Content Uniformity of Direct
Compression tablets
Contents
1
Summary
4
2
Introduction
4
3
The role of drug particle size
4
4
The role of mixing strategy
5
5
The role of excipients
5
6
Laboratory data
6
7
Conclusions
11
8
References
11
Content Uniformity of Direct Compression tablets
3
1
Summary
Achieving good tablet content uniformity requires drug particle size to be controlled such that there are
enough particles in a single dose to achieve adequate distribution.
It is essential to effectively deagglomerate the drug. Both the mixing scheme and the selection of fillerbinder contribute to deagglomeration. The mixing scheme should include a step specifically to reduce
agglomerates in a drug excipient premix to a sub-critical level, and free flowing excipients such as SuperTab
30GR or SuperTab 11SD can aid in the dispersal of agglomerates.
2
Introduction
Direct compression is the simplest way of making tablets, requiring only blending and tableting operations
for low and medium dose APIs where the tableting properties are primarily conferred by excipients. In order
to make satisfactory tablets by direct compression, especially when the API dose is low, it is necessary to
understand the factors that contribute to achieving acceptable drug content uniformity. These may be
summarised as drug particle size, mixing strategy and selection of key excipients (filler-binders).
This guide discusses these three factors, and is illustrated with data from DFE Pharma’s laboratory.
3
The role of drug particle size
This factor is not confined to direct compression. Any dosage form containing particles of a drug must
contain enough particles to enable them to be distributed evenly between individual dosage units.
Pharmacopoeial requirements for content uniformity are based on both the standard deviation of the data,
calculated as an acceptance value (AV) and on the range of the data. The acceptance value must not
exceed 15.0 at level 1 (analysis of 10 units) or 25.0 at level 2 (analysis of 30 units).
The acceptance value is calculated as
= − + ……..equation 1
where M = X (if 98.5 < X < 102.5) or M = 98.5 (if X < 98.5) or M = 102.5 (if X > 102.5), X is the sample
mean assay value, k is 2.4 (level 1) or 2.0 (level 2) and s is the sample standard deviation.
The AV corresponds to an RSD of 6.25% at level 1 or an RSD of 7.5% at level 2 when X=100.
The range of the data must be within 85 – 115% of the label strength at level 1 or within 75 – 125% of the
label strength at level 2.
It is possible to relate the potential RSD that is achievable for an API to its dose and its particle size
distribution. The general approach is based on consideration of the Poisson distribution which has the
property that the mean is equal to the variance. Thus it is possible to express the RSD of a Poisson
distribution as
= 100 ∗ √ ……… equation 2
where n is the average number of drug particles in a single unit.
The number of drug particles is related to the dose (G) and the particle diameter (d), and the RSD can be
written in terms of these parameters as
= 100√ ……………… equation 3
where ρ is the true density of the API. The diameter to be taken is the volume-weighted, volume-number
mean diameter (Egermann 1982).
Development of this approach (Rohrs 2005) leads to calculation of the required geometric median diameter
(dg) to achieve a given RSD.
+
./0
= 10 ∗ ∛{! # . [& '(.)* ,- ! +#]} ……………….. equation 4
"
11
where σg is the geometric standard deviation of the API particle size distribution.
4
Content Uniformity of Direct Compression tablets
To have a 99% chance of passing content uniformity criteria at level 1 requires an RSD of 3.84 (Rohrs 2005;
based on USP28 criteria). Using this value in equation 4 and assuming the API has true density of 1.5 g.cm-3
results in the values shown in table 1. For example, a 1 mg dose of an API requires a d50 of about 35 µm or
less if the ratio d90/d50 is about 3.2.
