Properties of a good tablet granulation

Flowability is measured by the Angle of Repose of the granule mix. Pour a granular material into a pile. The angle of repose, or critical angle of repose, is the steepest angle at which the pile does not slump. The angle of the side of the pile is measured from the horizontal. At this angle, the material on the surface of the slope is just about to slide. In general, a lower angle of repose means better powder flowability.

The flow properties of granules decide whether the tablet press fills the same way for the first tablet and for the four hundred thousandth. Poor flow causes weight variation between tablets. Weight variation is a content uniformity failure that nobody has found yet. Use this table as a guide:

Inter-particulate friction is the friction between granules. It has to be low for good flow. Low friction means minimal contact between granules. Granules touch each other least when they are spherical or near-spherical. In short, a spherical granule always gives good flow, so spherical shape is an ideal property.

Residual moisture content is the moisture left in the tablet granulation after drying removes the extra water. Too low a moisture content may easily lead to soft tablets that break. Granules with a higher moisture content will lead to picking and sticking, which means the granules stick to the punches of the tablet press. Excess moisture content may also lead to microbial contamination. It may also harm the API stability profile. This is how long the active drug stays stable.

The ideal moisture content may vary from product to product. A general guideline would be to fix the moisture content between 1.00 to 2.50% w/w of the granule mix. Some drug products are very hygroscopic, which means they take up water from the air. In some of these products, the moisture content is kept lower than 1%.

There is no single limit of moisture content in tablets that applies to all products. The limit is set for each formulation during development. It then becomes part of the specification. The granules are tested by loss on drying at the end of drying. If the granules have been stored, they are tested again before compression.

Moisture content versus water content: a warning. Residual moisture content from granulation is not the same as water content. Water content here means the water of hydration of the API. This is water that is part of the drug itself, as in a monohydrate or a dihydrate. Normal drying cannot remove this water, so do not confuse it with moisture content. Reading the two as one number leads to an over-dried batch.

Compressibility tells us how the granules will perform during the compression process. Ideally, the granules should undergo plastic deformation under the compression rollers at the optimum compression force. This means they change shape without breaking. They should then form good, cohesive and hard tablets. For this, the granules need enough porosity, which means small empty spaces inside them, so that they can compress.

You can see this porosity in the difference between the poured bulk density and the tapped bulk density of the granules. Poured density is measured on loose granules. Tapped density is measured after the granules are tapped down to settle. The larger the difference, the better the compressibility. This formula expresses compressibility best:

This measure is generally called Carr's Index, or the Compressibility Index. Note that this page's formula divides by the poured density [note: USP <1174> defines the reference Compressibility Index as dividing by the TAPPED density. Both are in use and they give different numbers; confirm which convention Fabtech's QC uses].

Ideal values lie between 8% to 25%.

The best performing granule is always a mix of granules and fines. Fines are the smallest particles in the mix. A tablet made from only granules and very few fines will look striated, with lines on its surface, and it will not look good at all. It may also be less hard and show other problems.

The granule mix should follow the pattern of a normal distribution curve, which is a bell-shaped curve. The biggest group is the granules of average particle size. Smaller groups of granules and fines are on either side of this group. A granule mix of mostly granules and few fines may not compress well.

Fine granules meaning: in this context, fine granules are the smallest fraction of the granule population. They are not waste to be sieved out. They fill the spaces between larger granules in the die, which is the mould in the tablet press where the tablet is formed. This produces a dense tablet that holds together. A granulation with no fines packs badly.

Determination of granular composition is done by sieve analysis. The granule mix passes through a stack of test sieves, and each sieve has a finer mesh than the one above it. The granules left on each sieve are weighed. This gives the granules size distribution as a percentage for each size fraction. The lab compares this distribution against the specification. It does not use a single average number, because an average hides the shape of the curve.

It is very important that granules are spherical or near-spherical, whatever the size of the granules or powder particles. For example, most direct compression excipients are very fine, yet they flow and compress very well. Direct compression excipients are ingredients made to be pressed into tablets without granulation. They work well because their fine particles are spherical.

This is why most processes that use a high shear mixer or a top spray granulator aim for near-spherical granules. These granules aid flow, compress well and perform better overall. The equipment and the process give the granules their shape. The formula does not. Three things produce the shape: the granulation technique chosen, the shear applied, and the drying route.

The granulation is made to produce a tablet, and the specification is written for the tablet. The ideal properties of a tablet are listed below. Each one depends on a granule property described above. The same is true for the flow properties of tablets. How evenly the tablets filled their dies tells you about the granules that filled them.

You can read the table in both directions. When a tablet fails friability, the cause is usually compressibility or moisture. The press is rarely the cause. Capping and lamination mean the top or the layers of the tablet split off. They are signs of over-dried granules or too little plastic deformation. Weight that varies across a run is first of all a flow problem. This is why the properties on this page are checked before compression starts. They are not judged later from the tablets.

Each of these checks is a test on the tablet: uniformity of dosage units, hardness, friability, disintegration and dissolution. Yet what each check really measures is the granulation.

If a granulation misses one of the five properties, correct it in the process that made it, not at the tablet press. The correction depends on which property failed:

• Flow is poor and the angle of repose is high. The granules are too irregular or too fine. Fix this in the granulation step. Use more binder, use longer wet massing (mixing the powder with the binder liquid), or use a route that produces a rounder granule.
• Moisture is above target. Extend the drying step and test again by loss on drying. Moisture below target is harder to fix, because re-wetting a dried granulation is not a normal operation.
• Compressibility is low. The granules are too dense to deform. Reduce densification during granulation, so the granules are packed less tightly, and check the mill screen size.
• The size distribution is wrong. Mill and sieve the granules again. A distribution that is all granules and no fines usually means the mill screen is too coarse.
• The shape is irregular. The equipment decides the shape. A fluid bed processor and a high shear mixer granulator produce different granule shapes from the same formula.

The full process that these steps belong to, from dispensing to packed tablet, is on the OSD manufacturing process page.