data. Feeding material
s (MPa)
k
DCPD
924.2
19.1180
9.1 12.4 12.1 11.8 15.9
6.8998 6.4918 6.3497 6.5436 5.7308
MCC MCC MCC MCC MCC MCC
granule granule granule powder powder
(bulk lubrication) (wall lubrication) (no lubrication) (bulk lubrication) (no lubrication)
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
of these relatively friable granules causes less well-lubricated interior surfaces to become exposed (De Boer et al., 1978). The effective angles of internal friction for the two unlubricated powders are relatively similar despite the evident large differences in their wall frictional characteristics (Fig. 5). However, other factors, such as particle shape and size distribution, are important that may account for this observation. There is no reduction in fe when the DCPD is lubricated in the bulk. This suggests that there is shear induced fracture of the particles that exposes fresh unlubricated surfaces, which is consistent with their brittle nature. Clearly, this mechanism does not operate for the MCC. Wall lubrication causes a small reduction in the coefficient of wall friction and this must account for the relatively large reduction in fe with a considerable scaling effect from single particles to assemblies. As in the case of the shear cell data, it is not possible to make direct comparisons of the absolute values of the maximum pressures and nip angles based only on the relative frictional characteristics. Other factors include the compressibility in particular and future work will involve examining the accuracy of theoretical models, such as that of Johanson (1965), in predicting the maximum roll pressure and nip angle based on the properties of the feed powders. However, it is possible to provide some qualitative interpretation of the changes with lubrication based on the measured wall and internal friction. For MCC, lubricating the rolls does not affect either the nip angle (Fig. 10) or the maximum roll pressure (Fig. 9), which is consistent with the insensitivity of the friction to wall lubrication. However, there is a reduction in both parameters for bulk lubrication that increases with the amount of MgSt. This is reflected in the reduction in the density and strength of the ribbons. As discussed above, it is difficult to boundary lubricate MCC. However, the bulk lubrication reduces the internal friction and increases the overall powder flowability. Therefore, the nip angle and the maximum pressure are reduced. In the case of DCPD, unlike MCC, the nip angle (Fig. 10), maximum pressure (Fig. 9) and also the density of the ribbons are all reduced by lubricating the rolls. The much greater sensitivity of the wall friction to boundary lubrication is a possible explanation since the values for the nip angle and maximum pressure are similar to those for critically bulk lubricated DCPD. That is, the bulk lubrication is again providing an internal source of the lubricant. The rate at which the ribbons are milled, as characterised by the parameter Nc, appears to be simply related to the fracture energy, as might reasonably be expected. It also appears that for the MCC, there is a close correlation between the ribbon densities and the fracture energies (Table 2), which is the expected behaviour. There is insufficient data to delineate a secondary effect of the presence of MgSt, which could reduce the strength by acting as a weak layer between the particles or it could behave as a binder. That the DCPD ribbons are mechanically weak almost certainly is the result of the stored elastic strains in the exit region that prevent coherent bonds forming between the particles. These strains will be much less for MCC since organic polymers exhibit elastoplastic deformation. The elastic recovery will be a contributory factor, together with the smaller nip angles, to the smaller densities of the DCPD ribbons compared with those formed from MCC. The strength of the DCPD tablets is much less than those formed from MCC (Table 3 and Fig. 13), which is analogous to the data for the strength of the ribbons as indicated by the fracture energy shown in Table 2. The relative values of the stored elastic strains are probably again the main governing factor. The insensitivity of the strength of the DCPD tablets to lubrication (Table 3, Figs. 12 and 13a) may be attributed to the fragmentation characteristics of the powder particles that cause fresh surfaces to
17
be exposed and thus inhibiting any potential binding by the MgSt. Bulk lubrication causes a reduction in the strength of the MCC tablets (Table 3, Figs. 12 and 13b), which suggests that the MgSt is acting as a weak boundary layer between the particles (Zuurman et al., 1999), which reduces the bonding strength (Table 4). Thus the influence of lubrication on both the DCPD and MCC tablets is also similar to the trends observed for the ribbons as shown in Table 2. Future work will be aimed at a comparable study of binary mixtures to reflect more realistic formulations. However, there are some general trends in the current work that may be worth considering in terms of practical applications. Firstly, in the case of MCC which is a major formulation component, for a given set of roll compaction conditions, the addition of a lubricant will reduce the nip angle and the maximum roll pressure. This will lead to a reduction in the strength of the ribbons that will increase the rate of milling, but reduce the sizes of the granules. Secondly, the strength of tablets will provide a useful ranking indicator for the strength of the ribbons and hence the rate at which they can be milled. For example, this approach could be applied to the influence of lubricants.
6. Conclusions Characterising the feed powder, the roll compaction process and the compacted ribbons, the milling of the ribbons, the tabletting of the milled granules and the tablets formed from the granules are useful strategies for understanding the influence of a boundary lubricant on the formulation. Overall, it was possible to develop a coherent but qualitative interpretation of the data that provides some mechanistic insights and has some practical implications. Conclusively, the application of bulk lubrication prevents the adhesion in compaction processes, but leads to reduction in the strength and solid fraction of the corresponding tablets for MCC. However, these negative effects are not shown for DCPD. Wall lubrication minimises the reduction in the tensile strength of the final product for both powders.