Measure of spread
of API distribution
σg
d90/d50
Dose (mg)
0.01
0.05
0.1
0.5
1
5
10
1.5
1.7
21
36
45
77
96
165
207
2
2.4
13
22
28
48
60
102
129
2.5
3.2
7.5
13
16
28
35
60
75
3
4.1
4.3
7.4
9.4
16
20
35
43
3.5
5.0
2.5
4.3
5.4
9.3
12
20
25
4
5.9
1.5
2.5
3.2
5.5
6.9
12
15
Table 1: Maximum particle median diameter (d50) required to give a 99% chance of passing USP content
uniformity requirements at level 1.
4
The role of mixing strategy
Many APIs are finely milled powders and are consequently cohesive with a tendency to agglomerate. An
appropriate mixing strategy includes a step to disperse these agglomerates to a sub-critical level (a level
which is unlikely to threaten the content uniformity requirements). Importantly this de-agglomeration step
should not be performed on the API itself, because of the tendency to agglomerate again (Egermann 1979),
but it should be performed on a premix of the API (approximately 10%) and an excipient (approximately
90%). The overall processing scheme is therefore
Premixing
De-agglomeration
Final mixing
Lubrication
Tableting
Deagglomeration may be performed by a variety of unit processes, including sieving, passing a premix
through a conical type mill, use of a blender with an intensifier bar or other high shear step. It has been
suggested that a critical agglomerate size is such that no single agglomerate exceeds 5% of the total API
dose (Egermann 1979). The sieve aperture through which a premix should be passed in order to meet this
requirement can be estimated. Table 2 is based on Egermann 1979 with the assumption that the bulk
density of the agglomerates is 0.5 g.cm-1. For example a premix of an API with dose of 1 mg needs to
passed through an ASTM 35 mesh / 500 µm sieve or finer.
For doses below 1 mg of API it may be preferred to make a premix with an excipient finer than direct
compression lactose.
Dose of API (mg)
0.01
0.05
0.1
0.5
1
5
10
Maximum agglomerate size (µm)
124
212
267
457
576
985
1241
Closest ASTM equivalent sieve
120#
70#
60#
40#
35#
18#
16#
125 µm
212 µm
250 µm
425 µm
500 µm
1 mm
1.18 mm
ISO equivalent mesh
Table 2: Maximum sieve aperture required to reduce agglomerates to a sub-critical level
5
The role of excipients
Selection of appropriate excipients, particularly filler-binders, may affect the content uniformity of tablets. It
has been found (Staniforth 1982 and 1987) that a macroporous excipient (one with surface cavities) is
beneficial in promoting physical stability of blends of coarse excipients and fine drugs, for a number of
reasons. First, there is the opportunity for multiple adhesive contact points between drug and excipient, and
also the location of drug particles in surface cavities means that they are less likely to be detached by rolling
or abrasive forces during mixing.
Content Uniformity of Direct Compression tablets
5
Differences in the surface structures of different types of lactose are shown in figure 1 which shows that
granulated forms of direct compression lactose possess appear to have the most surface cavities.
(a) Granulated Lactose
(b) Spray Dried Lactose
(c) Anhydrous Lactose
Figure 1: Surface structures of various forms of direct compression lactose by SEM
Examples of granulated lactose for direct compression include grades of lactose monohydrate (SuperTab
30GR and LactoPress Granulated), and anhydrous lactose (SuperTab 24AN).
6
Laboratory data
In the experiments described here, paracetamol was used as a model drug and the filler-binders were
SuperTab 11SD, SuperTab 30GR (both direct compression lactose monohydrate), SuperTab 21AN,
SuperTab 22AN (both direct compression anhydrous lactose) and Pharmacel 102 (microcrystalline cellulose).
The particle size distributions as determined by Sympatec laser diffraction are shown in the table below.
Component
Paracetamol
SuperTab 11SD
SuperTab 30GR
SuperTab 21AN
SuperTab 22AN
Pharmacel 102
Particle size distribution (µm)
d10
d50
d90
3,1
18
71
47
120
208
50
121
258
11
149
321
58
190
340
39
138
260
According to table 1, the paracetamol (d50 = 18 µm, d90 / d50 = 4.0) is suitable for doses of approximately
0.5 mg and higher.
