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Studies on direct compression of tablets XVII. Porosity—pressure curves for the characterization of volume reduction mechanisms in powder compression
Powder
Technology,
46 (1986)
67
67 - 75
Studies on Direct Compression of Tablets XVII. Porosity-pressure curves for the characterization mechanisms in powder compression M. DUBERG Department
of volume reduction
and C. IVYSTROM of Galenical Pharmacy,
Uppsala Biomedical
Center,
University
of Uppsala, Box 580, S-571 23
Uppeala (Sweden) (Received
August 22.1985)
SUMMARY
Several pharmaceutical materials together with some model substances were compressed in an instrumented single-punch press. During compression, compact heights and compression loads were measured at 1 ms intervals. From these data, the porosity-pressure function according to Heckel was calculated for both the compression and decompression phases. By dividing the entire compression cycle into three main phases, the dominating volume-reduction mechanisms for the materials tested were discussed. It was shown that fragmentation behaviour could be evaluated by linear regression from the initial phase of compression (phase I). By evaluating the decompression (phase III), information regarding both elastic and plastic deformation behaviour was obtained. The slope of the linear part of the compression curve (phase II) was shown to reflect the total deformation ability. The relationship between the information obtained and the bonding properties of the materials is briefly discussed.
INTRODUCTION
Compact strength depends on several physico-chemical properties of the powder to be compressed. Except for particle properties such as size [ 1, 2] , shape [ 31 and surface texture [3, 41, the inherent ability of the powder to reduce its volume during compression could affect the amount of interparticulate attraction in the final compact
*PartXI: Znt. J. Pharm., 23 (1985) 79. 0032.5910/86/$3.50
[5]. A decrease in compact porosity with increasing compression load is normally attributed to particle rearrangement, elastic deformation, plastic deformation and particle fragmentation. In compression studies of binary mixtures, the effect on compact strength of a second component [6 - 81 is shown to be dependent upon the dominating volume-reduction mechanisms involved. Pharmaceutical materials normally consolidates by more than one of these mechanisms [8 lo], which emphasizes the need for adequate characterization techniques. Several methods for the determination of volume-reduction mechanisms, both qualitatively and quantitatively, have been presented in the literature, e.g. scanning electron microscopy [lo - 131, work measurements from force-displacement curves [14 - 171, the use of ratios from axial and radial tensile strength measurements [l, 8, 111, measurement of surface area changes by permeametry [X3 201 and gas adsorption techniques [18 221 and measurement of porosity changes during compression [ 20 - 251. The latter technique, where changes in porosity against compression load are recorded and expressed by mathematical functions, has been extensively used. In studies of pharmaceutical materials, the function according to Heckel [23] has been used for the characterization of particle fragmentation and the degree of plastic deformation [26 - 311. The porosity could then be measured either on the ejected compact or on the compact under load. By continuously recording the porosity changes during one compression cycle, the measurement could be made very rapidly. Although this technique also allows the characterization of @ Elsevier Sequoia/Printed
in The Netherlands
66
materials with poor bonding capacity, several problems regarding the interpretation of such porosity-pressure curves has been reported [27,29,32,33]. In earlier reports, where consolidation properties of some pharmaceutical materials have been studied by several techniques [8, 27, 281, the limitations of using traditional Heckel plots to distinguish between elastic and plastic deformation was emphasized. This problem is to some extent reduced when the porosity of ejected compacts is measured. To obtain information about the elastic component during the recording of one compression cycle, the Heckel function was also applied to the decompression phase. The objective of this study was to evaluate such porosity-pressure curves for the characterization of volume-reduction mechanisms. This approach was applied to some pharmaceutical compounds undergoing densification by several mechanisms, as established in earlier reports. THEORY
Heckel regarded compression of metal powders as analogous to first-order kinetics, where the pores are the reactant and the densification the product. The relation was described by the equation In
(1)
where D is the relative density of the compact, P the applied pressure, A a constant describing densitification by particle movement and rearrangement and K is a measure of the ability of the compact to deform plastically. The constant A can be defined by the equation 1 A = In +B (2) ( l-D,, 1 where B represents densification by individual particle movement and rearrangement, and ln(l/(l -Do)) is densification by filling the die. The relative densities can be deduced from eqn. (2) as DA =D,,+Dg
(3)
D,-,can be determined experimentally and DA is given by
(4)
Thus, Da can be calculated. The values of D,,, DA and Da are, in general, only affected by particle shape and size [23, 301. The bulk properties of the particles have no significant effect on these parameters, and therefore they are of limited interest when discussing consolidation mechanisms. The value of K was related by Heckel to the yield strength Y of the material by the expression K = l/3 Y [23]. Later, the reciprocal of K was defined as the yield pressure P,. [31]. K is regarded as a material constant, and has been used to determine the deformation mechanisms of a material. To be able to use the Heckel parameters to compare different substances and powder qualities, it is important to standardize the experimental conditions such as tablet dimensions and speed of compaction [32]. The elastic deformation of the punches must also be considered [ 231. By compressing a nondeformable metal disc, the measurement of the punch movement can be corrected for this effect. The question of when to measure compact density is also important. Heckel suggested measurements ‘at pressure’, since elastic recovery affects tablet volume after compression. There are two ways to accomplish this: either by compressing a number of tablets at different pressures and recording tablet thickness at maximum upper punch pressure [ 10, 27, 341, or by continuously recording tablet thickness and the corresponding pressure during a single compression cycle [ 8, 11, 35 1. The latter technique has the advantage of speed and requires less powder. A disadvantage is that the consolidation time is different at each pressure. This could result in a concave Heckel plot for materials having pronounced time-dependent consolidation [ 11, 363. Most previous reports, as reviewed by Humbert-Droz et al. [35], have used a hydraulic press and have measured compact thickness at maximum upper punch pressure after ejection. The work reported here was carried out using a single-punch excenter press, where the thickness was measured at 1 ms intervals throughout the compression sequence.
