Intro into Tableting Part 1

A tablet press is a machine designed to manufacture tablets.

Different parts of the tablet presses have different functions, for example:

• Wipe off blades – remove excess granulation
• Turrets – hold the upper and lower punches

The simplest procedure for tabletting is known as Direct Compression. This process

• combines the process of blending the raw powders and compression\
• directly compresses excipients and powder API mixtures
• is recommended for water-sensitive and heat-sensitive drugs
• has fewer process steps than other tabletting methods, and therefore
• is low cost.

Disadvantages of Direct Compression

• Static charge might build up during the mixing of powders and screening which makes it difficult to achieve uniform drug distribution in the formulation
• Not recommended for low and high dose type of drugs
• More costly and larger tablets are necessary for high dose drugs as these are not easily compressed without additional diluents

Granulation

Granulation is a process employed before tabletting with the aim of converting the particles within the powder formulation into compressible granules that can be more easily and reliably formed into tablets in the tablet press.

Dry granulation

In dry granulation the powder mix is compressed without using any solvent or heat in the process. There are two approaches to dry granulation:

1. Slugging – the powder mixture is pre-compressed in a static press and the resulting slug is milled further so as to yield a more granulated mixture.
   Slugging helps strengthen the bonds between powder particles.
2. Roller compaction – is used to produce granules in large quantities - a Chillsonator roller is often used. Roller compaction are preferred to slugging as it offers a means of increasing the production rate, and provides more control over compaction pressure..

While dry granulation may be the ideal method of precompression in many ways, it has the disadvantage that uniform colour distribution may not be achieved throughout the granulated material. It also requires a dedicated granulation machine (e.g. a Chilsonator).

Common diluents that are added to powders for dry granulation are:

• Lactose
• Calcium phosphate
• Dextrose
• MCC
• sucrose
• Sta-Rx (modified starch)

Wet Granulation

Wet granulation is the most commonly used method of granulation. It involves the addition of a binder to the powder mixture which may be in the form of a solution, slurry or suspension.

Wet granulation is not ideal for moisture sensitive drugs and is more expensive than dry granulation in terms of the availability of space, labour, time and energy. The granulated material needs to be dried to remove any moisture or binder solvent. Equiment needed may include:

1. High Shear granulator e.g.,
• Littleford lodgie granulator
• Gral mixer
• Diosna granulator
• Littleford lodgie MGT granulator
2. Granulators that can dry the material, e.g.,
• Fluidized bed granulator
• Topo granulator
• Double cone or twin shell processor
• Day nauta mixer processor
3. Special granulators:
• Roto granulator
• Marumerizer

Excipients used in tablet production

Lactose – most commonly used excipient in the production of tablets. It can act as a diluent of the API.

Anhydrous lactose – does not undergo Maillard reaction when combined with amine drugs (the Maillard reaction is a reaction between amino acids and reducing sugar)*

2 grades of commercial lactose are available:

• 60-80 mesh (coarse)
• 80-100 mesh (regular grade)

*When spray-dried lactose is exposed to amines and moisture, it darkens when exposed to air. This is due to the fornation of Furaldehyde.

Modified starch e.g. Sta-Rx 1500 – it is a pre-gelatinized directly compressible starch

It is used as a diluent, disintegrating agent and a binder. Modified startch typically contains 10 wt.% water.

Hydrolyzed starch – commercial examples such as Embdex and Celutab both contain 90-92% dextrose and 3-5% maltose.

Dextrose – commercially available in coarse grain form as Cerelose

Mannitol – used for preparing chewable tablets. It is generally an expensive sweetener, and requires a large quantity of lubricants to be added to the formulation due to its poor flow characteristics.

Sugar/sucrose – these can be used as direct compressible diluents. Commercially available examples are:

• Sugar tab: 90-93% sugar + 7-10 % invert sugar
• Nutab: 95% sugar + 4% invert sugar with corn starch and magnesium stearate
• Dipac: 97% sugar + 3% dextrins

Avicel - A micocrystalline cellulose. Two grades are available: PH101 for powders (50 μm particles) and PH102 for granules (100 μm particles).

