granulation

Define powders and granules and explain why powders are granulated.

A powder is a solid substance consisting of tiny loose particles. In pharmaceutics, a powder dosage form consists of drug powder mixed with powdered excipients.

Powders may be used:

• Internally (e.g. oral antibiotic suspensions)

• Externally (e.g. antifungal dusting powders)

A granule is an aggregate of powder particles combined into a larger particle.

Granulation is required because it:

• Prevents segregation of components

• Improves powder flow

• Improves compaction/compressibility

Granules are generally more free-flowing and less prone to demixing than powders.

Explain how powder flow is measured and discuss the significance of powder flow properties.

Good powder flow is essential for consistent die filling, capsule filling and manufacturing efficiency.

Methods used to measure flow include:

Angle of Repose tan⁡θ=h/r

• θ > 50° = unsatisfactory flow

• 25–50° = satisfactory flow

Bulk Density Measures powder density including air spaces.

Carr's Compressibility Index Tapped Density−Poured Density/Tapped Density×100

Interpretation:

• 5–15% = excellent flow

• 18–21% = fair flow

40% = extremely poor flow

Hausner Ratio Tapped Density / Poured Density

Values close to 1 indicate good flow.

Critical Orifice Diameter

Measures the minimum opening through which powder can flow.

Compare dry granulation and wet granulation

Dry Granulation

• Powders are compressed into slugs.

• Slugs are milled and sieved.

• Suitable for moisture-sensitive drugs.

• Suitable for drugs that compress poorly after wet granulation.

Wet Granulation

• Powders are blended.

• Granulating fluid containing binder is added.

• Wet mass is screened and dried.

explain the bonding mechanisms responsible for granule formation.

1. Adhesive forces

Thin immobile liquid film binds particles.

2. Cohesive forces

Reduced particle separation increases van der Waals attraction.

3. Interfacial forces

Mobile liquid films create capillary forces between particles.

4. Solid bridges

Produced by crystallisation, binder hardening or partial melting after drying.

5. Mechanical interlocking

Irregular particles physically lock together.

Additionally, electrostatic and van der Waals forces contribute to particle attraction.

Describe granulation equipment

High-Speed Mixer Granulator

• Impeller mixes powders.

• Granulation fluid added through port.

• Chopper breaks moist mass into granules.

Fluidised-Bed Granulator

• Heated air fluidises powder.

• Granulation fluid sprayed onto fluidised bed.

• Simultaneous granulation and drying occur.

Shear Granulator

• Uses intense mechanical mixing.

• Largely redundant in modern pharmaceutical manufacture.

explain the role of water during wet granulation.

Water is the most important processing variable.

If too little water is added:

• Weak adhesive and cohesive forces develop.

• Plastic deformation is poor.

• Extrusion becomes impossible.

• Excess fines are produced.

If too much water is added:

• Extrusion becomes easy.

• Pellets agglomerate during spheronisation.

• Large spheres form.

The amount of granulating fluid is often the single most important factor affecting successful pellet production.

Explain the production of pellets by extrusion and spheronisation 8

Pellets are multiparticulate dosage forms typically 0.7–2.0 mm in diameter.

Production stages:

1. Dry blending

2. Wet granulation

3. Extrusion - formed rod shaped particles of uniform diameter

4. Spheronisation - formed spherical shaped particles from rod shaped particles

5. Drying - to achieve final water content

6. Screening - -to achive narrow particle size distribution

7. Coating (optional)

8. Capsule filling or tableting

advantages of pellets

• Immediate release

• Modified release

• Multiple APIs

• Separation of incompatible drugs

advantages of pellets in the gi trac

Pellets distribute throughout the GI tract more uniformly than tablets.

• Less irregular GI transit

• More consistent drug absorption

• Reduced dose variability

• Reduced ulceration risk (especially NSAIDs)

• Reduced risk of dose dumping

• High drug loading possible

processing advantages of pellets

• Better flow properties

• Higher bulk density

• Greater mechanical strength

• Low friability

• Smooth surfaces suitable for coating

• Regular shape allows efficient packing

disadvantages of pellets

• More labour intensive

• Higher energy requirements

• Requires large amounts of water

• More complex manufacturing process

Describe extrusion and spheronisation equipment and explain factors affecting pellet quality.

Extruders

Types include:

• Axial screw extruders

• Radial screw extruders

• Cylinder extruders

• Gear extruders

• Roll extruders

Important extrusion variables:

Extruder Type

Affects:

• Density

• Temperature

• Shear stress

• Shear rate

Extrusion Speed

May increase surface roughness and shark-skinning.

Extrusion Temperature

High temperatures cause evaporation of granulation fluid.

Screen Diameter

Controls pellet size.

Screen Thickness

Affects densification.

Shark-Skinning

A rough surface defect on extrudate caused by processing conditions and rheology.

Lubricants may reduce shark-skinning.

Discuss factors affecting pellet quality during spheronisation

Water Content

Too high:

• Pellets aggregate

• Large spheres form

Too low:

• Difficult extrusion

• Equipment damage possible

• Excess powder formation

Spheronisation Speed

Affects:

• Particle size

• Hardness

• Roundness

• Porosity

• Bulk density

• Tapped density

• Friability

• Flow properties

• Surface structure

Optimal speed is generally >400 rpm.

Spheronisation Time isUsually 2–10 minutes.

Spheroniser Overloading should be avoided.

why does water decreases during spheronisation and explain methods used to determine pellet moisture content.

Water decreases because:

• Friction during extrusion generates heat.

• Friction during spheronisation generates heat.

• Water evaporates into the environment.

Moisture Content Determination

Methods include:

• Thermogravimetric analysis (heated balance/TGA)

• Karl Fischer titration

• Dynamic Vapour Sorption (DVS)

calculation to dry pellets

o dry pellets:

1. Calculate water content.

2. Calculate sensible heat:

Q=mcΔT

3. Calculate latent heat:

Q=mL

4. Total heat required:

Qtotal=Q1+Q2