Acknowledgements The authors would like to thank AstraZeneca for funding the project and providing sample materials. The characterisation equipments used were obtained, through Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World, with support from AWM and part funded ERDF. References Bindhumadhavan, G., Seville, J.P.K., Adams, M.J., Greenwood, R.W., Fitzpatrick, S., 2005. Roll compaction of a pharmaceutical excipient: experimental validation of rolling theory for granular solids. Chem. Eng. Sci. 60, 3891–3897. Bolhuis, G.K., Lerk, C.F., Broersma, P., 1980. Mixing action and evaluation of tablet lubricants in direct compression. Drug Dev. Ind. Pharm. 6, 15–33. Bolhuis, G.K., Lerk, C.F., Zijlstra, H.T., De Boer, A.H., 1975. Film formation by magnesium stearate during mixing and its effect on tabletting. Pharm. Weekbl. 110, 317–325. Bowden, F.P., Tabor, D., 1950. The Friction and Lubrication of Solids. Oxford University Press, New York. De Boer, A.H., Bolhuis, G.K., Lerk, C.F., 1978. Bonding characteristics by scanning electron microscopy of powders mixed with magnesium stearate. Powder Technol. 20, 75–82. Duckworth, W., 1953. Discussion of Ryshkewitch paper. J. Am. Ceram. Soc. 36, 68. He, X.R., Secreast, P.J., Amidon, G.E., 2007. Mechanistic study of the effect of roller compaction and lubricant on tablet mechanical strength. J. Pharm. Sci. 96, 1342–1355. Herting, M.G., Kleinebudde, P., 2008. Studies on the reduction of tensile strength of tablets after roll compaction/dry granulation. Eur. J. Pharm. Biopharm. 70, 372–379.
18
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Johanson, J.R., 1965. A rolling theory for granular solids. J. Appl. Mech. 32, 842–848. Johansson, M.E., Nicklasson, M., 1986. Investigation of the film formation of magnesium stearate by applying a flow-through dissolution technique. J. Pharm. Pharmacol. 38, 51–54. Migue´lez-Mora´n, A.M., Wu, C.Y., Seville, J.P.K., 2008. The effect of lubrication on density distributions of roller compacted ribbons. Int. J. Pharm. 362, 52–59. Patel, B.A., Adams, M.J., Turnbull, N., Bentham, A.C., Wu, C.Y., 2010. Predicting the pressure distribution during roll compaction from uniaxial compaction measurements. Chem. Eng. J. 164, 410–417. Pintye-Hodi, K., Toth, I., Kata, M., 1981. Investigation of the formation of magnesium stearate film by energy dispersive X ray microanalysis. Pharm. Acta Helv. 56, 320–324. Roblot-Treupel, L., Puisieux, F., 1986. Distribution of magnesium stearate on the surface of lubricated particles. Int. J. Pharm. 31, 131–136. Tawashi, R., 1963a. Der Einfluss von Aerosil auf die Fleisseigenschaften von pulvern. Pharm. Ind. 25, 64–66.
Tawashi, R., 1963b. Der Einfluss von Aerosil auf die Packungseigenschaften von pulvern. Pharm. Ind. 25, 655–658. von Eggelkraut-Gottanka, S.G., Abu Abed, S., Muller, W., Schmidt, P.C., 2002. Roller compaction and tabletting of St. John’s wort plant dry extract using a gap width and force controlled roller compactor. II. Study of roller compaction variables on granule and tablet properties by a 3(3) factorial design. Pharm. Dev. Technol. 7, 447–455. Vromans, H., Bolhuis, G.K., Lerk, C.F., 1988. Magnesium stearate susceptibility of directly compressible materials as an indication of fragmentation properties. Powder Technol. 54, 39–44. Shen, Yu, Bindhu, Gururajan, Gavin, Reynolds, Ron, Roberts, Michael J., Adams, Chuan-Yu, Wu., A comparative study of roll compaction of free-flowing and cohesive pharmaceutical powders. Int. J. Pharm. doi:10.1016/j.ijpharm. 2012.02.033, in press. Zuurman, K., Van der Voort Maarschalk, K., Bolhuis, G.K., 1999. Effect of magnesium stearate on bonding and porosity expansion of tablets produced from materials with different consolidation properties. Int. J. Pharm. 179, 107–115.
Contents lists available at SciVerse ScienceDirect
Chemical Engineering Science journal homepage: www.elsevier.com/locate/ces
The effects of lubrication on roll compaction, ribbon milling and tabletting Shen Yu a, Michael Adams a, Bindhu Gururajan b, Gavin Reynolds b, Ron Roberts b, Chuan-Yu Wu a,n a b
School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Pharmaceutical Development, AstraZeneca, Macclesfield, Cheshire SK10 2NA, UK
a r t i c l e i n f o
abstract
Article history: Received 3 November 2011 Received in revised form 30 January 2012 Accepted 18 February 2012 Available online 12 March 2012
Lubricants are commonly used in the pharmaceutical industry to prevent adhesion and improve the efficiency of roll compaction and tabletting. The aim of the current work is to develop an improved understanding of the mechanisms involved. Two commonly used pharmaceutical excipients, microcrystalline cellulose (MCC) and di-calcium phosphate dihydrate (DCPD), were selected as the model feed powders with magnesium stearate (MgSt) as the lubricant. An instrumented roll compactor was used, the ribbons were milled using an oscillating mill and the granules were compressed into tablets. The wall and internal friction angles of the feed powders were measured and related to the performance of the roll compaction that was characterised by the nip angle and maximum pressure. The milling performance was related to the fracture energy of the ribbons. The tabletting was assessed by the density and strength of the tablets. A qualitative interpretation of the data was developed and the practical implications of the work are considered. It was also shown that the bulk lubrication results in the reduction in internal friction for MCC but not for DCPD. The wall friction of DCPD is reduced by both bulk and wall lubrication unlike MCC for which the friction coefficient is essentially unchanged. The behaviour of the powders in roll compaction can be ascribed to the variation of the frictional properties due to lubrication. It is found that wall lubrication does not affect either the nip angle or the maximum roll pressure during roll compaction of MCC, but for DCPD the nip angle and maximum pressure are reduced with wall lubrication. In addition, the nip angle and the maximum pressure during roll compaction of MCC and DCPD are reduced with bulk lubrication. Furthermore, bulk lubrication causes reduction in the bonding properties and hence the tensile strength for MCC, but not for DCPD. & 2012 Elsevier Ltd. All rights reserved.