Tablet formulations contained 2% paracetamol (equivalent to 5 mg), 97.5% of the filler binder and 0.5%
magnesium stearate. Blends (4 kg scale) were prepared according to one of the mixing schemes described
below and tableted at 250mg using a Kilian RTE-15 AM rotary press with 9mm tooling (lactose tablets) or
10 mm tooling (Pharmacel 102 tablets).
Tablet samples were taken throughout the tablet run (approximately 30 minutes) and at each sampling time
10 tablets were tested for weight uniformity and content uniformity. Paracetamol was analysed by
ultraviolet spectroscopy in water at 243nm, and the assay was determined to have RSD of 1.3%.
Mixing scheme A (no deagglomeration step): The paracetamol and the filler-binder were blended in a
cube mixer for 10 minutes and then the magnesium stearate was added and blended for a further 5
minutes.
Mixing scheme B (including deagglomeration): The paracetamol (80g) was blended with 500 g of the
filler-binder in a Turbula mixer at 90 rpm for 5 minutes. This premix was passed through a 500 µm sieve
before blending with the remainder of the filler binder in a cube mixer and lubrication. The maximum
sieve aperture required for a 5 mg dose of API is 1000 µm according to table 2, and therefore the final
blend should not contain any agglomerates of a critical size.
6
Content Uniformity of Direct Compression tablets
The weight uniformity of tablets made in the study is given in table 3. Weight uniformity is excellent and
will not have a significant contribution to content uniformity variation.
Mixing
scheme
A
(no sieving
step)
B
(including
sieving
step)
Tableting
time (min)
1
5
10
15
25
end
1
5
10
15
25
end
SuperTab
SuperTab
SuperTab
11SD
30GR
21AN
257 (0.4)
251 (0.5)
252 (0.5)
250 (0.4)
249 (0.3)
249 (0.5)
249 (0.4)
250 (0.5)
249 (0.7)
249 (0.5)
250 (0.3)
250 (0.5)
251 (0.4)
250 (0.3)
250 (0.3)
249 (0.4)
250 (0.5)
250 (0.5)
251 (0.2)
251 (0.5)
252 (0.4)
249 (0.3)
250 (0.3)
249 (0.5)
249 (0.2)
250 (0.4)
251 (0.7)
249 (0.2)
249 (0.3)
250 (0.5)
250 (0.2)
249 (0.3)
249 (0.6)
250 (0.4)
251 (0.4)
249 (0.5)
Table 3: Weight uniformity of tablets
SuperTab
22AN
251 (0.4)
249 (0.3)
250 (0.5)
250 (0.5)
250 (0.4)
249 (0.5)
250 (0.4)
249 (0.4)
249 (0.3)
250 (0.3)
250 (0.4)
249 (0.4)
Pharmacel
102
248 (0.6)
249 (0.9)
251 (0.8)
251 (0.6)
252 (1.1)
250 (0.9)
252 (0.5)
251 (0.5)
252 (0.4)
251 (0.3)
250 (0.2)
250 (0.4)
Content uniformity results for each of the 5 filler-binders evaluated are shown in the tables below. In the
Pass / Fail lines the asterisked Fail * notation means that the sample would fail at level 2 if tested.
