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Variations in the properties of microcrystalline cellulose from different sources
Powder
Technology,
54 (1988) 71 - 74
71
Letter Variations in the Properties of Microcrystalline Cellulose from Different Sources M. WHITEMAN and R. J. YARWOOD Wyeth Research (UK) Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 OPH (U.K.) (Received September 3,1987)
Introduction
Since its introduction in the early 196Os, microcrystalline cellulose has become the excipient of choice for most pharmaceutical tablet formulations. It is used extensively in direct-compression formulations, where its ability to form strong tablets without the addition of a binder make it particularly useful. Until recently there was only one major source of microcrystalline cellulose available (Avicel, FMC Coporation), but there are now several manufacturers competing for a share of the market. While it is clearly an advantage for pharmaceutical manufacturers to have more than one source of supply for key raw materials, it is also important that there is the minimum possible variation between alternative materials, as such variations can lead to processing problems and a reduction in product quality. It is known that large differences in compaction performance can exist for raw materials which may comply with the same pharmacopoeia1 monograph [l -61, and it has been shown that the particle size and moisture content of microcrystalline cellulose powders can affect their tensile strength [7]. In the work reported here, five samples of microcrystalline cellulose have been examined and compared with Avicel PHlOl and Avicel PH102. Materials
A. Microcrystalline cellulose (Steetley Chemicals Ltd., Basingstoke, England) B. Unimac MGlOO (Chemitrade Ltd., London, England)
C. Unimac MG200 (Chemitrade Ltd., London, England) D. Emcocel (Forum Chemicals Ltd., Reigate, England) E. Avicel PHlOl (Honeywill & Stein Ltd., Wallington, England) F. Avicel PH102 (Honeywill & Stein Ltd., Wallington, England) G. Microcrystalline cellulose (Becpharm Ltd., London, England) Disintegrant: 3.4% Crospovidone NF (Kollidon CL, BASF, Cheadle, England) Lubricant: 0.5% Magnesium stearate BP Each sample of microcrystalline cellulose was mixed with crospovidone and magnesium stearate in a Hobart planetary mixer for 5 min prior to compression. The batch size was 400 g.
Methods
Sieve analysis was performed on each sample and the median particle size was determined from a cumulative percentage oversize plot. Particle size was also determined using the Coulter Counter Model PCA I. Particle density was determined using a Micromeritics’ helium-air pycnometer. Specific surface area was measured using the Micromeritics’ Flowsorb II nitrogen adsorption apparatus. Bulk and tapped densities were determined and the Carr compressibility index calculated [8]. Loss on drying was measured using a Sartorius 7093 01 infra-red moisture balance (75 “C/10 min). The blended powders were compressed on an instrumented Manesty F3 single-punch tablet machine, operating at 67 strokes min-’ with lo-mm flat-faced tooling. The target tablet weight was 300 mg. For each sample, tablets were made at up to six different compaction pressures and stored in sealed containers for 48 h before physical testing. Tablet weight variation was determined for 20 tablets from each sample, crushing force measured using an Erweka TBH28 tablet tester, and tensile strength calculated according to the method of Fell and Newton [9]. 0 Elsevier Sequoia/Printed in The Netherlands
72 TABLE 1 Physical characteristics of microcrystalline
cellulose
Material
True density (g cm+)
Loose bulk density (g cme3)
Tapped bulk density (g cm+)
Car-r’s index (%)
Loss on drying (%)
Median particle size by sieving (pm)
Median particle size by Coulter (Ctm)
Specific surface area (m’g-‘)
A
1.53
0.271
0.323
16.1
4.4
87
-
-
B C D E F G
1.53 1.53 1.53 1.53 1.53 1.53
0.348 0.364 0.320 0.315 0.345 0.327
0.466 0.439 0.380 0.394 0.406 0.411
25.3 17.1 15.8 20.1 15.0 20.4
4.4 4.2 4.6 4.5 4.6 4.4
47 90 67 69 87 63
48 80 66 53 91 57
1.00 0.80 0.91 1.00 0.97 0.67
Disintegration time was determined using the BP disintegration apparatus without disks, using water at 37 “C. Tablet thickness was measured using a Mercer dial gauge and used to calculate porosity. Each of these determinations was performed on six tablets from each sample. Results and discussion Table 1 shows some of the physical characteristics of the samples tested. Sample A has much lower bulk and tapped densities than the other samples, although the median particle size by sieving was similar to that for Avicel PH102 (F). Sample C also had a similar median size and size distribution to Avicel PH102. For the remaining samples, the degree of similarity with Avicel PHlOl depends upon whether we consider sieving or Coulter Counter results. D and G have similar sieve analyses to Avicel PHlOl (E), but B is the closest in size by Coulter Counter. There were some differences between the surface areas of the samples, with G being particularly low. In general, the values were slightly lower than the 1.3 m2 g-l reported by Zografi et al.
