Tabletting 2- Tablet manufacture

Question 1

What are the three steps to prepare a tablet by compression?

Answer 1

1. Material flows into a die
2. Material is compressed between 2 punches
3. Tablet is ejected from the die

To be able to form a tablet, material must possess certain characteristics

• flow uniformly and rapidly into the die
• cohere when compressed to form stable tablet
• eject smoothly from the die

Question 2

What are the three methods of preparing substances for tabletting?

Describe some points about tablet manufacture

Answer 2

• Direct compression
• Dry granulation (slugging or compaction)
• Wet granulation

Tablet Manufacture

• Mixing (blending) is a key step in most methods of tablet manufacture.
• Need to obey principles of geometric dilution (method of doubling) to obtain even mix of powders prior to compression or granulation to ensure uniformity of dose in tablets.
• The smaller the proportion of active drug in the tablet, the greater the importance of adequate mixing.

Question 3

What is direct compression? Discuss advantages and disadvantages

Answer 3

• Simplest method of tabletting – compress tablet directly from the powdered material. No pre-treatment by wet or dry granulation is necessary.
• Few materials are suitable eg KCl, NH4Cl 
• Direct compression excipients available to allow other active ingredients to be compressed directly.
• If the drug comprises <25% of tablet weight it can be formulated with a direct compression vehicle.
• Active ingredient is blended with a direct compression vehicle which is a blend of suitable excipients which will flow uniformly into a die cavity. Excipients incorporated in the vehicle are usually diluents, dry binders and disintegrants
• Directly compressible vehicles include compressible sugar (Di-Pac), microcrystalline cellulose (Avicel) and starch.

Advantages of direct compression

• economy
• elimination of heat and moisture
• prime particle dissociation or disintegration (i.e. no de-aggregation step)
• stability (no heat & moisture)
• particle size uniformity

Disadvantages of direct compression

• Possibility of compression failures, certain drug-direct compression vehicle combinations will not produce a satisfactorily compressed tablet (variability between batches of raw drug)
• Mixing problems, as particles may have different densities
• Limited colouring options
• Special particle size requirements - fine and hence their flow characteristics depend upon the spherical shape of particles

Question 4

What is dry granulation? Discuss its advantages and disadvantages

Answer 4

Powder is compacted and then comminuted into smaller granules

• SLUGGING :Powder mixture is directly compressed into a large flat tablet.
• The least desirable of all methods of granulation.
• The resulting “slug” is ground to a uniform size, lubricant is added and the combination is compressed into the finished tablet.
• Aspirin tablets can be made by slugging.
• roller cmpaction is a similar process

Advantages of dry granulation

• Moisture sensitive drugs (No granulating fluid)
• Heat sensitive materials (No drying)
• For improved disintegration (no binder)
• No migration of active ingredients (compared with drying wet granules, where migration of ingredients leads to uneven distribution in some instances)

Disadvantages of dry granulation

• Requires specialised machinery
• Does not permit uniform colour
• Dusty process
• High compression force may slow the dissolution rate

Question 5

What is wet granulation? Why use granules? Disadvantages of wet granulation.

Answer 5

The most common method of tablet preparation

• The powder mixture (drug, diluent and disintegrant) is granulated by wet massing with a granulating liquid (BINDER), wet sizing and drying.
• The texture of the wet granulation is important for the production of tablets of suitable characteristics.

Why use granules?

• Uniform particle size – avoids segregation of constituent ingredients
• Excellent flow properties –> even filling of dies –> tablets of consistent mass
• Reduces dust generation
• Wet granulation allows good distribution and uniform content of low dose drugs and colourings that are dissolved in the binding solution.
• Presence of binder facilitates bonding within tablet – cohesiveness and compressibility improved
• Fracture of granules on compression exposes clean powder surfaces for optimal bonding requiring lower compression pressure

Disadvantages of wet granulation

• Aqueous binding solutions unsuitable for moisture sensitive drugs – anhydrous solvents required, or a different method eg direct compression, slugging
• Hydrates of active ingredient may occur during wetting
• Polymorphic transformations may occur

Question 6

Describe the 6 steps of wet granulation

Answer 6

1. Dry mixing ingredients

• Determines the accuracy of the active ingredient content of each tablet. Importance of mixing increases with reduction in proportion of active ingredient in tablet.
• Cube blenders, cone blenders and Y-cone blenders have been used for this operation, high shear mixer-granulators now preferred.

2. Wetting

• The liquid binder or moistening agent added slowly to ensure uniform moistening.
• The process is stopped when mass of required consistency is attained. A mass that clings together but remains crumbly is ideal.

3. Preliminary granulation

• The damp granulation mass is passed through a #6-10 sieve/screen to produce coarse granules.
• Machinery is available for this operation – granulators or extruders

4. Drying

• The wet granules are dried to maintain flow properties and ensure good compression. Improperly dried granules can produce poor tablets (soft tablets and problems with sticking and picking)
• A residual amount of moisture should be left in the granules (keeps binders in hydrated state and reduces static electricity) 
• Care should be taken to avoid solute migration during drying (a problem with tray drying – minimise by drying slowly at low temperatures).

tray drying: Can be carried out on trays in hot air ovens at 50-55oC or lower & a circulating air current. Heat energy used but microwave radiation can be used also.

fluidised bed drying

> Fluidised–bed dryers are preferred now. 15x faster than flat bed drier, less granule damage, greater control of conditions. Can mix fine powders with granules after drying

>Heated dry air is fed into the container & should be of sufficient velocity to lift the granules from the bottom of the bowl onto a cushion of warm air where they are held in a state of turbulence until dry.