69 TABLE 1 Sequences of volume-reduction Expected mechanisms for metalsb
mechanismsa Expected mechanisms for organic compound&
Experimentally observed mechanisms for organic compoundsd
El : Elastic deformation of initial, weak particles PI : Plastic deformation of initial, weak particles F1 : Fragmentation of initial particles into a number of smaller descrete particles of higher strength
FI
E: Elastic deformation
E2 : Elastic deformation of smaller particles formed
E2
P: Plastic deformation
Pz : Plastic deformation of smaller particles formed
p2
F: Particle fragmentation
F2 : Fragmentation of smaller particles formed
aHere not including particle rearrangement. bRepresenting materials with low concentrations of crystal defects, pores and flaws. ‘Representing materials with high concentration of defects. dUtilizing, for example, porosity-pressure functions.
A perfect method for characterizing consolidation behaviour should be able to separate the different volume-reduction mechanisms involved in compaction. For metals and other materials possessing a high crystalline order or homogeneous structure, with low concentrations of crystal defects, pores or flaws, the relationship between material deformation and an increase in applied stress are well established. After an initial elastic deformation, the materials undergo plastic deformation and finally, if the stress is high enough, the material shows brittle behaviour and fragments (Table 1). However, most pharmaceutical materials, mainly organic compounds, exhibit consolidation properties far removed from this simple model. The main difference reported is that many materials seem to undergo particle fragmentation during the initial loading [ 10, 11, 23,311, followed by elastic and/or plastic deformation at higher loads. This phenomenon could possibly be explained by considering the fairly complex particle structure of many pharmaceutical compounds (Table 1). They often consist of aggregates
of primary particles or of highly porous particles. These ‘secondary’ particles could then during the initial loading behave as mainly brittle units, with a negligible deformation ability, and produce a large number of smaller discrete particles. These particles, formed during compression, would then show elastic and plastic deformation, possibly followed by a final fragmentation, when the compression load is further increased. When using the porosity function according to Heckel to describe the mechanisms involved in the compression of such complex materials as pharmaceutical compounds, several problems have been reported, as discussed in the Introduction. Firstly, an initial fragmentation will give a deviation from the straight line as predicted by Heckel for metal powders. Secondly, it is difficult to distinguish between elastic and plastic deformation as evaluated from the slope of the linear part of the profile. These problems could possibly be overcome by evaluating the whole compression cycle by the Heckel equation. The compression cycle could then be divided into three main phases, as illustrated in
I’
PHASE III
be to identify the time difference between maximum compression load and minimum porosity [37]. This time-lag could be interpreted as a reflection of plastic deformation, i.e. plastic flow would not stop at maximum load, but continue over a time-period when the pressure is released.
EXPERIMENTAL
CORPACTIONPRESSURE
Fig. 1. A compression cycle, evaluated using the Heckel function, separated into three phases to be used for the evaluation of volume-reduction mechanisms involved in compaction of pharmaceutical powders.
Fig. 1. During phase I, when the applied pressure is relatively low, the porosity reduction could be strongly enhanced by particle fragmentation. The curvature of the plot could be evaluated as the deviation from a straight line and expressed as the correlation coefficient (CC) as described in earlier papers [ 10, 111. The CC could then serve as a tool to quantify the fragmentation tendency. A linear curve is obtained for non-fragmenting materials. At higher pressures (phase II), elastic and/or plastic deformation are the dominating mechanisms. The reciprocal of the slope, the so-called yield pressure PY, has been claimed to reflect the plasticity of the material [31]. A low P,,-value should then indicate a high degree of plastic deformation. Since, for some materials, the density values ‘at pressure’ contain an elastic component, this could result in a false low P,-value [8, 271. During decompression (phase III), elastic properties of the particles could result in an increase in porosity. The decompression curve should be approximately horizontal when no elastic deformation is present, i.e. the instantaneous elastic expansion of the tablet is negligible. Since phase III could give information about the elastic component, it seems possible to elucidate the contribution of plastic deformation during phase II. Another means to evaluate phase III could
Materials Three model substances, undergoing volume reduction mainly by one major mechanism, were used to evaluate the usefulness of the Heckel equation applied to both compression and decompression curves. &eon Polyblend 503 (BP Chemicals, U.K.) is a blend of 52% poly(viny1 chloride) and 48% nitrile rubber, which deforms elastically. Sodium chloride (cubic crystalline puriss., Kebo-Grave, Sweden), which mainly deforms plastically (e.g. [ 121). Emcompress (dicalcium phosphate dihydrate, E. Mendell Co., Inc., U.S.A.), consisting of aggregates which fragment to a large extent during compression (e.g. [lo] ). To illustrate the usefulness and interpretation of fully evaluated Heckel plots, some pharmaceutical substances and additives were also tested. Aspirin (ASA 7013, BP, Monsanto, U.S.A.), phenacetin Ph. Nord.), sodium bicarbonate (puriss., Kebo-Grave, Sweden), lactose (CG monohydrate crystalline, CCF, Friesland, The Netherlands) and paracetamol (crystalline, BP, Bayer, F.R.G.). Magnesium stearate (Ph. Nord.) was used as an external lubricant. Methods Compression All powders were stored for at least 2 days at 20 “C and 45% RH before compression. Plane compacts with a diameter of 1.13 cm were compressed at 150 MPa (maximum upper punch pressure) using an instrumented single-punch press (Korsch EK 0, F.R.G.) at 3 0 rev- min- i. The powder for each compact was individually weighed on an analytical balance and then manually filled into the die. The fill weight for each substance was adjusted to give a compact thickness of
71
-
2.0.
Ei I g
1.6.
F
0
50
(aI
0.84 .
(b)
O
50
100
150
UPPER PUNCH PRESSURE (MPA)
+
I
-
150
100
UPPER PUNCH PRESSURE (MPA)
1.4.
6 I F:
1.2
F
cc:
0.3761
ER: 4.08
0
(cl
50
100
Z
150
UPPER PUNCH PRESSURE (MPA)
Fig. 2. He&e1 plots of the model substances. (a), Polyblend; (b), sodium chloride; (c), Emcompress. CC: correlation coefficient, PY: yield pressure, ER: elastic recovery, arrow denotes position for minimum porosity.
