The Manufacturing Process — Part 2

The Formula — We have determined that a formula contains many ingredients other than just the active ingredient. The ingredients within the formula in addition to the active are called excipients.

Excipients are needed to make a good quality tablet at the required tablet press speed. They help the flow, compressibility and the ability of the tablet to eject from the tablet press without falling apart. Excipients also enhance the hardness, disintegration, appearance, color, taste, and the overall performance of the tablet.

As stated previously, a formula that is designed on a slow speed tablet press may not work on a high speed press. Even the best tablet press with all the best design features may not be able to compress a formula at any speed. Each formula has a limit to how fast it can be compressed. In order to increase the speed, the formula must be changed.

Why Granulate?

1. To improve powder flow.
2. To improve compressibility.
3. To reduce fines.
4. To control the tendency of powders to segregate.
5. To control density.
6. To capture and fuse small quantities of active material.

The average tablet press speed in the pharmaceutical industry produces 3,000 tpm (tablets per minute) or 50 tablets per second. Tablet press speeds can exceed 10,000 tpm or 166 tps.

Granule Formation in the Wet Granulating Process

Most of the early research in granulating took place in pans and drums and some of the theory and knowledge gained using that equipment is not directly applicable in all technologies. There are however at least three theories which have been accepted by academics as applicable. These three mechanisms are:

1. Nucleation
2. Transition in the funicular and capillary stage
3. Ball growth. In nucleation, the formation starts with loose agglomerates or single particles which are wetted by the binding solution and form small granules by pendular bridging. Continued addition of binding solution and tumbling action consolidates and strengthens the granules through the funicular stage and into the capillary stage. In this transition stage the granules continue to grow by one of two mechanisms: single particle addition and multiple granule formation.

Theoretically, at the end of the transition stage there are a large number of small granules with a fairly wide size distribution.

Wet Granulating Process Steps

In the pre-mix step the powders to be granulated are added and mixed prior to the introduction of the binder. In the wet massing step the binder is added to the mixture and the components are massed to a predetermined end point.

In the drying step the wet mass is dried to a predetermined end point, commonly measured with a test called the “LOD” or loss on drying test. The finished granulation is then milled to reduce the size of any caked material into a standardized particle size distribution. This distribution is usually measured using a series of screens lined up top to bottom from largest screen to a pan to collect the dust.

In the final blend, the lubricant is added to the granulation producing the final blend. Granulation is actually caused by a complex interaction of several variables and knowledge of each is necessary to control the granule formation process. If we establish which variables are critical to granule formation, we will have the basis to control granule growth for a reproducible process.

How Granules are Tested

There are four standardized tests which are commonly performed on either milled or finished granules:

1. LOD- water content
2. Bulk Density, mg/ml
3. Particle Size Distribution
4. Angle of Repose, flow gradient

Two of the four tests, Loss on Drying (LOD) and Particle Size Distribution, are commonly performed by operators on the production floor. In some cases, the operator only performs the LOD and the other three tests are performed in the laboratory. The practice varies depending on the situation.

-Michael Tousey, Techceuticals

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