Solid Oral Dosage Forms - Granules

Question 1

What is Granulation?

Answer 1

Process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules

Question 2

Classification of granules

Answer 2

• Bulk granules: solve the variation in particle size in bulk powders e.g. methylcellulose granules - used as laxative
• Divided granules: Granulated products sufficient for 1 dose e.g. effervescent granules
• Powdered oral antibiotic syrups: for patients who have difficulty taking capsules and tablets
• Powders for injections: unstable powders in solution; not to be taken orally

Question 3

Reasons for granulating

Answer 3

• Prevent demixing of the constituents of the powder mix: smaller particles at the bottom, larger particles above; control PSD -> uniform acceptable formulation
• Improve flow properties of the mix: particles with small size, irregular shape/surface are cohesive and retard flow; advantage in making tablets/filling capsules for feeding of high-speed equipment
• Less surface area per unit weight than powders: more stable, less likely to cake in the container than powders
• Improve compaction characteristics of the mix
• Reduction of toxic hazards associated with handling of toxic powder materials
• Less hygroscopic compared to powders -> less cake formation and adherence
• Occupy less volume -> more convenient for storage
• To capture and fuse small quantities of active material
• Prevent powder segregation

Question 4

Methods for granulation

Answer 4

• Wet

- Dry - Slugging, Roller compaction

Question 5

What is wet granulation?

Answer 5

Massing of a mix of dry primary powder particles using a granulating fluid (contain volatile and non-toxic solvent and a binder/adhesive)

Question 6

Advantages of wet granulation

Answer 6

• Improve content uniformity for low dose drugs

- Improve drug dissolution by enhancing wettability through hydrophilization

Question 7

Disadvantages of wet granulation

Answer 7

• Costly
• Process complexity
• Possible affect on drug substance (if drug is affected by the solvent)

Question 8

How are granules tested?

Answer 8

• Loss on drying - water content
• Bulk density
• PSD
• Angle of repose, flow gradient

Question 9

Parameters affecting granulation processes

Answer 9

• Particle size, density and shape
• Moisture sorption, particle wetting
• Impellor torque, compaction rate, velocity of roller - mixing device characteristics
• Binder solution composition, viscosity, droplet size, binder-solid interactions

Question 10

Dry granulation by:

Answer 10

• Slugging: mix with dry binders then compress into large crude tablets using heavy duty “slugging press” and then mill the slugs to form granules
• Roller compaction: powder blend forced between rollers to form a cake -> cake milled to form granules

Question 11

Explain particle-bonding mechanism

Answer 11

Bonding mechanism include:

1. Adhesion + cohesion force in the immobile liquid films between individual primary powder particles - thin immobile liquid films in a powder effectively decrease the interparticulate distance and increase the contact area between particles
2. Interfacial forces in mobile liquid films within granules: pendular state, follicular state, capillary state
3. Formation of solid bridges after solvent evaporation: partial melting, hardening binder, crystallization of dissolved substances
4. Attractive forces between solid particles - weak electrostatic and vdw forces
5. Mechanical interlocking

Question 12

Mechanism of granule formation

Answer 12

1. Nucleation: Particle-particle contact -> adhesion due to liquid bridges -> more particles join -> pendular state -> more agitation -> capillary state -> nuclei for further growth
2. Transition: Nuclei grow by addition of single particles to the nuclei/combination of 2 or more nuclei (size suitable for tablets, capsules)
3. Ball growth: more agitation -> large spherical granules -> more agitation -> granuule coalescence to produce unusable/overmassed systems

Question 13

Examples of wet granulators

Answer 13

• Shear granulators
• High speed mixers/granulators
• Fluidized bed
• Spray Drying
• Extrusion

Question 14

Explain how does shear granulator works

Answer 14

Powder is mixed and fed to a bowl of mixer and granulating liquid is added. Moist mass is then transferred to oscillating granulator and is forced through a sieve screen to form discrete granules. The granules are dried in an oven/fluidized-bed and then blended with lubricant before tabletting

Question 15

Explain how high speed mixers works

Answer 15

Unmixed powder is placed in a bowl and mixed by rotating impeller then granulating liquid is added with continuous mixing and chopping. Granular product is discharged passing it through a wire mesh to break large aggregates. Granules are then dried in a fluidized-bed, compressed into tablets.

Question 16

Explain how fluidized-bed granulators work

Answer 16

Powder particles are fluizidized in a stream of air while granulation fluid is sprayed from a nozzle onto the bed of powders. Heat and filtered air is blown or sucked through the bed of unmixed powders to fluidized the particles and mix the powders. It requires proper balance of inlet air temp. and feed rate -> decides the quality of granules.

• high inlet air temp -> rapid evaporation of the binder solution -> smaller friable granules
• low inlet air temp -> slow drying -> larger, denser, stronger granules
• Higher feed rates -> slow drying -> larger, denser, stronger granules
• Lower feed rates -> smaller, friable granules

Question 17

Explain how does spray driers work

Answer 17

A dry, granular product is obtained from a solution/suspension rather than dry primary particles

Question 18

Process of sphenorization

Answer 18

Moist granulates are fed onto the rotating pelletizing plate and the rotation of the plate and air entering will cause uniform rolling movement of the product which will smoothed spheric pellets. Dust particles are rolled up and bonded into the pellet

Question 19

Advantages of sphenorization

Answer 19

• Good flow behaviour
• Narrow PSD -> control release of drugs
• Particle diameter
• Optimum starting shape for coating
• Pellets have a higher density than spray granulates and agglomerates

Question 20

Binders for wet granulation

Answer 20

• Pregelatinized starch
• Starch
• Gelatin
• Hydroxypropylmethylcellulose (HPMC)
• Polyvinyl-pyrrolidone (PVP)
  => solvent: water for all (or hydroalcoholic solvent for HPMC and PVP)

Question 21

For dry granulation, the compact formation is facilitated by?

Answer 21

• Increased time under pressure facilitates bonding between particles
• Use of highly compatible excipients that can effectively function as dry binders - microcrystalline cellulose

Question 22

3 States of water distribution

Answer 22

1. Pendular state - low level of moisture; particles held tgt by lens shaped rings of liquid
2. Funicular state - Intermediate between pendular and capillary states
3. Capillary state - no air between the particles; particles are held by capillary action

Question 23

Advantages of fluidized-bed granulators

Answer 23

• granulation is performed in 1 unit, saving labor costs, transfer losses and time
• process can be automated once the conditions affecting the granulation have been optimized

Question 24

Disadvantage of fluidized-bed granulators

Answer 24

• not practical for drugs sensitive to water/heat

Question 25

Application for sphenorizers/pelletizers

Answer 25

- controlled drug release | - processing: increased bulk density, improve flow properties, decrease problems of dust