0.3 cm at maximum compaction load. The punch faces and die wall were lubricated with a 1 wt.% magnesium stearate suspension in ethanol before each compression. Measurement of tablet height The height of the compact was recorded every millisecond with an inductive displacement transducer. The values were corrected for the elastic deformation of the punches. The corresponding upper punch pressures were also recorded. The analog signals were converted to digital form using a la-bit A/D converter. The digital signals were then stored on a floppy disc for further calculations. Porosity function The porosity changes during a compression cycle were calculated by means of the Heckel equation and plotted us. upper punch pressure. The curvature of phase I was evaluated by calculating the CC in the pressure interval 2 - 50 MPa, using linear regression analysis. Phase II was evaluated by calculating the yield pressure PY(reciprocal of the slope K) in the
interval 40 - 100 MPa. Phase III was evaluated by denoting if the minimum porosity was reached at a time-event significantly different from the time of maximum load. The elastic component as given by phase III was then calculated as the relative increase in porosity ER.
RESULTS AND DISCUSSION
The Heckel plots of the model substances are shown in Fig. 2, whereas the dominating volume-reduction mechanisms are summarized in Table 2. Sodium chloride and Emcompress are practically non-elastic (phase III shows no marked decrease and ER values are low), therefore both PY and CC give correct information concerning the known plasticity and fragmentation tendency of the two materials. Sodium chloride represents a homogeneous, non-porous material with consolidation behaviour similar to, for example, metal powders. Consequently, no substantial fragmentation is observed as the initial part of the profile. After passing a minute elastic
72 TABLE 2
LACTOSE
Sequences of dominating volume-reduction nisms determined for test materials Materials
^^
mecha-
2.0' 1.8.
Mechanisms according to Table 1
Breon Polyblend 503 Sodium chloride Emcompress Sodium bicarbonate Lactose Paracetamol Phenacetin Aspirin
E P FI P FI F1 F1 F1
c
1.6' P,: 140 MPA CC: 0.9841
+ Pz
ER: 10.5 I
+‘(Ez)+P2
+‘ E2 + P2 +’ E2 +’ E2 + P2
0.8' 0
50
PARACETAMOL
6
2.6-
P,: 127 MPn cc: 0.9753 'E
ER: 19.7 X
1.1' 0
50
100
150
UPPER PUNCH PRESSURE (MPA)
Fig. 5. Heckel plot of paracetamol. PHENACETIN I 1.7 .
_
1.5'
6 I -
T
P,: 290 fiPA
1.3'
cc:
r
0.9724
ER: 28.4 X
1.1 .
0.9
SODIUM BICARBONATE
0
4
50
100
150
UPPER PUNCH PRESSURE MPA)
Fig. 6. Heckel plot of phenacetin.
1.8-
cc: 0.9962 ER: 1.01 X
0.8 . 0
150
Fig, 4. Heckel plot of lactose.
phase, the particles are deformed almost solely by plastic deformation. Emcompress, which could be regarded as a powder consisting of aggregates, is extensively fragmented even at relatively low loads. These particles continue to fragment at intermediate loads and subsequently appear to undergo mainly plastic deformation, as indicated by the time difference between maximum load and minimum porosity. The rubber powder, on the other hand, consolidates solely by elastic deformation. This is shown by the identical compression and decompression profiles and an extremely high ER value. The use of Py and CC for this material are of no significance. Heckel plots for the other materials are presented in Figs. 3 - 7 and the dominating volume reduction mechanisms are listed in Table 2. Sodium bicarbonate is a non-elastic substance, phase III is approximately horizontal and ER is very low. The correlation coefficient is close to unity and thereby indicates 2.0.
100
UPPER PUNCH PRESSURE (MPA)
50
100
UPPER PUNCH PRESSURE (MPA)
Fig. 3. Heckel plot of sodium bicarbonate.
150
a low degree of fragmentation. With the information from phase III, it can be concluded that the relatively low Py is reflecting plastic deformation. This is also indicated by the time-lag in phase III. In general, sodium bicarbonate shows similar behaviour to sodium chloride, which is well known to densificate mainly by plastic deformation.
73 ASPIRIN
I 3.5' Py: 73 tIPA
=: 3.0.
cc: 0.9777 5
2.5.
ER: 114 X
2.0.
/ 1.31 ' 0
50 UPPER WNCH
100 PRESSURE
150
(tIPA)
Fig. 7. Heckel plot of aspirin.
Lactose shows a slight decrease during phase III, which indicates some elastic deformation. The CC is low and reflects a high degree of fragmentation. The relatively low Py is influenced by the elastic properties of lactose and therefore probably overestimates the degree of plastic deformation. The total densificiation behaviour is of the same type as Emcompress. The difference is that lactose particles do not fragment as extensively, which gives a higher CC value. This difference has earlier been shown by permeametry surface area measurements [19]. Another difference from Emcompress is that the small particles formed during phase I exhibit some elastic behaviour, as indicated by phase III. Parucetamol is known to exhibit elastic properties, which is shown by the deviation from the horizontal in phase III. The CCvalue indicates extensive fragmentation, and therefore it is reasonable to assume that the low Py is caused to a large extent by elastic deformation, The extensive fragmentation of paracetamol particles has been confirmed by other techniques [ 191. By measuring the increase in surface area by permeametry it was shown that paracetamol belongs to the same group of materials as Emcompress. Although the particles created during phase I deform plastically, as seen from the timelag in phase III, the important feature of these particles is the marked elastic behaviour. For phenacetin, the large deviation from horizontal indicates elastic deformation, and the low CC reflects extensive fragmentation. The high P,, probably reflects the fact that the particles formed during phase I are not very deformable in nature. The absence
of any significant plastic deformation, as indicated by the minute time-lag in phase III, implies that the bonding ability is limited, which could explain the substantial increase in compact volume during decompression. The increase in porosity with decreasing pressures (phase III) for aspirin indicates a substantial elastic deformation. The CC is low and reflects extensive fragmentation. A low Py here probably reflects that the small aspirin particles formed in phase I are undergoing extensive deformation, i.e. elastic and plastic deformation as indicated by the timelag in phase III.