Keywords: Dry granulation Roll compaction Milling Tabletting Lubrication Magnesium stearate
1. Introduction In the pharmaceutical industry, especially for drug development with formulations that are sensitive to heat and moisture, dry granulation is preferred to wet size enlargement processes that require solution or melt binders. Dry granulation generally involves roll compaction in which the feed powders are compressed between counter-rotating rolls to form a coherent ribbon; granules are obtained by milling the ribbons. For most cohesive feed powders, a lubricant is generally required to improve flowability and to prevent adherence to the roll surfaces. Magnesium stearate (MgSt) is widely used as the lubricant for this purpose. It is a common boundary lubricant and such materials reduce solid–solid friction by providing a film with an interfacial shear strength that is smaller than that of the underlying surfaces. The distribution of the lubricant on the surfaces of the particles is a critical factor in controlling the effectiveness when used for powders. A number of
n
Corresponding author. Tel.: þ44121 4145365; fax: þ44121 4145324. E-mail address: [email protected] (C.-Y. Wu).
0009-2509/$ - see front matter & 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.ces.2012.02.026
mechanisms have been proposed on this basis (Bolhuis et al., 1975, 1980; Pintye-Hodi et al., 1981; Tawashi, 1963a, b) as summarised in Table 1. The most commonly accepted mechanism is the formation of Langmuir–Blodgett monolayer of MgSt and the filling of cavities by MgSt (Roblot-Treupel and Puisieux, 1986), especially with prolonged mixing time (Johansson and Nicklasson, 1986). It is probable that the large variations in particle sizes and surface topographies for different feed powders will result in a considerable variation in the performance of the lubricant. There have been a number of studies of roll compaction with MgSt as the lubricant (He et al., 2007; Migue´lez-Mora´n et al., 2008; von Eggelkraut-Gottanka et al., 2002). von Eggelkraut-Gottanka et al. (2002) compacted two different batches of dry herbal extract using a gap width and force controlled roll compactor and investigated the influence of processing parameters and the amount of magnesium stearate using multilinear stepwise regression analysis. It was reported that the disintegration time of the tablets increased with the concentration of MgSt due to an increase in hydrophobicity. They also argued that incorporation of MgSt into the granules (in the internal phase of the tablet) minimised the increase in disintegration time, while preserving its functionality as a lubricant.
10
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Table 1 Proposed mechanisms for the lubrication of MgSt based on the nature of the surface coverage. Mechanisms
References
Monomolecular film formation such that the inter-particle surfaces are separated by several molecular layers Uniform mono-particulate continuous layers with the separation between the particles involving a few MgSt particles The cavities on the host particle surfaces filled by MgSt to form smooth surfaces Non-uniform distribution of MgSt on the host particle surfaces
Bolhuis et al. (1975)
Tawashi (1963a, b)
Bolhuis et al. (1980) Pintye-Hodi et al. (1981)
He et al. (2007) roll-compacted MCC (grade Avicel PH 102, 44–75 mm sieve fraction) without lubricant and with 0.5% (w/w) MgSt. Heckel analysis, tablet tensile strength and dynamic indentation measurements were performed in order to evaluate the mechanisms for the loss of re-workability of the feed powder after roll compaction, especially with the addition of MgSt. They concluded that workhardening occurred in the process, and that over-lubrication due to the presence of MgSt appeared to be the major cause for the decrease in mechanical strength of the tablets. Migue´lez-Mora´n et al. (2008) investigated roll compaction with MCC (grade Avicel PH 102) under three conditions: (1) unlubricated, (2) lubricated roll surfaces and (3) lubricated powders, and showed that the most uniform feeding of the powders and the most uniform density of the compacted ribbons were obtained when the powder was lubricated internally with MgSt, while a reduction in the maximum pressure during roll compaction was observed. Their work clearly demonstrated that MgSt can affect the roll compaction of MCC. Despite the previous studies, the relationships between the performance of roll compaction, and the downstream processes of milling and tabletting, and the lubrication mechanisms have not been established. In particular, the influence of the lubricant on the milling behaviour, and the properties of the granules and tablets are not well understood. These were the aims of the current work, in which MCC and DCPD were chosen as the feed powders. They are both commonly used pharmaceutical excipients but with distinctive particle sizes, surface topographies and sensitivities to lubrication with MgSt; it has been reported that the lubrication of DCPD with MgSt is very insensitive to the mixing conditions (Vromans et al., 1988), unlike MCC (Zuurman et al., 1999). 2. Materials MgSt is a white odourless flake-like powder (see Fig. 1). Calipharm D grade DCPD (Rhodia, France) is a brittle crystalline powder with shale-like particles (Fig. 2a). MCC (Avicel grade PH 102, FMC Biopolymer, USA) is a crystalline powder (crystallinity 478%) with needle-shaped particles (see Fig. 2b) that exhibits greater plastic deformation than DCPD, which is relatively brittle. The true densities for MCC and DCPD were measured using a helium pycnometer (AccuPycII 1340, Micromeritics, USA) and are 1569 kg/m3 and 2582 kg/m3, respectively. The mean particle sizes for the two materials are 96.3 mm and 8.1 mm, respectively, measured using a particle size analyser (Model Helos, SympaTec, Germany). Various amounts of MgSt (w/w 0.15–1.5%) were mixed with the two powders using a double-cone blender. Preliminary studies (not presented here) revealed that the frictional and flow properties of the powders did not change for mixing times longer than 5 min, which was the time period finally selected for all the experiments reported here. The surface morphologies of the powders lubricated with 0.75% (w/w) MgSt are shown in Fig. 2c and d.
