Manufacturing of tablets

Manufacturing of tablets

Requirements for tableting

As shown in Figure 20.2, tableting involves compression of a powder blend in a die cavity between the upper and the lower punches. Several punches and dies are arranged on three rotary turrets on a high-speed rotary tablet press that move concurrently in a circular motion as the tablets are made. As the turret moves, the powder is fed into the dies at one port through a hopper and feed frame, dose adjusted, compressed, ejected, and the tablets are collected at another port. This process requires

Figure 20.2 Tabletting process.

·           Uniform flow of blend into the die cavity through a hopper and feedframe.

·           Nonsegregation of powder blends in the hopper and during loading in the die cavity.

·           Compactibility (ability to reduce in volume and compress on applica-tion of force by the punches) of the powder in the die cavity during compression.

·           Nonsticking of the powder blend to walls of dies and surfaces of punches.

·           Adequate cohesion of the powder blend to form a strong tablet.

Powder flow and compressibility

Powder flow is required for transporting the materials through the hopper of a tableting machine and roller compactor (for dry granulation or roller compaction-based processes). Inadequate powder flow can lead to variable die filling, which produces tablets that vary in weight, drug content, and strength (hardness). Therefore, steps must be taken to ensure that the proper powder flow is maintained. Incorporation of a glidant and/or a lubricant into the formulation enhances the powder flow. Increasing the sphericity of particles also improves the flow. Processes such as spray drying, fluid-bed granulation or extrusion spheronization increase the sphericity of granules. In addition, increasing the density of granules, such as by granulation, also improves the powder flow. The most popular method of increasing the flow properties of powder is by granulation. As discussed earlier, granulation could be either dry granulation, which does not use a granulating fluid, or wet granulation, which involves wetting with a fluid followed by drying.

Compressibility is the property of forming a stable, intact compact mass when pressure is applied. Some materials compress better than others do. Compressibility is an outcome of the extent of plastic deformation that a material can undergo combined with cohesive forces among the powder blend that will keep the material in the compressed state. Most materi-als exhibit different degrees of elastic recovery, that is, expansion toward original higher volume on removal of stress. Low elastic recoveries coupled with high plastic deformability and high interparticle adhesion promote the formation of strong compacts at low compression forces.

Granulation generally improves compressibility. Materials that do not compress well produce soft tablets.

Types of manufacturing processes

Based on the characteristics of the starting materials that influence the properties of the powder blend, three general processes are used for prepar-ing granulation blends for compression:

·           Direct compression

·           Dry granulation or roller compaction

·           Wet granulation

The purpose of both wet and dry granulation is to improve the flow of the mixture and to enhance its compression properties by increasing particle size, density, and sphericity. The selection among these processes is based on the physicomechanical properties of the API and the raw material blend (API with excipients). For example, stability of the API to other ingredients used for preparing granulation blends and processing conditions (e.g., use of water during wet granulation) is critical. For example, dry granulation may be preferred for moisture and/or heat sensitive APIs.

1. Direct compression: Direct compression is the preferred method if powder blend has adequate flow, compactibility, and cohesion with low segregation potential. This is the simplest process that involves the least extent of material handling. Direct compression involves simply mixing the required ingredients and compressing them into tablets on the press.

2. Dry granulation: Dry granulation is preferred in circumstances where powder flow, cohesion, and/or segregation potential need to be improved, but compactibility is adequate. This process involves com-pacting a powder blend. It can be carried out by either of two processes: (a) slugging, which involves compression using large punches and dies in a tablet press; or (b) roller compaction, which involves forcing the powder blend between two counterrotating rolls that are pressed together under hydraulic pressure. This squeezes the powder blend into a solid cake between rollers. As shown in Figure 20.3, the compacted material is milled to form granules, which are generally larger in par-ticle size than starting powder blend. These granules are then mixed with extragranular excipients and compressed on the tablet press.

Figure 20.3 (a) A high shear granulator. (From Vector Corporation, http://www. vectorcorporation.com.) and (b) a low shear granulator. (From Hobart Corporation, http://www.hobartcorp.com. With Permission.)

3. Wet granulation: Wet granulation is preferred when compactibility of the powder is not very high and there is a need to improve the flow, cohesion, and/or segregation potential of the powder blend. The powder blend is loaded in a granulator (vessel with a rotating blade to mix the powder, Figure 20.4) and granulated with a solu-tion of the binder or water (if a dry binder is added to the powder mixture). Water is the most widely used blender vehicle. The use of nonaqueous granulation liquids, such as ethanol, is no longer pre-ferred for safety and environmental reasons. The formed granules are dried in a tray or fluid bed dryer at moderately elevated tempera-tures. Dried granules are then mixed with extragranular excipients and compressed on the tablet press.

Figure 20.4 A roller compaction process. (From Kurimoto Ltd., http://www.kurimoto. co.jp. With Permission.)

a. Low or high-shear wet granulation: Depending on the design of the granulator, wet granulation could impart low or high levels of shear to the powder blend and are termed accordingly. For example, a flat-bottom bowl granulator with horizontal blades that move in a circular motion at the bottom of the powder bed (Figure 20.4a) leads to high shear, whereas the use of verti-cal blades in an oval bowl (Figure 20.4b) lead to low shear. The extent of shear can affect porosity, compactibility, and density of granules. Low-shear granulation generally yields higher porosity, higher compactibility, and lower density of the formed granules. A choice between low- and high-shear granulation is based on the sensitivity of the desired product quality attributes to process conditions.

b. Fluid-bed granulation: Fluid-bed granulation involves the spray of the granulating liquid on the fluidized powder bed. This process combines the drying step with the granulation step. In this pro-cess, the evaporation of the granulating liquid is concurrent with the granulation of the powder blend. It is a relatively slow, but a well-controlled process that leads to the generation of granules, which are more porous, less dense, and more uniform in shape and size.

4. Moisture-activated dry granulation: Other processes commonly employed for preparing powder blend for compression involve a com-bination of the three basic processes. For example, MADG involves spraying of a minimum amount of water on the powder blend before compression to improve powder adhesion.

5. Continuous granulation: Use a continuous granulation process mini-mizes the material transfers and enables flexibility of batch size. Continuous processes are based on a tunnel or channel of powder flow with sequential positions where different steps of a process—such as water addition, drying, and milling in the case of wet granulation— are carried out in tandem.

Packaging and handling considerations

Following compression and coating, tablets are stored in tight containers and protected from high temperature and humidity places. Products that are prone to decomposition by moisture generally are copackaged with des-iccants, such as silicon dioxide. Drugs that are adversely affected by light are packaged in light-resistant containers.