CONCLUSIONS
By evaluating the compression cycle using the Heckel equation for both the compression and decompression phases, it is possible to obtain a fairly comprehensive characterization of the mechanisms of volume reduction. The information given by the Heckel plots support earlier findings that several of the materials tested show an initial particle fragmentation (Table 2). The correlation coefficient calculated at relatively low pressures (phase I) reflects the fragmentation tendency of a material. The new, smaller particles formed in phase I seem to deform elastically to varying degrees, whereafter most of the materials exhibit plastic deformation when further pressure is applied (Table 2). This can be seen in phase III where a time-lag reflects plastic deformation and the ER value indicates the elastic component. Emcompress has a minute elastic behaviour whereas paracetamol, phenacetin and aspirin show significant elastic components. Lactose seems to possess intermediate properties in this respect. Phenacetin was the only fragmenting material without any significant plastic behaviour as indicated by the lack of time-lag during phase III. Both sodium chloride and sodium bicarbonate behaved similarly to that expected, for example, for metal powders, showing mainly plastic deformation. No significant fragmentation could be detected at low loads, and the elastic component was minute. From the data obtained it is evident that the slope of phase II could not be used alone for the characterization of plastic deforma-
l ruf*rcfrln
0
0.2
0.1 POROSITY
AT
MAXIMUM
COMPRESSION
0.3 LOAD
(
-
)
Fig. 8. Yield pressure as a function of minimum porosity for the materials tested.
tion. The Py value is instead reflecting the particles total ability to deform. This is illustrated in Fig. 8, where Py is plotted against the porosity at maximum compaction load, giving an approximate linear relation. For the materials undergoing extensive fragmentation, a relatively high P,, would be expected, since those can be regarded as fine particulate qualitities of non-fragmenting materials. For most of the latter materials a decrease in particle size would normally result in compacts wigh higher porosity [ 311. With the aid of phase III, the respective importance of both elastic and plastic deformation for the P,-value could be elucidated, thereby avoiding possible misinterpretation. The effect of consolidation behaviour on bonding ability and compact strength is not fully understood. It has been claimed that consolidation by plastic deformation is most effective in reducing compact porosity, and that a large porosity reduction is of vital importance to create the conditions necessary for bonding. However, the results in this study suggest that this may be true for some materials but cannot be regarded as a general rule. In an earlier study it was suggested that the surface area used for interparticulate attraction is only a minor fraction of the external particle surface area available [38]. A pharmaceutical compact could then be described as an agglomerate kept coherent by a number
’
of bonding points. If this model is correct, the important factor for bonding is probably not the particle bulk behaviour as characterized by the Heckel function during phases I and II, but the possibility for certain points at the surface of the particles to establish interparticulate attraction. This is demonstrated by the behaviour of the so-called fragmenting materials. Although fragmentation is the dominant mechanism during initial loading, the particles created are still able to deform and develop substantial bonding, which has been shown for a number of such materials. This bonding ability is probably enhanced by local plastic deformation at the points of contact. Unfortunately, the mechanisms characterized by the use of porositypressure functions is probably the total bulk behaviour rather than the effects limited to the particle surface. The elastic component, as characterized in phase III, could be important for the compactability of powders. A high compact strength would not be expected for elastic materials, since bonds could be broken by the elastic expansion during compact ejection. Only when particles bond with a strong bond type, or when a large number of bonds are present, will sufficient bonds remain to maintain compact strength after ejection. Several of the materials tested are known to cause problems such as lamination during compression. These materials, phenacetin, paracetamol and to some extent aspirin, are also the materials showing the most pronounced elastic expansion during phase III. The kind of porosity-pressure function evaluated in this study could be useful when investigating the effect of dry binder additions [6 - 81 to improve compact strength. During compression of fragmenting materials, new surfaces are created. The dry binder particles are held in the matrix in a position where they are unable to exert their effect on these newly created surfaces. This limited effect would be further reduced with materials that after fragmentation exhibit elastic behaviour, since the binder will probably not be able to counteract the breakage of bonds due to elastic expansion. Materials consolidating by fragmentation and elastic deformation, as demonstrated for phenacetin, probably cannot be directly compressed, but have to be granulated. As shown in earlier
75
reports [6 - 81, the addition of dry binders to plastically deforming materials, such as sodium bicarbonate, strongly increased the compact strength.
REFERENCES
10 11 12 13 14 15 16
G. Alderborn and C. Nystriim, Acta Pharm. Suet., 19 (1982) 381. E. Shotton and D. Ganderton, J. Pharm. Pharmacol., 13 (19610 144T. G. Alderborn and C. Nystriim, Acta Pharm. Suet., 19 (1982) 147. R. Hiittenrauch, Acta Pharm. Technol., Suppl. 6, 24 (1978) 55. G. Milosowich, Drug Cosmet. Znd., 92 (1963) 557. C. Nystriim, J. Mazur and J. Sjagren, Znt. J. Pharm., 10 (1982) 421. C. Nystriim and M. Glazer, Znt. J. Pharm., 23 (1985) 255. M. Duberg and C. Nystriim, Znt. J. Pharm. Technol. and Prod. Man& in press. P. Humbert-Droz, R. Gurny, D. Mordier and E. Doelker, Znt. J. Pharm. Technol. & Prod. Manuf., 4 (1983) 29. A. H. de Boer, G. K. Bolhuis and C. F. Lerk, Powder Technol., 25 (1978) 75. M. Duberg and C. Nystrom, Acta Pharm. Suet., 19 (1982) 421. J. S. Hardman and B. A. Lilley, Nature, 228 (1970) 353. L Krycer, D. G. Pope and J. A. Hersey, Znt. J. Pharm. Technol. & Prod. Manuf., 3 (1982) 93. C. J. de Blaey and J. Polderman, Pharm. Weekblad, 105 (1970) 241 and 106 (1971) 57. G. Ragnarsson and J. Sjijgren, J. Pharm. Pharmacol., 37 (1985) 145. A. Stamm and C. Mathis, Acta Pharm. TechnoZ., Suppl. 1, 7 (1976) 7.