Fig. 1. Scanning electron micrograph of magnesium stearate.
3. Experimental 3.1. Ring shear cell tests The effective angle of internal friction of the feed powders and milled granules was measured using an RST-XS ring shear cell tester (Dietmar Schulze, Germany) with normal stresses in the range of 4–10 kPa. This instrument was also used to measure the angles of wall friction against a smooth stainless steel plate (surface roughness Ra 0.3 mm) with normal stresses in the range of 1.1–20 kPa. The morphologies of the powders before and after the wall friction measurements were attained using a Scanning electronic microscopy (6060, JEOL, Japan) and are shown in Fig. 2e and f.
3.2. Roll compaction The powders were compacted using a laboratory scale instrumented roll compactor developed at the University of Birmingham (Bindhumadhavan et al., 2005; Migue´lez-Mora´n et al., 2008; Patel et al., 2010). It consists of two stainless steel rolls of 46 mm in width and 100 mm in radius. Gravity powder feeding was employed, which involved an initial constant volume of powder in a hopper with a rectangular cross-section that was filled manually, and the excess was levelled gently. In the current study, the minimum roll gap, S, and the roll speed, u, were fixed at 1.0 mm and 1 rpm, respectively. The angular position, y, was measured from the minimum roll gap, and the corresponding radial roll pressure, p was measured using a piezoelectric pressure sensor (PCB 105C33, Techni-Measure, Studley, UK), which fitted in the centre of one roll, allowed the roll pressure distributions to be obtained. The influence of bulk and wall lubrication was investigated. In the case of wall lubrication, the metal roll surfaces were lubricated with ethanol suspensions of MgSt having concentrations of 0.25% and 1%. The dimensions (i.e. length, width and thickness) of the ribbons were measured using a digital calliper (Mitutoyo, Hampshire, UK) to determine their volumes, from which the bulk densities were obtained. The fracture energies of the ribbons were measured by 3-point bending configuration using a universal mechanical testing machine (Instron, High Wycombe, UK). This involved integrating the force–displacement data to determine the total work to fracture. The fracture energy was obtained as the ratio of the work and the area of the fracture surface.
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
11
Fig. 2. Scanning electron micrographs of DCPD and MCC powders with and without MgSt. (a) Unlubricated DCPD; (b) unlubricated MCC; (c) bulk lubricated DCPD (0.75% w/w MgSt); (d) Bulk lubricated MCC (0.75% w/w MgSt); (e) bulk lubricated DCPD after ring shear cell tests; (f) lubricated MCC after ring shear cell tests.
3.3. Milling Segments of ribbons (100 g) were cut to specific dimensions (approximately 22 22 mm) in order to minimise the effects of variations due to different shapes and sizes. An oscillating mill (Fig. 3, Coeply, AR 401) was used for the milling with a screen size of 630 mm, and a milling speed of 200 rpm. The mass throughput of granules as a function of time was measured using a computerised balance. 3.4. Uniaxial compression The feed powders and granules obtained from the milling process were compressed uniaxially into tablets in a stainless steel die with an internal diameter of 13.0 mm (Specac, UK) using a universal material testing machine (Z030, Zwick Roell, Germany). The compression speed was 0.5 mm/s, which is comparable to the
effective uniaxial component (i.e. the horizontal speed) in the roll compactor. The masses of MCC and DCPD powders and granules that were fed into the die were 0.8 and 1.1 g, respectively. The corresponding initial powder heights at a pre-compression load of 5 N were 15.05 and 9.43 mm for MCC and DCPD, respectively. The samples were then compressed with uniaxial strains of 0.66 and 0.53 in order to produce tablets of similar thickness (ca. 5 mm). Compressibility factors were determined from the stress–strain relationships in uniaxial compression using the same multi-variate fitting approach as proposed by Patel et al. (2010). Three cases were considered for the uniaxial compression of the feed powders: (1) unlubricated, (2) lubricated powder and (3) lubricated inner wall of the die. Once the tablets were ejected, the dimensions (i.e. diameter, thickness) and masses were measured so that the bulk densities could be determined. The tablets were then compressed diametrically to determine their tensile strength using the universal material testing machine.
12
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Screen Mesh
143 mm
Blade Mesh
136 mm 40 mm Blade
Fig. 3. (a) Photograph of the oscillating mill showing the blades and screen; (b) schematic diagram of the cross-sectional geometry.
