Granulation

granules

aggregates of particles in a spherical shape. Granules typically contain a drug and can either be a dosage form on their own or they can be used to prepare other dosage forms

why do granules have better flow than powders?

• spherical shape

• less likely to generate static charge

• less absorbant

why is flowability important for pharmaceutical manufacturing?

drug powders or granules need to flow through machinery in order to be compressed into tablets or to fill capsules

what happens if a drug powder/granule has poor flow?

the tablet die can be underfilled and this will change the dose of drug contained within the tablet.

• Additionally, as powder moves along the process, different ingredients within the powder may separate or become less homogeneously mixed throughout the powder due to different properties (flow, density, etc) of each powder.

why are granules beneficial for capsules?

they can be made from a powder mixture and contain all the necessary pharmaceutical ingredients keeping them together and keeping them from unmixing

purpose of chemical binder

used to hold or glue these powder aggregates together creating the granule

• also beneficial when the granules are used for tablets as it helps to hold the tablet together when the granules are compacted

granules are typically more __________ shaped than powders which is why they have improved flow

spherically

granules are typically more spherically shaped than powders which is why they have improved _______

flow

are granules more or less dense than powder?

more dense

• improves flow

effect of granules on oxidation and moisture absorption

prevent— since drug & excipents are primarily inside the granule

why do granules have an improvement in taste?

drug is primarily contained inside the granule & less is present on surface of granule to be tasted

• additionally, typically use viscous polymers → when polymer hydrates & becomes viscous after contact w saliva, it can help prevent diffusion of drug in mouth (prevents pt from tasting)

components of granules

• diluent

• disintegrant

• granulating fluid

• binder

• glidant

• lubricant

diluent

used to add substance to drug formulations

• need to make up the entire weight of the tab/capsule

disintegrant

help to break down the tablet in water or other aqueous fluid to allow the contained drug to be released

• can break up the tablet (extra-granular)

• can break up individual granules (intra-granular) if those are final dosage form

how do disintegrants work?

often absorb water and then push the tablet apart as they grow.

granulating fluid

part of wet granulation process

• granulating fluid/liquid/agent is used to create a wet mass of powder so it can be passed thru a sieve to form granules

***KEY PROPERTY = surface tension

key property of granulating fluid

surface tension

• water has high surface tension & is therefore a commonly used agent

diff bw water & alcohol as granulating fluid

water has higher surface tension, alcohol has lower & should only be used in small amt for drying & helping to wet hydrophobic powders by using it to wet them first

how is water used as a granulating fluid?

alone or in combo w others

3 common granulating agents

1. water

2. ethanol

3. isopropanol

use of ethanol as granulating agent

○ Used in combination with water

○ Used as a wetting agent for hydrophobic powders

○ Used to aid in granule drying since it evaporates readily

use of isopropanol as granulating agent

○ Used in combination with water

○ Used to aid in granule drying since it evaporates readily

binder

agent used to help hold granules together after forming for powders that have les cohesion

• typically combined w granulating fluid or can be combined in powder form w powder itself

preferred method for incorporation of binder

combine with granulating fluid

• more effective

excess binder can lead to…

• hard granules

• lack of granule disintegration

• poor drug dissolution

• slowed absorption

list 6 common binders & their solvent for granulation

1. methyl cellulose (water)

2. hydroxypropyl cellulose (water)

3. hydroxypropylmethyl cellulose (water)

4. ethylcellulose (alcohol)

5. polyethylene glycol (water & alcohol)

6. polyvinylppyrollidone (water & alcohol)

glidant

improve the flow of granules and are an extra-granular excipient

• particularly important for granules used in tableting and for filling capsules and are not typically used when granules are the final dosage form

• adds to exterior of dried granules once they’ve been formed

3 commonly used glidants

1. colloidal silicon dioxide

2. talc

3. starch/corn starch

lubricant

used for granules that are used in tableting and capsule filling. help the granules to slide past one another under compression in the tablet die or in the process of capsule filling.