17 M. Diirr, D. Hanssen and H. Harwalik, Pharm. Znd., 34 (1972) 905. 18 G. Alderborn and C. Nystrdm, Powder Technol., 44 (1985) 37. 19 G. Alderborn, K. Rasanen and C. Nystrom, Znt. J. Pharm., 23 (1985) 79. 20 G. Alderborn, M. Duberg and C. NystrGm, Powder Technol, 41 (1985) 49. 21 N. A; Armstrong and R. F. Gaines-Nutt, Powder TechnoZ., 9 (1974) 287. 22 N. G. Stanley-Wood and M. S. Shubair, Powder TechnoZ., 25 (1980) 57. 23 R. W. Heckel, Trans. Metall. Sot. AZME, 221 (1961)671 and 221 (1961) 1001. 24 A. R. Cooper and L, E. Eaton, J. Am, Ceram. Sot., 45 (1962) 97. 25 K. Kawakita and Y. Tsutsumi, Bull. Chem. Sot. Jpn., 39 (1966) 1364. 26 G. K. Bolhuis, C. F; Lerk, H. T. Zijlstra and A. H. de Boer, Pharm. Weekblad, 110 (1975) 317. 27 J. T. Fell and J. M. Newton, J. Pharm. Sci., 60 (1971) 1866. 28 P. Paronen and M Juslin, J. Pharm. Pharmacol., 35 (1983) 627. 29 P. J. Rue and J. E. Rees, J. Pharm. Pharmacol., 30 (1978) 642. 30 P. York and N. Pilpel, J. Pharm. Pharmacol., Suppl. 25 (1973) 1P. 31 J. A. Hersey and J. E. Rees, Proc. Particle Size Analysis Conference, Bradford, England (1970). 32 P. York, J. Pharm. Pharmacol., 31 (1979) 244. 33 J. A. Hersey, J. E. Rees and E. T. Cole, J. Pharm. Sci., 62 (1973) 2060. 34 Z. T. Chowhan and Y. P. Chow, Znt. J. Pharm. Technol. &Prod. Manuf., 2 (1981) 29. 35 P. Humbert-Droz, D. Mordier and E. Doelker, Pharm. Acta Helv., 57 (1982) 136. 36 J. E. Rees and P. J. Rue, J. Pharm. Pharmacol., 30 (1978) 601. 37 B. Emschermann and F. Miiller, Pharm. Znd., 43 (1983) 191. 38 C. NystrGm and P. G. Johansson, Powder Technol., in press.
Technology,
46 (1986)
67
67 - 75
Studies on Direct Compression of Tablets XVII. Porosity-pressure curves for the characterization mechanisms in powder compression M. DUBERG Department
of volume reduction
and C. IVYSTROM of Galenical Pharmacy,
Uppsala Biomedical
Center,
University
of Uppsala, Box 580, S-571 23
Uppeala (Sweden) (Received
August 22.1985)
SUMMARY
Several pharmaceutical materials together with some model substances were compressed in an instrumented single-punch press. During compression, compact heights and compression loads were measured at 1 ms intervals. From these data, the porosity-pressure function according to Heckel was calculated for both the compression and decompression phases. By dividing the entire compression cycle into three main phases, the dominating volume-reduction mechanisms for the materials tested were discussed. It was shown that fragmentation behaviour could be evaluated by linear regression from the initial phase of compression (phase I). By evaluating the decompression (phase III), information regarding both elastic and plastic deformation behaviour was obtained. The slope of the linear part of the compression curve (phase II) was shown to reflect the total deformation ability. The relationship between the information obtained and the bonding properties of the materials is briefly discussed.
INTRODUCTION
Compact strength depends on several physico-chemical properties of the powder to be compressed. Except for particle properties such as size [ 1, 2] , shape [ 31 and surface texture [3, 41, the inherent ability of the powder to reduce its volume during compression could affect the amount of interparticulate attraction in the final compact
*PartXI: Znt. J. Pharm., 23 (1985) 79. 0032.5910/86/$3.50
[5]. A decrease in compact porosity with increasing compression load is normally attributed to particle rearrangement, elastic deformation, plastic deformation and particle fragmentation. In compression studies of binary mixtures, the effect on compact strength of a second component [6 - 81 is shown to be dependent upon the dominating volume-reduction mechanisms involved. Pharmaceutical materials normally consolidates by more than one of these mechanisms [8 lo], which emphasizes the need for adequate characterization techniques. Several methods for the determination of volume-reduction mechanisms, both qualitatively and quantitatively, have been presented in the literature, e.g. scanning electron microscopy [lo - 131, work measurements from force-displacement curves [14 - 171, the use of ratios from axial and radial tensile strength measurements [l, 8, 111, measurement of surface area changes by permeametry [X3 201 and gas adsorption techniques [18 221 and measurement of porosity changes during compression [ 20 - 251. The latter technique, where changes in porosity against compression load are recorded and expressed by mathematical functions, has been extensively used. In studies of pharmaceutical materials, the function according to Heckel [23] has been used for the characterization of particle fragmentation and the degree of plastic deformation [26 - 311. The porosity could then be measured either on the ejected compact or on the compact under load. By continuously recording the porosity changes during one compression cycle, the measurement could be made very rapidly. Although this technique also allows the characterization of @ Elsevier Sequoia/Printed
in The Netherlands
66
materials with poor bonding capacity, several problems regarding the interpretation of such porosity-pressure curves has been reported [27,29,32,33]. In earlier reports, where consolidation properties of some pharmaceutical materials have been studied by several techniques [8, 27, 281, the limitations of using traditional Heckel plots to distinguish between elastic and plastic deformation was emphasized. This problem is to some extent reduced when the porosity of ejected compacts is measured. To obtain information about the elastic component during the recording of one compression cycle, the Heckel function was also applied to the decompression phase. The objective of this study was to evaluate such porosity-pressure curves for the characterization of volume-reduction mechanisms. This approach was applied to some pharmaceutical compounds undergoing densification by several mechanisms, as established in earlier reports. THEORY
Heckel regarded compression of metal powders as analogous to first-order kinetics, where the pores are the reactant and the densification the product. The relation was described by the equation In
(1)
where D is the relative density of the compact, P the applied pressure, A a constant describing densitification by particle movement and rearrangement and K is a measure of the ability of the compact to deform plastically. The constant A can be defined by the equation 1 A = In +B (2) ( l-D,, 1 where B represents densification by individual particle movement and rearrangement, and ln(l/(l -Do)) is densification by filling the die. The relative densities can be deduced from eqn. (2) as DA =D,,+Dg
(3)
D,-,can be determined experimentally and DA is given by
(4)
Thus, Da can be calculated. The values of D,,, DA and Da are, in general, only affected by particle shape and size [23, 301. The bulk properties of the particles have no significant effect on these parameters, and therefore they are of limited interest when discussing consolidation mechanisms. The value of K was related by Heckel to the yield strength Y of the material by the expression K = l/3 Y [23]. Later, the reciprocal of K was defined as the yield pressure P,. [31]. K is regarded as a material constant, and has been used to determine the deformation mechanisms of a material. To be able to use the Heckel parameters to compare different substances and powder qualities, it is important to standardize the experimental conditions such as tablet dimensions and speed of compaction [32]. The elastic deformation of the punches must also be considered [ 231. By compressing a nondeformable metal disc, the measurement of the punch movement can be corrected for this effect. The question of when to measure compact density is also important. Heckel suggested measurements ‘at pressure’, since elastic recovery affects tablet volume after compression. There are two ways to accomplish this: either by compressing a number of tablets at different pressures and recording tablet thickness at maximum upper punch pressure [ 10, 27, 341, or by continuously recording tablet thickness and the corresponding pressure during a single compression cycle [ 8, 11, 35 1. The latter technique has the advantage of speed and requires less powder. A disadvantage is that the consolidation time is different at each pressure. This could result in a concave Heckel plot for materials having pronounced time-dependent consolidation [ 11, 363. Most previous reports, as reviewed by Humbert-Droz et al. [35], have used a hydraulic press and have measured compact thickness at maximum upper punch pressure after ejection. The work reported here was carried out using a single-punch excenter press, where the thickness was measured at 1 ms intervals throughout the compression sequence.