4. Results
position data to the following equations given by Johanson (1965):
4.1. Ring shear cell tests
ds 4ðp=2yvÞtan fe ¼ s dx D=2½1 þ S=Dcos y½cotðAmÞcotðA þ mÞ
ð1Þ
ds kð2 cos y1S=DÞtan y ¼ s dx D=2½ð1 þS=Dcos yÞcos y
ð2Þ
Fig. 4 shows the wall shear stress as a function of the normal stress for the feed powders mixed with different amounts of MgSt; the gradients are equal to the coefficients of friction. In the case of the unlubricated powders, the gradients for DCPD and MCC are 0.5 and 0.09, respectively which for DCPD reduces to 0.1 when 0.75% (w/w) MgSt was added to the bulk, while for MCC the values are unaffected by the addition of the lubricant. The influence of the amount of lubricant on the wall friction in terms of the angle of wall friction, fw, is shown in Fig. 5, together with the corresponding effective angles of friction, fe. The value of fe for unlubricated DCPD is only slightly greater than for MCC and it does not decrease with increasing MgSt unlike MCC. The values of fe and fw of the granules produced by milling as a function of the amount of MgSt added to the feed powders are presented in Fig. 6. Only slight differences in the values of fe are observed between those for the granules (Fig. 6) and powders (Fig. 5). The wall friction for granules produced from unlubricated MCC is greater than the feed powder while lubrication leads to a reduction in the wall friction. For DCPD, the effect of MgSt on the wall friction for granules is not significant.
4.2. Roll compaction A simplified model of roll compaction was developed by Johanson (1965), who divided the space between the two counterrotating rolls into three different regions, termed the slip, nip and release regions. The slip region corresponds to the zone where the powders are fed into the compactor. They slip along the roll surfaces and rearrange in this region, and only small roll pressures are developed. The location where the velocity of the powder flow is equal to that of the roll surfaces is defined as the boundary of the nip region. In this zone, the powders are dragged to the smallest gap and compressed by the increasing pressure developed during the process. Powder densification primarily takes place in this region. The compacts then enter the release region after passing the smallest gap. Elastic recovery of the compacts occurs in this region. The maximum pressure and nip angle are two major parameters determining the performance of a roll compactor. A typical pressure distribution measured in the current work is shown in Fig. 7; the maximum pressure is 100 MPa and the nip angle is 81. The nip angles, which are a measure of the size of the compaction region, were determined from the measured roll pressure distributions using the method presented by Yu et al. (in press), which involves fitting the measured pressure gradient–angular
where the x coordinate corresponds to the centre of the gap between the rolls with an origin at the minimum roll gap such that positive values are against the direction of flow and D is the diameter of the rolls. k is the compressibility factor of the powder obtained from uniaxial compression experiments. The parameters n and A are functions of fe and fw as defined by the following expressions: 1 sin fw v¼ parcsin fw ð3Þ 2 sin fe A¼
y þv þ p=2 2
ð4Þ
where s is the pressure in an orthogonal direction to the roll surfaces at an angular position y with y ¼0 being the minimum roll gap, S. The data in the slip region were fitted to Eq. (1) and those in the nip region were fitted to Eq. (2) as exemplified in Fig. 8. The fitting parameters for Eq. (1) (i.e. slip region) were fe and fw, while that for Eq. (2) was k. The nip angle corresponds to the intersection of the two equations. The maximum roll pressures and nip angles are shown in Figs. 9 and 10. For MCC, the maximum pressure and nip angle were unaffected when the roll surfaces were lubricated but they were reduced by bulk lubrication. For DCPD, both roll and bulk lubrication resulted in reductions in the nip angle and maximum pressure. However, the maximum pressure and nip angle reach constant values at 0.25% w/w MgSt. Provided that there is sufficient MgSt to induce the maximum possible lubrication, the reduction in the nip angle and maximum pressure is similar.
4.3. Milling The solid fraction and fracture energies of the ribbons are given in Table 2. Solid fraction is used in order to compare the level of densification for the tablets. Bulk lubrication causes a large reduction in the values of solid fraction and fracture energy for MCC, but wall lubrication leads to a much smaller reduction. At the same roll compaction conditions (i.e. roll gap and roll speed), the solid fractions of the DCPD ribbons were smaller than those for MCC and the values were reduced by both wall and bulk lubrication. They were too fragile for measuring the fracture energies.
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
13
Fig. 4. Variation of the wall shear stress with normal stress for (a) DCPD and (b) MCC, with various amounts of MgSt in bulk.
Fig. 5. Frictional angles of MCC and DCPD as a function of amount of MgSt.
Fig. 6. Frictional angles of MCC and DCPD granules as a function of amount of MgSt.
14
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Fig. 11 shows the typical variation of the mass throughput with the number of milling cycles. The mass throughput increases with the number of cycles, but the rate decreases. It is possible to
describe the data using first order kinetics: dm ¼ kn ðm1 mÞ dN
ð5Þ
where N is the number of cycles, and m and mN are the mass of granules for N ¼N and N ¼N, respectively. Integrating subject to m¼0 at N ¼0 yields m1 m N ¼ exp ð6Þ m1 Nc where Nc is the characteristic number of milling cycles at which m¼ 1 e 1. Thus smaller values of this parameter correspond to more rapid breakdown of the ribbons. Eq. (6) can be re-arranged as N m ¼ m1 1exp ð7Þ Nc
Fig. 7. Typical pressure profile in roll compaction.
The values of Nc for the ribbons made from the unlubricated feed powders and those with wall and bulk lubrication are given in Table 2. It is clear that values for MCC are reduced by lubrication and are much greater than the values for DCPD, while for DCPD, the value of Nc is not sensitive to lubrication. Both the solid fraction and fracture energy for MCC decrease significantly when lubrication is applied, and hence so does the value of Nc. However, the solid fraction and Nc for DCPD are not affected by the lubrication. 4.4. Uniaxial compression
Fig. 8. Determination of nip angle from the pressure gradient data for MCC (S¼ 1.0 mm, u¼ 1.0 rpm).