TABLE 2 Coefficients of tablet weight variation Sample
Mean applied pressure (MPa)
Coefficient of variation (%)
A
-
-
B
C
D
E
[lOI.
Flow properties can sometimes be predicted from the Carr index, but in the present study there was no correlation between the index and the coefficient of tablet weight variation (Table 2); the low Carr Index value for A indicates that it should flow very well, but it flowed very poorly and it was not possible to make acceptable tablets from blend A. Samples B, C and G showed
13.6 21.5 I 41.5 50.5 \ 64.3
2.3 4.0 3.4 4.7 4.1
’ 6.5 12.3 I 27.4 44.4 58.1 67.3
1.4 1.4 1.7 1.2 1.8 2.4
10.8 16.4 I 28.7 34.9 50.0 61.1
2.3 1.0 1.6 1.4 1.1 1.0
6.9 19.7 I 33.2 45.2 62.1
1.7 1.1 1.2 1.1 1.2
I 54.9 67.8 41.6 29.2 17.3 8.1
0.9 1.1 1.4 1.0 1.3 1.5
4.7 13.0 23.9 33.4 61.3
4.0 2.1 3.1 1.9 3.9
F
G
73
relatively high coefficients of variation compared with D, E and F. Tensile strength, CJX,is plotted against mean compaction pressure in the Figure. For each material, there is an initial nearlinear portion which reaches a plateau at higher pressures. Sample D shows a similar strength-pressure profile to Avicel PHlOl and sample C shows a similar profile to Avicel PH02. Samples B and G exhibit profiles intermediate between those for the two Avicel grades.
lb
20
3b
4-O
50
$0
7b
MEAN APPLIED PRESSURE ( MPa) Fig. Tensile strength as a function of compaction pressure for tablets made from microcrystalline cellulose.*,B;m,C;fD;r,E;+,F;x,G.
For relatively loosely-packed powder beds, Khan and Pilpel [7 ] found that increasing the particle size of Avicel led to a reduction in bed tensile strength. However, for more densely packed compacts (tablets), it was found by McKenna and McCafferty [ll] that particle size variation had little or no effect on the tablet tensile strength. Neither of these studies relates directly to the work reported here since they deal with single-component systems, whereas the present authors have combined microcrystalline cellulose with magnesium stearate and crospovidone. The deleterious effects of magnesium stearate on tablet formulations are well-known and in a recent study, van der Watt [12] showed that
the extent of these effects with microcrystalline cellulose and magnesium stearate was dependent upon both the particle size of the cellulose and the mixing time. It was found that reducing the particle size of the cellulose increased the strength of the compacts, while increasing the mixing time led to a reduction in tensile strength for all fractions studied. It is difficult to tell whether such particlesize mixing time effects were occurring in the present study, since mixing times were relatively short. Particle size differences alone do not adequately explain the observed differences in the compaction pressuretensile strength profiles because samples with similar median particle size and size distribution gave tablets having quite different strengths. Khan and Pilpel [7] also found that the moisture content of Avicel powders (0 - 15%) influenced the tensile strength of packed beds, and Khan et al. [13] reported that it influenced the tensile strength of compacts using selected formulations. However, for the materials studied here, the similarity in moisture contents suggests that this is not a major reason for the different compression properties obtained. It is possible that some aspects of the manufacturing process used by the different suppliers leads to different surface properties in the microcrystalline cellulose produced. No such differences were observed using optical microscopy and it is unlikely that scanning electron microscopy would be widely used as a quality control technique for this material. It is clear from this work that the compression properties of different batches of microcrystalline cellulose cannot be predicted by compendia1 (NF or BP) tests or by any of the simple m-house tests used. It seems appropriate therefore that some form of compaction profile be included in in-house specifications for this material, especially in cases where it is used in direct-compression formulations. References M. R. Billany and J. H. Richards, Drug Dev. Znd. Pharm., 8 (1982) 497. H. Vromans, A. H. de Boer, G. K. Bolhuis, C. F. Lerk, K. D. Kussendrager and H. Bosch, Pharm. WeekbM Sci. Ed., 7 (1985) 186. H. Vromans, A. H. de Boer, G. K. Bolhuis, C. F. Lerk and K. D. Kussendrager, Acto Pharm. Suet., 22 (1985) 163.