4 commonly used lubricants

1. magnesium stearate

2. stearic acid

3. sodium stearyl fumarate

4. calcium stearate

fusion method of granulation

used in small scale compounding for effervescent granules

1. ingredients are blended in a mortar/pestle before heating in a flat container on a hot plate

2. spatula is used to compact material & it will slowly get moist & form a cake in the container due to the citric acid releasing its bound water

3. cake is flipped & compacted more

4. after heating, cake is passed thru sieve of appropriate size to form desired granules

5. after, granules are laid out to dry at a temp below 54C to prevent effervescent rxn from occurring, before re-sieving in a sieve w larger holes to catch any fused granules

6. effervescent granules must be stored in an air tight container to prevent pre-emptive rxn w humidity in air

effervescent granule

contain drug, diluent, a flavor, a sweetener, a base of sodium bicarbonate or sodium carbonate, and citric acid

why are granules laid out to dry at a temp below 54C in fusion method?

to prevent the effervescent reaction from occurring

wet granulation

1. A granulating fluid, with or without a binder, is added to powder to form a wet mass before passing it through a sieve

2. A block is typically used to push the wet mass through a sieve.

3. The resulting granules are then oven-dried and re-sieved.

granulation endpoint

amount of granulating fluid added to granules

effect of adding too much granulating fluid

can cause the granules to form long strings coming out of the sieve (like noodles) rather than forming granules and adding too little fluid will cause the granules to fall apart

granulation endpoint can vary based upon…

particle size of the powders and the room temperature

• therefore granulation endpoint = approximationto

To determine if the granulation endpoint has been reached by the wet mass, a __________ can be formed

ball of the wet mass

• If the ball cleanly splits in half, then it is ready for granulation

• if the ball doesn’t break cleanly then too much granulating fluid has been added

melt granulation

binder is added as a powder rather than in the granulating fluid

how is binder activated in melt granulation?

by heating it in the powder mixture until it is molten

steps of melt granulation

1. binder is added as powder

2. binder is activated by heating in the powder mixture until its molten

3. powders then become bound together by the molten binder

**Ensuring consistent heating and mixing is critical to ensuring the binder is homogeneously distributed throughout the powder

unlike wet granulation, melt granulation does not require _______ agents

granulating

• advantageous for water-sensitive drugs/excipients

melt granulation is not suitable for drugs that are unable to handle ___________

high heat needed to melt the binder

2 techniques to produce granules that are very close to spherical rather than approximately spherical

1. extrusion or spheronization

2. rotor granulator

extrusion/spheronization process

1. uses same wet mass as wet granulation

2. place in extruder that forms elongated strands of wet mass

3. these are moved to the spheronizer which breaks up the elongated strands & creates spheres thru friction w bottom of the spheronizer

4. spherical granules/beads can be dried and sprayed w coating

extrusion/spheronization is particularly useful method for ____________ as it allows for precise control of the drug release from the formulation

sustained-release formulations

rotor granulator process

1. powder is placed in machine

2. granulating fluid is sprayed onto it

3. powder rotates in the granulating fluid & slowly forms individual spherical granules

4. granules are dried

which process can take powder to sustained release coated beads in a single machine?

rotor granulator

dry granulation

uses either slugging or roller compaction to form granules without granulating fluid

• slugging is typically used for small batches

what strategy is used for small batches?

slugging

slugs

thin tablets, formed using compression force & then are crushed & passed thru mesh to form granules

residual powder from dry granulation process can be reused to form _________

new slugs

roller compaction

uses powder fed through a hopper and then pressed out under pressure into two rollers. The resulting material can then be run through a granulator which moves it through a mesh to control its size.

advantage of dry granulation

lack of both granulation fluid and heat needed since the granules are already dry. This is beneficial for drugs that may be sensitive to either of those elements.