Manufacturing of pharmaceutical tablets

Manufacturing methods for tablets

1. Compression: Tablets are formed by compressing a powder or granule blend into a solid dose using high pressure

2. Extrusion/Melt granulation: This technique uses heat or mechanical energy to melt and extrude materials, forming granules that are later compressed into tablets

3. Moulding: Powder mixtures are moistened and shaped in moulds, then dried to form tablets

4. Freeze-drying: A liquid or semi-solid mixture is frozen and dried under vacuum to yield a porous, fast-dissolving tablet

5. 3D printing: Layer-by-layer deposition of materials allows fabrication of tablets with precise geometry and tailored release profiles

Tablet production stages

1. Die filling - powder flows from hopper to die closed at base by lower punch

2. Powder compaction - upper punch lowers into die and applies compression force until tablet is formed

3. Tablet ejection - lower punch rises, and tablet is ejected

Compression and compaction

• Compressibility

• Tendency to reduce in volume when force is applied

• For powders, compression can lead to changes in the physical properties of the primary powder particles

Elastic deformation:

• Revisible

• Cohesive forced will be lost

Plastic deformation:

• Irreversible

• Cohesive forces will be retained

Compression and compaction - factors that affect yield point

• Polymorphism

• Salf form

• Moisture content

• Partcile size

• Compression force

What can compression lead to for granules?

• Changes in the physical properties of the primary powder particles

• Changes in the physical properties of the granules

Why is it important for powders to cohere when forming tablets?

Form tablets highly resistant to:

• Fractures

• Capping: partial or total fracture of the top or bottom layer in a tablet

• Lamination: separation of tablets into layers

What may go wrong during tablet manufacture?

• High weight and dose variation

• Low mechanical strength

• Capping and lamination

• Adhesion of powder to punch tips and surface

• High friction during tablet ejection

Excipients and tablet manufacturing considerations - die filling

• Die is filled by volume not weight

• Poor powder flow = lack of reproducibility in die filling

• Different volumes = different weight

• Weight/content uniformity

• Glidants - improve powder flow be decreasing cohesive forces

• Particularly important for direct compression

• Added just before compression

Excipients and tablet manufacturing considerations - powder/granule compaction

• Compression force and inter-particle bond

• Binders – adhesive

• Fillers – good technical properties (compactability)

• Promote inter-particle bond formation

• Granulation

• Direct compression

Excipients and tablet manufacturing considerations - tablet ejection

• Friction between tablet and die wall will obstruct ejection

• May lead to tablet fracture

• Lubricants reduce friction

• Anti-adherent: prevent sticking to punches and die wall

Excipients and tablet manufacturing considerations - direct compression

• Filler: good compactability, good flow

• Binder: ductile material (plastic deformation)

• Disintegrant: to promote disintegration after administration

• Glidant: increase powder flow in the hopper shoe and die

• Antiadherent: prevent sticking to punches and die wall

• Lubricant: decrease friction during tablet ejection

What are the three main methods used to manufacture pharmaceutical tablets?

1. Direct compression – powders are blended and compressed directly into tablets without granulation

2. Wet granulation – powders are mixed with a liquid binder to form granules, which are dried and compressed

3. Dry granulation – powders are compacted into larger masses or slugs, which are milled into granules before compression

What is direct compression?

API and excipients are blended together and compressed directly into tablets without undergoing a granulation process

• The powder blend must have suitable flow and compression properties

Suitable for:

• Heat sensitive APIs

• Good flow, not prone to segregation

• Compactability

• Drugs with adequate solubility

• Highly potent drugs

Advantages and disadvantages of direct compression

Advantages:

• Production cost - no additional process

• Product stability - API present in original form

• Drug dissolution - disintegration to primary particles

Disadvantages:

• Powder flowability and bulk density required

• More expensive dry binders and required

Why granulate before tabletting?

• Powder flow properties – weight/content uniformity

• Mixing homogeneity

• • Die filling

• Compactability

• Dissolution of poorly soluble drugs

• Storage

What is wet granulation?

Powders are mixed with a granulating liquid, usually containing a binder, to form larger aggregates called granules

• The granules are then dried, sized and compressed into tablets

• Liquid content - 20%-50% of the dry powder weight

• Binder added as dry powder before granulating fluid

• Dry binder dissolved in granulating fluid

What are the main steps involved in wet granulation?

1. Weighing: Measure the API and excipients

2. Sieving: Remove lumps and break up aggregates

3. Dry mixing: Mix the API with suitable excipients, such as diluents

4. Binder preparation: Prepare a binder solution or dispersion

5. Wet massing: Add the granulating liquid to the powder blend to form a wet mass

6. Granulation: Pass the wet mass through a sieve or use a granulator to produce granules

7. Drying: Remove excess moisture from the granules

8. Sizing: Pass dried granules through a sieve to obtain a suitable particle size distribution

9. Final blending: Add external excipients, such as disintegrants and lubricants

10. Compression: Compress the final blend into tablets

What is dry granulation?

Powders are compacted together without adding a liquid binder

• The compacted material is then broken down into granules, which are blended with additional excipients and compressed into tablets

• Liquid not required

• Primary powder particles aggregated under high pressure

  • Slugging - large tablet

  • Rolling - sheet or flakes

• Milling

• Sieving - to achieve desired granule size

• Suitable for moisture sensitive materials

What are the main steps involved in dry granulation?

1. Weigh and measure the API and excipients

2. Sieve ingredients if necessary

3. Blend the powders together

4. Compact the powder using a roller compactor or slugging machine

5. Break down the compacted material into granules

6. Mill and sieve the granules to obtain a suitable size

7. Blend with additional excipients, such as lubricants and disintegrants

8. Compress the final blend into tablets

Tablet presses

1. Single-punch press

• Research and development

• Low output (130-200 tablet per minute)

2. Rotary press

• Large scale production

• Up to 10,000 tablets per minute

3. Compaction simulator

• Used for optimisation of compression settings

• Predict potential compression issues

• Mimic production process

Melt granulation

• Moisture sensitive

Moulded tablets

• Drug mixed with diluent – water soluble e.g., lactose, sucrose, mannitol

• Liquid added to allow moulding – alcohol/water mixture

• Tablet generated after evaporation under vacuum

Advantage:

• Disintegrate quickly

Disadvantage

• Small size limits use to drugs active at low doses

Freeze-dried tablets

Process:

• Mixing of drug with gelatine and sugars

• Filling of blister

• Freezing

• Freeze-drying and sealing

Freeze-dried tablets - advantages and disadvantages

Advantages:

• Fast disintegration – ODTs are typically produced by freeze drying

• Suitable for patients with difficulty swallowing

• Useful for thermo-labile materials

Disadvantages

• Taste and feel may be an issue

• Tablets are soft and will break if forced through the blister

3D printed tablets

• Emerging field in pharmaceutical manufacturing

• Materials deposited layer by layer to form dosage form entity – e.g. API, binder

• Deposition – solidification

• Laser-based writing systems

• Printing-based inkjet systems

• Nozzle-based deposition systems

3D printed tablets - advantages

• Dimensions and designs unachievable by traditional methods

• Personalised medicine

• Polypills – multiple drugs in one tablet with individual dose and release profile

• Controlled drug release

• Patient compliance

3D printed tablets examples

• Spritam – levetiracetam

• Anti-epileptic - partial-onset seizures

• First FDA approved 3D printed medicine

• Binder jetting technology