69 TABLE 1 Sequences of volume-reduction Expected mechanisms for metalsb
mechanismsa Expected mechanisms for organic compound&
Experimentally observed mechanisms for organic compoundsd
El : Elastic deformation of initial, weak particles PI : Plastic deformation of initial, weak particles F1 : Fragmentation of initial particles into a number of smaller descrete particles of higher strength
FI
E: Elastic deformation
E2 : Elastic deformation of smaller particles formed
E2
P: Plastic deformation
Pz : Plastic deformation of smaller particles formed
p2
F: Particle fragmentation
F2 : Fragmentation of smaller particles formed
aHere not including particle rearrangement. bRepresenting materials with low concentrations of crystal defects, pores and flaws. ‘Representing materials with high concentration of defects. dUtilizing, for example, porosity-pressure functions.
A perfect method for characterizing consolidation behaviour should be able to separate the different volume-reduction mechanisms involved in compaction. For metals and other materials possessing a high crystalline order or homogeneous structure, with low concentrations of crystal defects, pores or flaws, the relationship between material deformation and an increase in applied stress are well established. After an initial elastic deformation, the materials undergo plastic deformation and finally, if the stress is high enough, the material shows brittle behaviour and fragments (Table 1). However, most pharmaceutical materials, mainly organic compounds, exhibit consolidation properties far removed from this simple model. The main difference reported is that many materials seem to undergo particle fragmentation during the initial loading [ 10, 11, 23,311, followed by elastic and/or plastic deformation at higher loads. This phenomenon could possibly be explained by considering the fairly complex particle structure of many pharmaceutical compounds (Table 1). They often consist of aggregates
of primary particles or of highly porous particles. These ‘secondary’ particles could then during the initial loading behave as mainly brittle units, with a negligible deformation ability, and produce a large number of smaller discrete particles. These particles, formed during compression, would then show elastic and plastic deformation, possibly followed by a final fragmentation, when the compression load is further increased. When using the porosity function according to Heckel to describe the mechanisms involved in the compression of such complex materials as pharmaceutical compounds, several problems have been reported, as discussed in the Introduction. Firstly, an initial fragmentation will give a deviation from the straight line as predicted by Heckel for metal powders. Secondly, it is difficult to distinguish between elastic and plastic deformation as evaluated from the slope of the linear part of the profile. These problems could possibly be overcome by evaluating the whole compression cycle by the Heckel equation. The compression cycle could then be divided into three main phases, as illustrated in
I’
PHASE III
be to identify the time difference between maximum compression load and minimum porosity [37]. This time-lag could be interpreted as a reflection of plastic deformation, i.e. plastic flow would not stop at maximum load, but continue over a time-period when the pressure is released.
EXPERIMENTAL
CORPACTIONPRESSURE
Fig. 1. A compression cycle, evaluated using the Heckel function, separated into three phases to be used for the evaluation of volume-reduction mechanisms involved in compaction of pharmaceutical powders.
Fig. 1. During phase I, when the applied pressure is relatively low, the porosity reduction could be strongly enhanced by particle fragmentation. The curvature of the plot could be evaluated as the deviation from a straight line and expressed as the correlation coefficient (CC) as described in earlier papers [ 10, 111. The CC could then serve as a tool to quantify the fragmentation tendency. A linear curve is obtained for non-fragmenting materials. At higher pressures (phase II), elastic and/or plastic deformation are the dominating mechanisms. The reciprocal of the slope, the so-called yield pressure PY, has been claimed to reflect the plasticity of the material [31]. A low P,,-value should then indicate a high degree of plastic deformation. Since, for some materials, the density values ‘at pressure’ contain an elastic component, this could result in a false low P,-value [8, 271. During decompression (phase III), elastic properties of the particles could result in an increase in porosity. The decompression curve should be approximately horizontal when no elastic deformation is present, i.e. the instantaneous elastic expansion of the tablet is negligible. Since phase III could give information about the elastic component, it seems possible to elucidate the contribution of plastic deformation during phase II. Another means to evaluate phase III could
Materials Three model substances, undergoing volume reduction mainly by one major mechanism, were used to evaluate the usefulness of the Heckel equation applied to both compression and decompression curves. &eon Polyblend 503 (BP Chemicals, U.K.) is a blend of 52% poly(viny1 chloride) and 48% nitrile rubber, which deforms elastically. Sodium chloride (cubic crystalline puriss., Kebo-Grave, Sweden), which mainly deforms plastically (e.g. [ 121). Emcompress (dicalcium phosphate dihydrate, E. Mendell Co., Inc., U.S.A.), consisting of aggregates which fragment to a large extent during compression (e.g. [lo] ). To illustrate the usefulness and interpretation of fully evaluated Heckel plots, some pharmaceutical substances and additives were also tested. Aspirin (ASA 7013, BP, Monsanto, U.S.A.), phenacetin Ph. Nord.), sodium bicarbonate (puriss., Kebo-Grave, Sweden), lactose (CG monohydrate crystalline, CCF, Friesland, The Netherlands) and paracetamol (crystalline, BP, Bayer, F.R.G.). Magnesium stearate (Ph. Nord.) was used as an external lubricant. Methods Compression All powders were stored for at least 2 days at 20 “C and 45% RH before compression. Plane compacts with a diameter of 1.13 cm were compressed at 150 MPa (maximum upper punch pressure) using an instrumented single-punch press (Korsch EK 0, F.R.G.) at 3 0 rev- min- i. The powder for each compact was individually weighed on an analytical balance and then manually filled into the die. The fill weight for each substance was adjusted to give a compact thickness of
71
-
2.0.