SuperTab 11SD
1
5
Tableting time (mins)
10
15
25
end
Mixing
scheme A
AV
Pass / Fail
Range (%)
Pass / Fail
2.6
Pass
97 – 99
Pass
3.5
Pass
95 - 98
Pass
4.7
Pass
94 - 98
Pass
42.8
Fail
96 - 154
Fail *
10.3
Pass
95 - 111
Pass
15.3
Fail
94 - 116
Fail
Mixing
scheme B
AV
Pass / Fail
Range (%)
Pass / Fail
3.3
Pass
99 - 102
Pass
3.1
Pass
100 - 102
Pass
3.3
Pass
98 - 100
Pass
2.0
Pass
97 - 101
Pass
4.6
Pass
97 - 101
Pass
3.6
Pass
97 - 107
Pass
SuperTab 30GR
Tableting time (mins)
10
15
1
5
25
end
Mixing
scheme A
AV
Pass / Fail
Range (%)
Pass / Fail
2.3
Pass
99 - 102
Pass
1.4
Pass
100 - 102
Pass
1.7
Pass
98 – 100
Pass
2.2
Pass
97 – 101
Pass
2.6
Pass
97 – 101
Pass
6.5
Pass
96 - 107
Pass
Mixing
scheme B
AV
Pass / Fail
Range (%)
Pass / Fail
4.3
Pass
95 – 99
Pass
1.4
Pass
98 - 100
Pass
2.3
Pass
97 - 101
Pass
2.5
Pass
98 - 101
Pass
3.2
Pass
96 – 98
Pass
3.9
Pass
95 - 98
Pass
Content Uniformity of Direct Compression tablets
7
SuperTab 21AN
1
5
Tableting time (mins)
10
15
25
end
Mixing
scheme A
AV
Pass / Fail
Range (%)
Pass / Fail
19.9
Fail
88 – 109
Pass
15.8
Fail
89 - 102
Pass
21.5
Fail
85 - 104
Pass
18.6
Fail
87 - 103
Pass
17.4
Fail
86 - 101
Pass
33.9
Fail
88 - 134
Fail *
Mixing
scheme B
AV
Pass / Fail
Range (%)
Pass / Fail
8.4
Pass
99 - 107
Pass
4.2
Pass
96 - 102
Pass
3.9
Pass
98 - 103
Pass
3.7
Pass
97 - 102
Pass
3.9
Pass
97 - 102
Pass
1.8
Pass
99 - 101
Pass
1
5
25
end
Mixing
scheme A
AV
Pass / Fail
Range (%)
Pass / Fail
4.6
Pass
96 - 103
Pass
25.2
Fail
98 - 132
Fail *
6.5
Pass
99 – 107
Pass
6.3
Pass
100 – 107
Pass
5.5
Pass
99 - 107
Pass
9.7
Pass
93 - 108
Pass
Mixing
scheme B
AV
Pass / Fail
Range (%)
Pass / Fail
8.0
Pass
92 - 98
Pass
4.4
Pass
95 - 100
Pass
4.6
Pass
97 - 103
Pass
2.9
Pass
97 - 101
Pass
5.5
Pass
95 - 101
Pass
4.5
Pass
98 - 105
Pass
25
end
SuperTab 22AN
Pharmacel 102
1
5
Tableting time (mins)
10
15
Tableting time (mins)
10
15
Mixing
scheme A
AV
Pass / Fail
Range (%)
Pass / Fail
132.2
Fail
85 - 261
Fail *
36.8
Fail
83 - 128
Fail *
29.4
Fail
88 - 118
Fail
59.2
Fail
85 - 161
Fail *
108.5
Fail
94 - 182
Fail *
33.0
Fail
87 - 128
Fail *
Mixing
scheme B
AV
Pass / Fail
Range (%)
Pass / Fail
6.1
Pass
94 - 102
Pass
3.4
Pass
97 - 103
Pass
6.0
Pass
97 - 106
Pass
2.7
Pass
98 - 102
Pass
6.0
Pass
93 - 97
Pass
3.7
Pass
96 - 100
Pass
The data for the content uniformity of the tablets are plotted below. The data for mixing scheme A (without
sieving) are plotted in grey, and the data for mixing scheme B (with sieving) are plotted in orange. At each
tableting time the individual symbols represent the single tablet assays and the line represents the average
assay. Red lines represent the level 1 range limits for single tablet assays. The numbers to the right of each
plot are the mean assay, the RSD, the minimum and the maximum assays for the 60 tablets overall.