The solid fraction and tensile strength of the tablets made from the feed powders and granules with and without lubrication are given in Table 3. The solid fractions for each of the powders and granules are approximately constant, which should be the case given the way that the experimental procedure was carried out. It can be seen that the solid fraction for MCC powder and granules are not affected when lubricated, while the values for the granules are smaller than those for the powders due to the loss of tabletability. At the same time, the tensile strength of the tablets decreases significantly when the amount of MgSt is increased. In contrast, the solid fractions for DCPD are not affected by lubrication, and the values for the powders and granules are comparable. With an increasing amount of MgSt, a small increase in the tensile strength is observed. The overall variation of the tablet strength with the amount of MgSt is shown in Fig. 12. The strength of the unlubricated MCC tablets (i.e. when the concentration of MgSt is zero) is about a factor of 6 greater than the corresponding DCPD tablets.
Fig. 9. Effects of lubrication on the maximum roll pressures.
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
15
Fig. 10. Effects of lubrication on nip angle in roll compaction.
Table 2 Effects of lubrication on the bulk density and fracture energy of the ribbons and the characteristic number of milling cycles. MCC
No lubrication Lubricated roll surface 0.25% MgSt (bulk lubrication) 1% of MgSt (bulk lubrication) a
DCPD 2
Solid fraction
Fracture energy (J/m )
Nc
Solid fraction
Fracture energy of the ribbon (J/m2)
Nc
0.683 7 0.035 0.644 7 0.024 0.537 7 0.013 0.475 7 0.000
112 7 3 1097 3 697 1 527 3
951 872 536 306
0.498 7 0.016 0.436 7 0.008 0.470 7 0.011 0.448 7 0.023
a
15 13 13 13
a a a
Ribbons are too fragile for 3-point bend measurement.
case, 0.5% (w/w) MgSt was applied for the bulk lubrication. Fig. 13 shows the data produced from the granules and powders under various lubrication conditions for DCPD and MCC. It is clear that the strength of DCPD tablets is not significantly affected by lubrication and granulation since all the data superimpose onto a single master curve (Fig. 13a). In contrast, in the case of bulk lubrication, a reduction of 30% in tensile strength is observed for MCC (Fig. 13b). The tablets made from granules are weaker than those made from the feed powders, which is consistent with results reported in the literature (Herting and Kleinebudde, 2008). The Ryshkewitch–Duckworth equation (Duckworth, 1953) was employed to fit the experimental data
st ¼ sekð1fÞ
Fig. 11. Typical milling results for roll compacted ribbons made from unlubricated MCC powders at the roll gap of 1.0 mm, roll speed of 1.0 rpm.
The strengths of the MCC tablets are reduced by bulk lubrication but not by wall lubrication whereas lubrication has little effect on the strength of DCPD tablets. For both MCC and DCPD, the tablets made from granules possess lower tensile strength compared to those made directly from the feed powders. In order to explore the correlation between the solid fraction and tensile strength of the tablets, additional experiments were carried out. Powders and granules were compressed with compression pressures in a range of 52.7–165.7 MPa with an interval of 22.6 MPa to produce tablets with various solid fractions. In this
ð8Þ
where st is the tensile strength of the compacts at a solid fraction of f, s is the tensile strength for the same material at zero porosity, k is a constant representing the bonding capacity of the material with a larger value of k indicating weaker bonding capacity. Typical data fitting are shown in Fig. 13, and the values of the fitting parameters are listed in Table 4. For DCPD, the values of s and k for the various cases considered are essentially identical. For MCC, granulation and lubrication lead to a reduction in the value of s, but an increase in the value of k, indicating a reduction in bonding capacity.
5. Discussion The coefficient of wall friction for unlubricated DCPD is about a factor of 5 greater than that for MCC (Fig. 5). This arises from the smaller interfacial shear strength of organic compared with
16
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Table 3 Effects of lubrication on the solid fractions and tensile strength of the tablets. MCC feed powder
No lubrication Lubricated roll surface Lubricated die wall 0.25% MgSt 1% of MgSt
MCC granules
Solid fraction
Tensile strength (kPa)
Solid fraction
Tensile strength (kPa)
0.7127 0.005 – 0.7067 0.004 0.7007 0.003 0.6937 0.004
5690 7 12 – 5673 7 4 3871 7 13 3113 7 14
0.6387 0.005 0.6357 0.004 – 0.6427 0.003 0.6467 0.003
4221 7 17 4263 7 21 – 2940 7 12 2203 7 6
DCPD feed powder
No lubrication Lubricated roll surface Lubricated die wall 0.25% MgSt 1% of MgSt
DCPD granules
Solid fraction
Tensile strength (kPa)
Solid fraction
Tensile strength (kPa)
0.5897 0.002 – 0.5957 0.001 0.5917 0.003 0.5887 0.005
951 7 2 – 952 7 4 960 73 983 7 4
0.5847 0.003 0.5917 0.005 – 0.5947 0.004 0.5967 0.002
789 7 3 796 7 5 – 799 7 8 792 7 8
Fig. 12. Effects of lubrication on the tablet strength, the data points on the vertical dash line (x¼ 0) present the values for unlubricated cases.