Ei I g
1.6.
F
0
50
(aI
0.84 .
(b)
O
50
100
150
UPPER PUNCH PRESSURE (MPA)
+
I
-
150
100
UPPER PUNCH PRESSURE (MPA)
1.4.
6 I F:
1.2
F
cc:
0.3761
ER: 4.08
0
(cl
50
100
Z
150
UPPER PUNCH PRESSURE (MPA)
Fig. 2. He&e1 plots of the model substances. (a), Polyblend; (b), sodium chloride; (c), Emcompress. CC: correlation coefficient, PY: yield pressure, ER: elastic recovery, arrow denotes position for minimum porosity.
0.3 cm at maximum compaction load. The punch faces and die wall were lubricated with a 1 wt.% magnesium stearate suspension in ethanol before each compression. Measurement of tablet height The height of the compact was recorded every millisecond with an inductive displacement transducer. The values were corrected for the elastic deformation of the punches. The corresponding upper punch pressures were also recorded. The analog signals were converted to digital form using a la-bit A/D converter. The digital signals were then stored on a floppy disc for further calculations. Porosity function The porosity changes during a compression cycle were calculated by means of the Heckel equation and plotted us. upper punch pressure. The curvature of phase I was evaluated by calculating the CC in the pressure interval 2 - 50 MPa, using linear regression analysis. Phase II was evaluated by calculating the yield pressure PY(reciprocal of the slope K) in the
interval 40 - 100 MPa. Phase III was evaluated by denoting if the minimum porosity was reached at a time-event significantly different from the time of maximum load. The elastic component as given by phase III was then calculated as the relative increase in porosity ER.
RESULTS AND DISCUSSION
The Heckel plots of the model substances are shown in Fig. 2, whereas the dominating volume-reduction mechanisms are summarized in Table 2. Sodium chloride and Emcompress are practically non-elastic (phase III shows no marked decrease and ER values are low), therefore both PY and CC give correct information concerning the known plasticity and fragmentation tendency of the two materials. Sodium chloride represents a homogeneous, non-porous material with consolidation behaviour similar to, for example, metal powders. Consequently, no substantial fragmentation is observed as the initial part of the profile. After passing a minute elastic
72 TABLE 2
LACTOSE
Sequences of dominating volume-reduction nisms determined for test materials Materials
^^
mecha-
2.0' 1.8.
Mechanisms according to Table 1
Breon Polyblend 503 Sodium chloride Emcompress Sodium bicarbonate Lactose Paracetamol Phenacetin Aspirin
E P FI P FI F1 F1 F1
c
1.6' P,: 140 MPA CC: 0.9841
+ Pz
ER: 10.5 I
+‘(Ez)+P2
+‘ E2 + P2 +’ E2 +’ E2 + P2
0.8' 0
50
PARACETAMOL
6
2.6-
P,: 127 MPn cc: 0.9753 'E
ER: 19.7 X
1.1' 0
50
100
150
UPPER PUNCH PRESSURE (MPA)
Fig. 5. Heckel plot of paracetamol. PHENACETIN I 1.7 .
_
1.5'
6 I -
T
P,: 290 fiPA
1.3'
cc:
r
0.9724
ER: 28.4 X
1.1 .
0.9
SODIUM BICARBONATE
0
4
50
100
150
UPPER PUNCH PRESSURE MPA)
Fig. 6. Heckel plot of phenacetin.
1.8-
cc: 0.9962 ER: 1.01 X
0.8 . 0
150
Fig, 4. Heckel plot of lactose.
phase, the particles are deformed almost solely by plastic deformation. Emcompress, which could be regarded as a powder consisting of aggregates, is extensively fragmented even at relatively low loads. These particles continue to fragment at intermediate loads and subsequently appear to undergo mainly plastic deformation, as indicated by the time difference between maximum load and minimum porosity. The rubber powder, on the other hand, consolidates solely by elastic deformation. This is shown by the identical compression and decompression profiles and an extremely high ER value. The use of Py and CC for this material are of no significance. Heckel plots for the other materials are presented in Figs. 3 - 7 and the dominating volume reduction mechanisms are listed in Table 2. Sodium bicarbonate is a non-elastic substance, phase III is approximately horizontal and ER is very low. The correlation coefficient is close to unity and thereby indicates 2.0.
100
UPPER PUNCH PRESSURE (MPA)
50
100
UPPER PUNCH PRESSURE (MPA)
Fig. 3. Heckel plot of sodium bicarbonate.
150
a low degree of fragmentation. With the information from phase III, it can be concluded that the relatively low Py is reflecting plastic deformation. This is also indicated by the time-lag in phase III. In general, sodium bicarbonate shows similar behaviour to sodium chloride, which is well known to densificate mainly by plastic deformation.
73 ASPIRIN
I 3.5' Py: 73 tIPA
=: 3.0.
cc: 0.9777 5
2.5.
ER: 114 X
2.0.