5. Re-sizing (regranulation)

• Reduces the coarse granules to a uniform size, so that little variation in weight of compressions occurs.
• A smaller mesh screen than for the wet granulation is used (#12-20 Mesh)
• Avoid production of excess “fines”. 10-20% fines desirable to fill spaces between granules –> uniform mass and smoother tablet. Excess fines blow out around punches –> dust, wastage, binding in die

6. Addition of lubricant, disintegrant and flavour

• Lubricant and extragranular disintegrant added as “fines” after granulation so they are outside the granules. Blended gently with granules.
• Liquid flavours are diluted with volatile solvents and sprayed on granules for even distribution

Question 7

What are some alternative methods for granulation?

Answer 7

Fluidised Bed Granulation

• Powder particles are suspended in an air stream and the granulating liquids (binders) are sprayed on the suspended powder and build up on the particles to give granules ready for compression

Spray Drying

• Produces small spherical granules from suspension of drug and binder in liquid
• Used for preparation of fillers and direct compression vehicles.

Single Pot Processing

• Mixing, granulation, drying in one enclosed apparatus  Time efficient, reduced contamination and dust

Question 8

How does the tablet press and compression work?

Answer 8

• The key elements of the tablet press are the die(s) and punches.
• The granules are fed from the hopper via the feed shoe into the die and the granules are compressed by pressure applied by the punch(es).
• In single punch machines the lower punch remains stationary during compaction and pressure is applied by the upper punch alone. In rotary presses, both punches move to apply pressure.
• Chewable, effervescent and compressed tablets can be made using a tablet press
• SUCCESSFUL TABLET PREPARATION = PUNCHES AND DIES MUST BE MAINTAINED IN PERFECT CONDITION

Question 9

How does single punch machine work?

Answer 9

• Lower punch remains in fixed position during compression.
• Position of the lower punch is adjustable and controls the volume of the die and therefore the tablet weight.
• Feed shoe delivers granules to the die and smooths off the top as it returns.
• Upper punch applies force to compress the granules. Amount of force applied can be adjusted.

Question 10

How does a single punch tablet press work?

Answer 10

• Upper punch retracts from the die
• Lower punch rises to level with top of die to eject the finished tablet
• Shoe swings over die for next fill and pushes tablet down chute. Simultaneously, the lower punch returns to its original position for the next fill cycle

When preparing tablets on single punch machine

• Appropriately sized die and punches are selected
• Lower punch is set at desired level for weight of tablet
• A few tablets are compressed manually and tested for weight and hardness
• Lower punch is adjusted to give correct weight
• Force applied via upper punch is adjusted to produce tablets of suitable hardness
• Batch of tablets is compressed.

Question 11

What is the rotary tablet press?

Answer 11

• Rotary tablet presses have increased capacity for producing large numbers of tablets (>10,000 per minute)
• Similar process to single punch machine, but have multiple sets of punches and dies on rotating turret.
• In rotary press, both upper and lower punches move and apply pressure.
• Upper punches descend and lower punches ascend under rollers to compress tablets (at the end)
• Compression occurs as upper and lower punches pass between a pair of rollers producing a squeezing effect on granules.
• May self-adjust to correct variations in mass or hardness during the compression process.

Question 12

What happens during compaction?

Answer 12

Several stages are evident during the compaction process:

1. Particles rearrange themselves into closer packing
2. As compression continues, the particles begin to deform at the points of contact
3. Initially deformation is elastic (If pressure removed at this point deformation will be reversed).
4. Eventually particles deform plastically (irreversible)
5. Particles either bond together or undergo brittle fracture

Surface area changes occur during compaction (initial increase and ultimate decrease)

• Applied and transferred forces cause a particular pattern of density distribution in the powder compact in the die.
• Removal of the compression force and ejection from the die leads to stress relaxation in the tablet.
• In some cases tablets may fracture when ejected - capping.

Question 13

Discuss compressed orally dispersible tablets

Answer 13

• Orally dispersible tablets are intended to disintegrate rapidly in the mouth without additional water.
• This can be achieved by incorporating superdisintegrants and a small amount of effervescent disintegrant into thin (high surface area), soft compressed tablets.
• Moisture in the mouth is wicked into the tablet rapidly –> rapid disintegration (30-45 seconds)
• Flavouring agents are required in the formulation

Question 14

What are moulded orally dispersible tablets?

Answer 14

made by a number of different processes.

• Zydis delivery system uses moulding and freeze-drying to create tablets.
• A foam of gelatin, sugar(s), flavouring and drug is created and this is poured into the blister packaging (mould).
• The tablets are freeze-dried (lyophilised) by freezing below the eutectic temperature, reducing the pressure and gently increasing temperature to achieve sublimation of ice.
• Blisters are sealed immediately to prevent access of moisture.