inorganic materials. Boundary lubricants provide a weak interfacial layer with coefficients of friction being typically 0.1 (Bowden and Tabor, 1950), which represents the minimum value that can generally be achieved. This is similar to that measured for unlubricated MCC and consequently boundary lubrication was ineffective at reducing friction. Organic polymers are generally difficult to boundary lubricate since they typically have similar interfacial shear strengths to boundary lubricants being both organic in nature. However, the coefficient of friction for unlubricated DCPD was 0.5 and therefore it could be effectively reduced by the application of MgSt to the observed minimum value of 0.1. There is clearly a minimum amount of MgSt required to achieve a uniform and robust surface layer. The coefficient of wall friction for unlubricated MCC increases after granulation, while the value for DCPD decreases (Fig. 6). This may be ascribed to the size enlargement and changes in the surface morphology. For the granules produced from feed powders with bulk lubrication, boundary lubrication is only effective for MCC. There is likely to be at least two contributory factors to the wall friction for DCPD granules being practically unchanged by the addition of MgSt. Firstly, in the milling process, some of the particles are lost because of their small size ( 8 mm) and, because of their relatively large surface-to-volume ratio, this causes a disproportional loss of the adhered MgSt. Secondly, even if DCPD granules are initially well-lubricated on the surface, fragmentation
Fig. 13. Tensile strength as a function of solid fraction of the tablets produced under various lubricating conditions for (a) DCPD and (b) MCC, the solid line presents the fitting results to Eq. (8).
Table 4 The value of fitting parameters in Eq. (8) obtained from multivariate fitting to experimental data. Feeding material
s (MPa)
k
DCPD
924.2
19.1180
9.1 12.4 12.1 11.8 15.9
6.8998 6.4918 6.3497 6.5436 5.7308
MCC MCC MCC MCC MCC MCC
granule granule granule powder powder
(bulk lubrication) (wall lubrication) (no lubrication) (bulk lubrication) (no lubrication)
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
of these relatively friable granules causes less well-lubricated interior surfaces to become exposed (De Boer et al., 1978). The effective angles of internal friction for the two unlubricated powders are relatively similar despite the evident large differences in their wall frictional characteristics (Fig. 5). However, other factors, such as particle shape and size distribution, are important that may account for this observation. There is no reduction in fe when the DCPD is lubricated in the bulk. This suggests that there is shear induced fracture of the particles that exposes fresh unlubricated surfaces, which is consistent with their brittle nature. Clearly, this mechanism does not operate for the MCC. Wall lubrication causes a small reduction in the coefficient of wall friction and this must account for the relatively large reduction in fe with a considerable scaling effect from single particles to assemblies. As in the case of the shear cell data, it is not possible to make direct comparisons of the absolute values of the maximum pressures and nip angles based only on the relative frictional characteristics. Other factors include the compressibility in particular and future work will involve examining the accuracy of theoretical models, such as that of Johanson (1965), in predicting the maximum roll pressure and nip angle based on the properties of the feed powders. However, it is possible to provide some qualitative interpretation of the changes with lubrication based on the measured wall and internal friction. For MCC, lubricating the rolls does not affect either the nip angle (Fig. 10) or the maximum roll pressure (Fig. 9), which is consistent with the insensitivity of the friction to wall lubrication. However, there is a reduction in both parameters for bulk lubrication that increases with the amount of MgSt. This is reflected in the reduction in the density and strength of the ribbons. As discussed above, it is difficult to boundary lubricate MCC. However, the bulk lubrication reduces the internal friction and increases the overall powder flowability. Therefore, the nip angle and the maximum pressure are reduced. In the case of DCPD, unlike MCC, the nip angle (Fig. 10), maximum pressure (Fig. 9) and also the density of the ribbons are all reduced by lubricating the rolls. The much greater sensitivity of the wall friction to boundary lubrication is a possible explanation since the values for the nip angle and maximum pressure are similar to those for critically bulk lubricated DCPD. That is, the bulk lubrication is again providing an internal source of the lubricant. The rate at which the ribbons are milled, as characterised by the parameter Nc, appears to be simply related to the fracture energy, as might reasonably be expected. It also appears that for the MCC, there is a close correlation between the ribbon densities and the fracture energies (Table 2), which is the expected behaviour. There is insufficient data to delineate a secondary effect of the presence of MgSt, which could reduce the strength by acting as a weak layer between the particles or it could behave as a binder. That the DCPD ribbons are mechanically weak almost certainly is the result of the stored elastic strains in the exit region that prevent coherent bonds forming between the particles. These strains will be much less for MCC since organic polymers exhibit elastoplastic deformation. The elastic recovery will be a contributory factor, together with the smaller nip angles, to the smaller densities of the DCPD ribbons compared with those formed from MCC. The strength of the DCPD tablets is much less than those formed from MCC (Table 3 and Fig. 13), which is analogous to the data for the strength of the ribbons as indicated by the fracture energy shown in Table 2. The relative values of the stored elastic strains are probably again the main governing factor. The insensitivity of the strength of the DCPD tablets to lubrication (Table 3, Figs. 12 and 13a) may be attributed to the fragmentation characteristics of the powder particles that cause fresh surfaces to
17
be exposed and thus inhibiting any potential binding by the MgSt. Bulk lubrication causes a reduction in the strength of the MCC tablets (Table 3, Figs. 12 and 13b), which suggests that the MgSt is acting as a weak boundary layer between the particles (Zuurman et al., 1999), which reduces the bonding strength (Table 4). Thus the influence of lubrication on both the DCPD and MCC tablets is also similar to the trends observed for the ribbons as shown in Table 2. Future work will be aimed at a comparable study of binary mixtures to reflect more realistic formulations. However, there are some general trends in the current work that may be worth considering in terms of practical applications. Firstly, in the case of MCC which is a major formulation component, for a given set of roll compaction conditions, the addition of a lubricant will reduce the nip angle and the maximum roll pressure. This will lead to a reduction in the strength of the ribbons that will increase the rate of milling, but reduce the sizes of the granules. Secondly, the strength of tablets will provide a useful ranking indicator for the strength of the ribbons and hence the rate at which they can be milled. For example, this approach could be applied to the influence of lubricants.
