content uniformity paper - dfe pharma...for doses below 1 mg of api it may be preferred to make a...

Content Uniformity of Direct Compression tablets

Content Uniformity of Direct Compression tablets 3

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

4 Content Uniformity of Direct Compression tablets

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 filler-binder 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.

�� =10� ∗ ∛{!��"�# . [&'(.)*�+,- !./0

�11+#]} ……………….. equation 4

where σg is the geometric standard deviation of the API particle size distribution.


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

Dose (mg)

σg d90/d50 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 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#

ISO equivalent mesh 125 µm 212 µm 250 µm 425 µm 500 µm 1 mm 1.18 mm

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.

Premixing De-agglomeration Final mixing Lubrication Tableting


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 Particle size distribution (µm)

d10 d50 d90

Paracetamol 3,1 18 71

SuperTab 11SD 47 120 208

SuperTab 30GR 50 121 258

SuperTab 21AN 11 149 321

SuperTab 22AN 58 190 340

Pharmacel 102 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.


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

Tableting

time (min)

SuperTab

11SD

SuperTab

30GR

SuperTab

21AN

SuperTab

22AN

Pharmacel

102

A

(no sieving

step)

1 257 (0.4) 251 (0.5) 252 (0.5) 251 (0.4) 248 (0.6)

5 250 (0.4) 249 (0.3) 249 (0.5) 249 (0.3) 249 (0.9)

10 249 (0.4) 250 (0.5) 249 (0.7) 250 (0.5) 251 (0.8)

15 249 (0.5) 250 (0.3) 250 (0.5) 250 (0.5) 251 (0.6)

25 251 (0.4) 250 (0.3) 250 (0.3) 250 (0.4) 252 (1.1)

end 249 (0.4) 250 (0.5) 250 (0.5) 249 (0.5) 250 (0.9)

B

(including

sieving

step)

1 251 (0.2) 251 (0.5) 252 (0.4) 250 (0.4) 252 (0.5)

5 249 (0.3) 250 (0.3) 249 (0.5) 249 (0.4) 251 (0.5)

10 249 (0.2) 250 (0.4) 251 (0.7) 249 (0.3) 252 (0.4)

15 249 (0.2) 249 (0.3) 250 (0.5) 250 (0.3) 251 (0.3)

25 250 (0.2) 249 (0.3) 249 (0.6) 250 (0.4) 250 (0.2)

end 250 (0.4) 251 (0.4) 249 (0.5) 249 (0.4) 250 (0.4)

Table 3: Weight uniformity of tablets 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 Tableting time (mins)

1 5 10 15 25 end

Mixing

scheme A

AV 2.6 3.5 4.7 42.8 10.3 15.3

Pass / Fail Pass Pass Pass Fail Pass Fail

Range (%) 97 – 99 95 - 98 94 - 98 96 - 154 95 - 111 94 - 116

Pass / Fail Pass Pass Pass Fail * Pass Fail

Mixing

scheme B

AV 3.3 3.1 3.3 2.0 4.6 3.6

Pass / Fail Pass Pass Pass Pass Pass Pass

Range (%) 99 - 102 100 - 102 98 - 100 97 - 101 97 - 101 97 - 107


SuperTab 30GR Tableting time (mins)

1 5 10 15 25 end

Mixing

scheme A

AV 2.3 1.4 1.7 2.2 2.6 6.5


Range (%) 99 - 102 100 - 102 98 – 100 97 – 101 97 – 101 96 - 107


Mixing

scheme B

AV 4.3 1.4 2.3 2.5 3.2 3.9


Range (%) 95 – 99 98 - 100 97 - 101 98 - 101 96 – 98 95 - 98



SuperTab 21AN Tableting time (mins)

1 5 10 15 25 end

Mixing

scheme A

AV 19.9 15.8 21.5 18.6 17.4 33.9

Pass / Fail Fail Fail Fail Fail Fail Fail

Range (%) 88 – 109 89 - 102 85 - 104 87 - 103 86 - 101 88 - 134

Pass / Fail Pass Pass Pass Pass Pass Fail *

Mixing

scheme B

AV 8.4 4.2 3.9 3.7 3.9 1.8


Range (%) 99 - 107 96 - 102 98 - 103 97 - 102 97 - 102 99 - 101


SuperTab 22AN Tableting time (mins)

1 5 10 15 25 end

Mixing

scheme A

AV 4.6 25.2 6.5 6.3 5.5 9.7

Pass / Fail Pass Fail Pass Pass Pass Pass

Range (%) 96 - 103 98 - 132 99 – 107 100 – 107 99 - 107 93 - 108

Pass / Fail Pass Fail * Pass Pass Pass Pass

Mixing

scheme B

AV 8.0 4.4 4.6 2.9 5.5 4.5


Range (%) 92 - 98 95 - 100 97 - 103 97 - 101 95 - 101 98 - 105


Pharmacel 102 Tableting time (mins)

1 5 10 15 25 end

Mixing

scheme A

AV 132.2 36.8 29.4 59.2 108.5 33.0

Pass / Fail Fail Fail Fail Fail Fail Fail

Range (%) 85 - 261 83 - 128 88 - 118 85 - 161 94 - 182 87 - 128

Pass / Fail Fail * Fail * Fail Fail * Fail * Fail *

Mixing

scheme B

AV 6.1 3.4 6.0 2.7 6.0 3.7


Range (%) 94 - 102 97 - 103 97 - 106 98 - 102 93 - 97 96 - 100


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.


Figure 2: plots of tablet assays using two mixing schemes and 5 filler-binders


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 filler-binder, 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


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 Definition and conversion of the mean particle diameter referring to mixing

homogeneity, H Egermann, Powder Technology. 1982, 31, 231— 232. Rohrs 2005 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

Egermann 1979 Mixing: agglomeration during sieving, Sci. Pharm., 1979, 47, 25 – 31 (in German) Staniforth 1982 Effect of vibration time, frequency and acceleration on drug content uniformity, JN

Staniforth, JE Rees, J. Pharm. Pharmacol., 1982, 34, 700 – 706. Staniforth 1986 Order out of chaos, JN Staniforth, J. Pharm. Pharmacol., 1987, 39, 329 – 334.


DFE Pharma (#code/month year)

content uniformity paper - dfe pharma...for doses below 1 mg of api it may be preferred to make a...

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