74 4 H. Vromans, G. K. Bolhuis, C. F. Lerk, K. D. Kussendrager and H. Bosch, Acta Pharm. Suet., 23 (1986) 231. 5 H. Vromans, G. K. Bolhuis, C. F. Lerk, H. van de Biggelaar and H. Bosch, Znt. J. Pharm., 35 (1987) 29. 6 A. H. de Boer, H. Vromans, C. F. Lerk, G. K. Bolhuis, K. D. Kussendrager and H. Bosch, Pharm. Weekblad Sci. Ed., 8 (1986) 145. 7 F. Khan and N. Pilpel, Powder Technol., 48 (1986) 145.
8 R. L. Car-r,Brit. Chem. Eng., 15 (1970) 1541. 9 J. T. Fell and J. M. Newton, J. Pharm. Sci., 59 (1970) 688. 10 G. Zografi, M. J. Kontny, A. Y. S. Yang and G. S. Brenner, Znt. J. Pharm., 18 (1984) 99. 11 A. McKenna and D. F. McCafferty, J. Pharm. Pharmacol,, 34 (1982) 347. 12 J. G. van der Watt, Znt. J. Pharm., 36 (1987) 51. 13 K. A. Khan, P. Musikabhumma and J. P. Warr, Drug. Dev. Znd. Pharm., 7 (1981) 525.
Technology,
54 (1988) 71 - 74
71
Letter Variations in the Properties of Microcrystalline Cellulose from Different Sources M. WHITEMAN and R. J. YARWOOD Wyeth Research (UK) Ltd., Huntercombe Lane South, Taplow, Maidenhead, Berkshire SL6 OPH (U.K.) (Received September 3,1987)
Introduction
Since its introduction in the early 196Os, microcrystalline cellulose has become the excipient of choice for most pharmaceutical tablet formulations. It is used extensively in direct-compression formulations, where its ability to form strong tablets without the addition of a binder make it particularly useful. Until recently there was only one major source of microcrystalline cellulose available (Avicel, FMC Coporation), but there are now several manufacturers competing for a share of the market. While it is clearly an advantage for pharmaceutical manufacturers to have more than one source of supply for key raw materials, it is also important that there is the minimum possible variation between alternative materials, as such variations can lead to processing problems and a reduction in product quality. It is known that large differences in compaction performance can exist for raw materials which may comply with the same pharmacopoeia1 monograph [l -61, and it has been shown that the particle size and moisture content of microcrystalline cellulose powders can affect their tensile strength [7]. In the work reported here, five samples of microcrystalline cellulose have been examined and compared with Avicel PHlOl and Avicel PH102. Materials
A. Microcrystalline cellulose (Steetley Chemicals Ltd., Basingstoke, England) B. Unimac MGlOO (Chemitrade Ltd., London, England)
C. Unimac MG200 (Chemitrade Ltd., London, England) D. Emcocel (Forum Chemicals Ltd., Reigate, England) E. Avicel PHlOl (Honeywill & Stein Ltd., Wallington, England) F. Avicel PH102 (Honeywill & Stein Ltd., Wallington, England) G. Microcrystalline cellulose (Becpharm Ltd., London, England) Disintegrant: 3.4% Crospovidone NF (Kollidon CL, BASF, Cheadle, England) Lubricant: 0.5% Magnesium stearate BP Each sample of microcrystalline cellulose was mixed with crospovidone and magnesium stearate in a Hobart planetary mixer for 5 min prior to compression. The batch size was 400 g.