Binders – these are materials that are designed to bond together the solid granules in tablets. A wide variety of binders are available, such as:

• Natural binders
• Starch paste
• Acacia
• Gelatin
• Tragacanth
• Cellulose
• Alginic paste
• Synthetic binders:
• Ethyl cellulose
• Methyl cellulose
• Sodium carboxymethly cellulose
• Polyvinypirollidone (PVP) also commonly called polyvidone or povidone – a water-soluble polymer
• Hydroxy propyl methyl cellulose (HPMC)
• Polyetheylene glycol (PEG)
• Hydroxyl methyl cellulose

Commonly available binders

• Walocel- Hydroxy propyl methyl cellulose
• Starch 1500 - Partially pregelatinized maize starch
• Methocel-HPMC
• Sugar

Disintegrants

Disintegrants are used to help tablets disintegrate in the gastroinesinal tracts

Examples:

• Starch- 5-20% of tablet weight
• Clays- Veegum HV, bentonite 10% level in colored tablet only
• Starch derivative - Primogel and Explotab (1-8%)
• Cellulose derivatives- Ac- Di-Sol (sodium carboxy-methyl cellulose)
• Cross-linked Polyvinylpyrrolidone

Superdisintegrants – are the new generation of disintegrant that are effective in low concentrations. When exposed to water in 30 minutes they swell up to ten times in volume.

Examples:

• Cross-carmellose: a cross-linked cellulose polymer
• Sodium starch glycolate: a starch derivative formed by molecular cross-linking
• Ethyl cellulose (may retard disintegration and dissolution time of tablet)
• Cross povidone: cross-linked povidone

Lubricants/Glidants/Anti-Adherents

Lubricants – are used to reduce friction between the surface of the tablet and the die/moulds especially during the ejection process.

Anti-adherents – are used to prevent the granules or powder from sticking to the dies and punches

Glidants – help improve the flow properties of the granules by reducing friction between them

Example of Common Lubricants:

• Stearic acid and its salts such as calcium and magnesium stearate (note that Stearic acid is less effective lubricant than its salts)
• High molecular weight poly ethylene glycolPEG
• Talc
• Surfactants
• Hydrocarbon oils

Example of Anti-adherents

• Talc
• Colloidal silica
• Magnesium stearate
• Starch

Example of Glidants/flow promoters

• Talc (5%)
• Starch (5-10% by weight)
• Aerosil
• Colloidal silica: Cab-o-sil
• Syloid

Colours – these may be imparted to tablets by adding dyes or lake pigments. The latter are dry powders that are absorbed by hydrous oxides in the formulation.

Flavours – Chewable Tablets often contain natural flavours or taste maskers. Popular with children’s tablets is fruit flavours such as orange or strawberry.

Sweetening Agents

• Aspartame – not stable in water
• Saccharine – 500x times more sweeter than sucrose, has bitter after taste, carcinogenic

Processing challenges in tablet making:

Capping – happens when there is a partial separation of the upper and lower sections of the tablet

Lamination – when the tablet separates into several layers (cause by the air entrapped in the granules)

These faults may be prevented by:

• reducing the final compression pressure
• precompression of theformulation before tabletting
• reducing the level of moisture in granules (for capping), or increase the binder concentration (for lamination)
• applying the correct the settings of the machine
• using flat punches which can prevent lamination or capping
• slowing down the rate of tabletting

Picking and Sticking

• Picking – the granules stick to the punches
• Sticking – the granules stick to the punch instead of creating a uniform tablet

Chipping – happens when there is severe sticking of granules in the punches resulting in tablets that have rough edges

Picking and sticking faults can be prevented by:

• reduction of excess moisture in the granules
• using large embossing or engraving
• using of lubricants
• using chromium-plated punch to produce a smooth tablet surface
• checking of low molecular weight lubricants added as the components may melt when exposed to heat generated by tablet compression

Mottling – an unequal color distribution among the tablets processed.

Mottling can be prevented by:

• using of alternative binders such as tragacanth or acacia
• lowering the drying temperature
• reducing the particle size of the powder
• changing the solvent system used

Poor Flow – this happens when there is bridging or rat holing in the feeding frame. To improve flowability, the use of glidants such as colloidal silica or talc is recommended.

Double Compression – happens when there is a free rotation of the lower or upper punches during the ejection period of the tablet.

To prevent punch rotation, keying in tooling is used. New machines have anti-turning devices that prevents the punches to rotate freely.