/ 1.31 ' 0
50 UPPER WNCH
100 PRESSURE
150
(tIPA)
Fig. 7. Heckel plot of aspirin.
Lactose shows a slight decrease during phase III, which indicates some elastic deformation. The CC is low and reflects a high degree of fragmentation. The relatively low Py is influenced by the elastic properties of lactose and therefore probably overestimates the degree of plastic deformation. The total densificiation behaviour is of the same type as Emcompress. The difference is that lactose particles do not fragment as extensively, which gives a higher CC value. This difference has earlier been shown by permeametry surface area measurements [19]. Another difference from Emcompress is that the small particles formed during phase I exhibit some elastic behaviour, as indicated by phase III. Parucetamol is known to exhibit elastic properties, which is shown by the deviation from the horizontal in phase III. The CCvalue indicates extensive fragmentation, and therefore it is reasonable to assume that the low Py is caused to a large extent by elastic deformation, The extensive fragmentation of paracetamol particles has been confirmed by other techniques [ 191. By measuring the increase in surface area by permeametry it was shown that paracetamol belongs to the same group of materials as Emcompress. Although the particles created during phase I deform plastically, as seen from the timelag in phase III, the important feature of these particles is the marked elastic behaviour. For phenacetin, the large deviation from horizontal indicates elastic deformation, and the low CC reflects extensive fragmentation. The high P,, probably reflects the fact that the particles formed during phase I are not very deformable in nature. The absence
of any significant plastic deformation, as indicated by the minute time-lag in phase III, implies that the bonding ability is limited, which could explain the substantial increase in compact volume during decompression. The increase in porosity with decreasing pressures (phase III) for aspirin indicates a substantial elastic deformation. The CC is low and reflects extensive fragmentation. A low Py here probably reflects that the small aspirin particles formed in phase I are undergoing extensive deformation, i.e. elastic and plastic deformation as indicated by the timelag in phase III.
CONCLUSIONS
By evaluating the compression cycle using the Heckel equation for both the compression and decompression phases, it is possible to obtain a fairly comprehensive characterization of the mechanisms of volume reduction. The information given by the Heckel plots support earlier findings that several of the materials tested show an initial particle fragmentation (Table 2). The correlation coefficient calculated at relatively low pressures (phase I) reflects the fragmentation tendency of a material. The new, smaller particles formed in phase I seem to deform elastically to varying degrees, whereafter most of the materials exhibit plastic deformation when further pressure is applied (Table 2). This can be seen in phase III where a time-lag reflects plastic deformation and the ER value indicates the elastic component. Emcompress has a minute elastic behaviour whereas paracetamol, phenacetin and aspirin show significant elastic components. Lactose seems to possess intermediate properties in this respect. Phenacetin was the only fragmenting material without any significant plastic behaviour as indicated by the lack of time-lag during phase III. Both sodium chloride and sodium bicarbonate behaved similarly to that expected, for example, for metal powders, showing mainly plastic deformation. No significant fragmentation could be detected at low loads, and the elastic component was minute. From the data obtained it is evident that the slope of phase II could not be used alone for the characterization of plastic deforma-
l ruf*rcfrln
0
0.2
0.1 POROSITY
AT
MAXIMUM
COMPRESSION
0.3 LOAD
(
-
)
Fig. 8. Yield pressure as a function of minimum porosity for the materials tested.
tion. The Py value is instead reflecting the particles total ability to deform. This is illustrated in Fig. 8, where Py is plotted against the porosity at maximum compaction load, giving an approximate linear relation. For the materials undergoing extensive fragmentation, a relatively high P,, would be expected, since those can be regarded as fine particulate qualitities of non-fragmenting materials. For most of the latter materials a decrease in particle size would normally result in compacts wigh higher porosity [ 311. With the aid of phase III, the respective importance of both elastic and plastic deformation for the P,-value could be elucidated, thereby avoiding possible misinterpretation. The effect of consolidation behaviour on bonding ability and compact strength is not fully understood. It has been claimed that consolidation by plastic deformation is most effective in reducing compact porosity, and that a large porosity reduction is of vital importance to create the conditions necessary for bonding. However, the results in this study suggest that this may be true for some materials but cannot be regarded as a general rule. In an earlier study it was suggested that the surface area used for interparticulate attraction is only a minor fraction of the external particle surface area available [38]. A pharmaceutical compact could then be described as an agglomerate kept coherent by a number
’
of bonding points. If this model is correct, the important factor for bonding is probably not the particle bulk behaviour as characterized by the Heckel function during phases I and II, but the possibility for certain points at the surface of the particles to establish interparticulate attraction. This is demonstrated by the behaviour of the so-called fragmenting materials. Although fragmentation is the dominant mechanism during initial loading, the particles created are still able to deform and develop substantial bonding, which has been shown for a number of such materials. This bonding ability is probably enhanced by local plastic deformation at the points of contact. Unfortunately, the mechanisms characterized by the use of porositypressure functions is probably the total bulk behaviour rather than the effects limited to the particle surface. The elastic component, as characterized in phase III, could be important for the compactability of powders. A high compact strength would not be expected for elastic materials, since bonds could be broken by the elastic expansion during compact ejection. Only when particles bond with a strong bond type, or when a large number of bonds are present, will sufficient bonds remain to maintain compact strength after ejection. Several of the materials tested are known to cause problems such as lamination during compression. These materials, phenacetin, paracetamol and to some extent aspirin, are also the materials showing the most pronounced elastic expansion during phase III. The kind of porosity-pressure function evaluated in this study could be useful when investigating the effect of dry binder additions [6 - 81 to improve compact strength. During compression of fragmenting materials, new surfaces are created. The dry binder particles are held in the matrix in a position where they are unable to exert their effect on these newly created surfaces. This limited effect would be further reduced with materials that after fragmentation exhibit elastic behaviour, since the binder will probably not be able to counteract the breakage of bonds due to elastic expansion. Materials consolidating by fragmentation and elastic deformation, as demonstrated for phenacetin, probably cannot be directly compressed, but have to be granulated. As shown in earlier
75
reports [6 - 81, the addition of dry binders to plastically deforming materials, such as sodium bicarbonate, strongly increased the compact strength.
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