Methods
Sieve analysis was performed on each sample and the median particle size was determined from a cumulative percentage oversize plot. Particle size was also determined using the Coulter Counter Model PCA I. Particle density was determined using a Micromeritics’ helium-air pycnometer. Specific surface area was measured using the Micromeritics’ Flowsorb II nitrogen adsorption apparatus. Bulk and tapped densities were determined and the Carr compressibility index calculated [8]. Loss on drying was measured using a Sartorius 7093 01 infra-red moisture balance (75 “C/10 min). The blended powders were compressed on an instrumented Manesty F3 single-punch tablet machine, operating at 67 strokes min-’ with lo-mm flat-faced tooling. The target tablet weight was 300 mg. For each sample, tablets were made at up to six different compaction pressures and stored in sealed containers for 48 h before physical testing. Tablet weight variation was determined for 20 tablets from each sample, crushing force measured using an Erweka TBH28 tablet tester, and tensile strength calculated according to the method of Fell and Newton [9]. 0 Elsevier Sequoia/Printed in The Netherlands
72 TABLE 1 Physical characteristics of microcrystalline
cellulose
Material
True density (g cm+)
Loose bulk density (g cme3)
Tapped bulk density (g cm+)
Car-r’s index (%)
Loss on drying (%)
Median particle size by sieving (pm)
Median particle size by Coulter (Ctm)
Specific surface area (m’g-‘)
A
1.53
0.271
0.323
16.1
4.4
87
-
-
B C D E F G
1.53 1.53 1.53 1.53 1.53 1.53
0.348 0.364 0.320 0.315 0.345 0.327
0.466 0.439 0.380 0.394 0.406 0.411
25.3 17.1 15.8 20.1 15.0 20.4
4.4 4.2 4.6 4.5 4.6 4.4
47 90 67 69 87 63
48 80 66 53 91 57
1.00 0.80 0.91 1.00 0.97 0.67
Disintegration time was determined using the BP disintegration apparatus without disks, using water at 37 “C. Tablet thickness was measured using a Mercer dial gauge and used to calculate porosity. Each of these determinations was performed on six tablets from each sample. Results and discussion Table 1 shows some of the physical characteristics of the samples tested. Sample A has much lower bulk and tapped densities than the other samples, although the median particle size by sieving was similar to that for Avicel PH102 (F). Sample C also had a similar median size and size distribution to Avicel PH102. For the remaining samples, the degree of similarity with Avicel PHlOl depends upon whether we consider sieving or Coulter Counter results. D and G have similar sieve analyses to Avicel PHlOl (E), but B is the closest in size by Coulter Counter. There were some differences between the surface areas of the samples, with G being particularly low. In general, the values were slightly lower than the 1.3 m2 g-l reported by Zografi et al.
TABLE 2 Coefficients of tablet weight variation Sample
Mean applied pressure (MPa)
Coefficient of variation (%)
A
-
-
B
C
D
E
[lOI.
Flow properties can sometimes be predicted from the Carr index, but in the present study there was no correlation between the index and the coefficient of tablet weight variation (Table 2); the low Carr Index value for A indicates that it should flow very well, but it flowed very poorly and it was not possible to make acceptable tablets from blend A. Samples B, C and G showed
13.6 21.5 I 41.5 50.5 \ 64.3
2.3 4.0 3.4 4.7 4.1
’ 6.5 12.3 I 27.4 44.4 58.1 67.3
1.4 1.4 1.7 1.2 1.8 2.4
10.8 16.4 I 28.7 34.9 50.0 61.1
2.3 1.0 1.6 1.4 1.1 1.0
6.9 19.7 I 33.2 45.2 62.1
1.7 1.1 1.2 1.1 1.2
I 54.9 67.8 41.6 29.2 17.3 8.1
0.9 1.1 1.4 1.0 1.3 1.5
4.7 13.0 23.9 33.4 61.3
4.0 2.1 3.1 1.9 3.9
F
G
73
relatively high coefficients of variation compared with D, E and F. Tensile strength, CJX,is plotted against mean compaction pressure in the Figure. For each material, there is an initial nearlinear portion which reaches a plateau at higher pressures. Sample D shows a similar strength-pressure profile to Avicel PHlOl and sample C shows a similar profile to Avicel PH02. Samples B and G exhibit profiles intermediate between those for the two Avicel grades.
lb
20
3b
4-O
50
$0
7b
MEAN APPLIED PRESSURE ( MPa) Fig. Tensile strength as a function of compaction pressure for tablets made from microcrystalline cellulose.*,B;m,C;fD;r,E;+,F;x,G.