8
Content Uniformity of Direct Compression tablets
Figure 2: plots of tablet assays using two mixing schemes and 5 filler-binders
Content Uniformity of Direct Compression tablets
9
The tabulated data and the plots reveal differences between the two mixing schemes and also between
excipients used.
When mixing scheme A was employed, only SuperTab 30GR gave acceptable data.
For SuperTab 11SD and SuperTab 22AN there were occasional super-potent tablets detected (a total of 3
out of 120 tablets analysed) and it is these tablets that lead to the higher AV results.
Two super-potent tablets were detected when SuperTab 21AN was used, and additionally there were
slightly high AV results at sampling times when there were no super-potent tablets.
Pharmacel 102 shows most clearly how deagglomeration can affect the content uniformity result.
When mixing scheme B was employed there were no failures in any of the tablets analysed using any fillerbinder, showing how the sieving step has effectively reduced the agglomerates to a sub-critical level. There
is little difference in the data between the different filler-binders. This confirms the importance of the
deagglomeration step in direct compression tableting.
It is probably no coincidence that the more free flowing excipients (SuperTab 30GR, 11SD and 22AN) give
better results than SuperTab 21AN and Pharmacel 102. In the cube mixer used in this study it is likely that
the better flowing excipients form a “rolling” powder bed than can, to some extent, ball mill the
paracetamol agglomerates. This probably does not happen when SuperTab 21AN and Pharmacel 102 are
used.
Note that only the use of the sieving step, or other deagglomeration step, gives assurance that
agglomerates have been suitably reduced. Even though use of SuperTab 30GR in mixing scheme A gave
acceptable analytical results, it is possible that super-potent tablets were present but not sampled in this
trial.
Except for occasional super-potent tablets, the overall appearance of the analytical data when a free flowing
excipient is used is very similar for both mixing schemes, with an approximate normal distribution of tablets
around 100% label strength. This is exemplified in Figure 3 for the SuperTab 22AN tablets. If the single
super-potent tablet is excluded, then the RSD given by mixing scheme A is 2.8% compared to 2.5% for
mixing scheme B.
Thus the small sample size required for pharmacopoeial content uniformity testing may not detect the
occasional super-potent tablet in a batch, and lead to false assurance of acceptable content uniformity.
Figure 3: Distribution of tablets assays with different mixing schemes
10
Content Uniformity of Direct Compression tablets
7
Conclusions
Excellent content uniformity of direct compression tablets can be achieved by following 3 guides
Ensure that the API has a particle size fine enough to be capable of adequate dispersion.
Ensure that the API is adequately dispersed by inclusion of a premix and deagglomeration step in
preparation of the compression mix.
Use a free flowing excipient to aid agglomerate dispersal, and with surface properties that are
favourable for drug adhesion.
8
References
Egermann 1982
Rohrs 2005
Egermann 1979
Staniforth 1982
Staniforth 1986
Definition and conversion of the mean particle diameter referring to mixing
homogeneity, H Egermann, Powder Technology. 1982, 31, 231— 232.
Particle Size Limits to Meet USP Content Uniformity Criteria for Tablets and Capsules,
BR Rohrs, GE Amidon, RH Meury, PJ Secreast, HM King, CJ Skoug, J. Pharm. Sci.,
2006, 95, 1049 - 1059
Mixing: agglomeration during sieving, Sci. Pharm., 1979, 47, 25 – 31 (in German)
Effect of vibration time, frequency and acceleration on drug content uniformity, JN
Staniforth, JE Rees, J. Pharm. Pharmacol., 1982, 34, 700 – 706.
Order out of chaos, JN Staniforth, J. Pharm. Pharmacol., 1987, 39, 329 – 334.
Content Uniformity of Direct Compression tablets
11
DFE Pharma (#code/month year)
12
Content Uniformity of Direct Compression tablets