6. Conclusions Characterising the feed powder, the roll compaction process and the compacted ribbons, the milling of the ribbons, the tabletting of the milled granules and the tablets formed from the granules are useful strategies for understanding the influence of a boundary lubricant on the formulation. Overall, it was possible to develop a coherent but qualitative interpretation of the data that provides some mechanistic insights and has some practical implications. Conclusively, the application of bulk lubrication prevents the adhesion in compaction processes, but leads to reduction in the strength and solid fraction of the corresponding tablets for MCC. However, these negative effects are not shown for DCPD. Wall lubrication minimises the reduction in the tensile strength of the final product for both powders.
Acknowledgements The authors would like to thank AstraZeneca for funding the project and providing sample materials. The characterisation equipments used were obtained, through Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World, with support from AWM and part funded ERDF. References Bindhumadhavan, G., Seville, J.P.K., Adams, M.J., Greenwood, R.W., Fitzpatrick, S., 2005. Roll compaction of a pharmaceutical excipient: experimental validation of rolling theory for granular solids. Chem. Eng. Sci. 60, 3891–3897. Bolhuis, G.K., Lerk, C.F., Broersma, P., 1980. Mixing action and evaluation of tablet lubricants in direct compression. Drug Dev. Ind. Pharm. 6, 15–33. Bolhuis, G.K., Lerk, C.F., Zijlstra, H.T., De Boer, A.H., 1975. Film formation by magnesium stearate during mixing and its effect on tabletting. Pharm. Weekbl. 110, 317–325. Bowden, F.P., Tabor, D., 1950. The Friction and Lubrication of Solids. Oxford University Press, New York. De Boer, A.H., Bolhuis, G.K., Lerk, C.F., 1978. Bonding characteristics by scanning electron microscopy of powders mixed with magnesium stearate. Powder Technol. 20, 75–82. Duckworth, W., 1953. Discussion of Ryshkewitch paper. J. Am. Ceram. Soc. 36, 68. He, X.R., Secreast, P.J., Amidon, G.E., 2007. Mechanistic study of the effect of roller compaction and lubricant on tablet mechanical strength. J. Pharm. Sci. 96, 1342–1355. Herting, M.G., Kleinebudde, P., 2008. Studies on the reduction of tensile strength of tablets after roll compaction/dry granulation. Eur. J. Pharm. Biopharm. 70, 372–379.
18
S. Yu et al. / Chemical Engineering Science 86 (2013) 9–18
Johanson, J.R., 1965. A rolling theory for granular solids. J. Appl. Mech. 32, 842–848. Johansson, M.E., Nicklasson, M., 1986. Investigation of the film formation of magnesium stearate by applying a flow-through dissolution technique. J. Pharm. Pharmacol. 38, 51–54. Migue´lez-Mora´n, A.M., Wu, C.Y., Seville, J.P.K., 2008. The effect of lubrication on density distributions of roller compacted ribbons. Int. J. Pharm. 362, 52–59. Patel, B.A., Adams, M.J., Turnbull, N., Bentham, A.C., Wu, C.Y., 2010. Predicting the pressure distribution during roll compaction from uniaxial compaction measurements. Chem. Eng. J. 164, 410–417. Pintye-Hodi, K., Toth, I., Kata, M., 1981. Investigation of the formation of magnesium stearate film by energy dispersive X ray microanalysis. Pharm. Acta Helv. 56, 320–324. Roblot-Treupel, L., Puisieux, F., 1986. Distribution of magnesium stearate on the surface of lubricated particles. Int. J. Pharm. 31, 131–136. Tawashi, R., 1963a. Der Einfluss von Aerosil auf die Fleisseigenschaften von pulvern. Pharm. Ind. 25, 64–66.
Tawashi, R., 1963b. Der Einfluss von Aerosil auf die Packungseigenschaften von pulvern. Pharm. Ind. 25, 655–658. von Eggelkraut-Gottanka, S.G., Abu Abed, S., Muller, W., Schmidt, P.C., 2002. Roller compaction and tabletting of St. John’s wort plant dry extract using a gap width and force controlled roller compactor. II. Study of roller compaction variables on granule and tablet properties by a 3(3) factorial design. Pharm. Dev. Technol. 7, 447–455. Vromans, H., Bolhuis, G.K., Lerk, C.F., 1988. Magnesium stearate susceptibility of directly compressible materials as an indication of fragmentation properties. Powder Technol. 54, 39–44. Shen, Yu, Bindhu, Gururajan, Gavin, Reynolds, Ron, Roberts, Michael J., Adams, Chuan-Yu, Wu., A comparative study of roll compaction of free-flowing and cohesive pharmaceutical powders. Int. J. Pharm. doi:10.1016/j.ijpharm. 2012.02.033, in press. Zuurman, K., Van der Voort Maarschalk, K., Bolhuis, G.K., 1999. Effect of magnesium stearate on bonding and porosity expansion of tablets produced from materials with different consolidation properties. Int. J. Pharm. 179, 107–115.