For relatively loosely-packed powder beds, Khan and Pilpel [7 ] found that increasing the particle size of Avicel led to a reduction in bed tensile strength. However, for more densely packed compacts (tablets), it was found by McKenna and McCafferty [ll] that particle size variation had little or no effect on the tablet tensile strength. Neither of these studies relates directly to the work reported here since they deal with single-component systems, whereas the present authors have combined microcrystalline cellulose with magnesium stearate and crospovidone. The deleterious effects of magnesium stearate on tablet formulations are well-known and in a recent study, van der Watt [12] showed that
the extent of these effects with microcrystalline cellulose and magnesium stearate was dependent upon both the particle size of the cellulose and the mixing time. It was found that reducing the particle size of the cellulose increased the strength of the compacts, while increasing the mixing time led to a reduction in tensile strength for all fractions studied. It is difficult to tell whether such particlesize mixing time effects were occurring in the present study, since mixing times were relatively short. Particle size differences alone do not adequately explain the observed differences in the compaction pressuretensile strength profiles because samples with similar median particle size and size distribution gave tablets having quite different strengths. Khan and Pilpel [7] also found that the moisture content of Avicel powders (0 - 15%) influenced the tensile strength of packed beds, and Khan et al. [13] reported that it influenced the tensile strength of compacts using selected formulations. However, for the materials studied here, the similarity in moisture contents suggests that this is not a major reason for the different compression properties obtained. It is possible that some aspects of the manufacturing process used by the different suppliers leads to different surface properties in the microcrystalline cellulose produced. No such differences were observed using optical microscopy and it is unlikely that scanning electron microscopy would be widely used as a quality control technique for this material. It is clear from this work that the compression properties of different batches of microcrystalline cellulose cannot be predicted by compendia1 (NF or BP) tests or by any of the simple m-house tests used. It seems appropriate therefore that some form of compaction profile be included in in-house specifications for this material, especially in cases where it is used in direct-compression formulations. References M. R. Billany and J. H. Richards, Drug Dev. Znd. Pharm., 8 (1982) 497. H. Vromans, A. H. de Boer, G. K. Bolhuis, C. F. Lerk, K. D. Kussendrager and H. Bosch, Pharm. WeekbM Sci. Ed., 7 (1985) 186. H. Vromans, A. H. de Boer, G. K. Bolhuis, C. F. Lerk and K. D. Kussendrager, Acto Pharm. Suet., 22 (1985) 163.
74 4 H. Vromans, G. K. Bolhuis, C. F. Lerk, K. D. Kussendrager and H. Bosch, Acta Pharm. Suet., 23 (1986) 231. 5 H. Vromans, G. K. Bolhuis, C. F. Lerk, H. van de Biggelaar and H. Bosch, Znt. J. Pharm., 35 (1987) 29. 6 A. H. de Boer, H. Vromans, C. F. Lerk, G. K. Bolhuis, K. D. Kussendrager and H. Bosch, Pharm. Weekblad Sci. Ed., 8 (1986) 145. 7 F. Khan and N. Pilpel, Powder Technol., 48 (1986) 145.
8 R. L. Car-r,Brit. Chem. Eng., 15 (1970) 1541. 9 J. T. Fell and J. M. Newton, J. Pharm. Sci., 59 (1970) 688. 10 G. Zografi, M. J. Kontny, A. Y. S. Yang and G. S. Brenner, Znt. J. Pharm., 18 (1984) 99. 11 A. McKenna and D. F. McCafferty, J. Pharm. Pharmacol,, 34 (1982) 347. 12 J. G. van der Watt, Znt. J. Pharm., 36 (1987) 51. 13 K. A. Khan, P. Musikabhumma and J. P. Warr, Drug. Dev. Znd. Pharm., 7 (1981) 525.