Lecture 5: powders and granules 2

Question 1

What is the purpose of particle engineering?

Answer 1

1. To obtain the optimal particle morphology (size & shape) and surface characteristics;
2. To improve manufacturability, processability, and biopharmaceutical (bioavailability, solubility etc) properties

Question 2

What are some ways we can employ particle engineering to improve the charcateristics and manufacturing?

Answer 2

1. Adjust particle sieze
2. Coating to make it smoother

Question 3

What are the processes by which tablets are made?

Answer 3

API + excipients –> milling –> blending –> direct compression into a tablet
OR
API + excipients –> milling –> blending –> granulation –> blending –> compression into tablet

Question 4

What are the types of granulation?

Answer 4

Dry & wet granulation

Question 5

What is the process of dry granulation?

Answer 5

Raw materials –> mixing and blending –> roller compaction into ribbons –> milling into granules –> mixing to make final blend –> compaction into tablet

Question 6

What are the pros and cons of dry granulation?

Answer 6

Pros: low segregation (uniform particle size) and good flowability
Cons: lower tablet strength (because no liquid holding them tgt) and fine generation (environmental safety, product loss, and the potential for cross-contamination.)

Question 7

What are the pros of dry granulation over direct compression?

Answer 7

1. The ingredients don’t get segregated when they are made into granules so there is a uniform mixture
2. Granules flow better because they are bigger
3. APIs with poor flowability can be processwed by DG
4. Good for APIs suceptible to hydrolysis because no water
5. No use of organic solvent so you dont need an explosive proof room incase it ignites
6. No drying required so its not exposed to heat

Question 8

What is an issue encountered with dry granulation?

Answer 8

DG tablets have low tensile strenght, so compressing them again and again will reduce tensile strength and make them more prone to breaking or crumbling.

Question 9

How does granule size impact tensile strength?

Answer 9

Increasing granule size decreases the tensile strength

Question 10

How does compaction pressure impact tensile strength?

Answer 10

A higher compaction pressure leads to a higher tensile strength because we introduce more energy into the system.

Question 11

How does granule surface area impact tensile strength?

Answer 11

Increasing granule surface area increases tensile strength because there is more bonding between the granules.
This is why greater particle size decreases tensile strength

Question 12

How does the number of rounds of roller compaction impact tensile strength?

Answer 12

With more rounds of roller compaction, the tensile strength decreases.

Question 13

What is the issue with roller compaction?

Answer 13

The different variables involved in RC: roller gap, roll pressure, size etc is understudied, so it is difficult to scale up this process because there are a lot of processes & parameters to consider

Question 14

How does porosity affact fine generation?

Answer 14

Porosity is the quality or degree of having minute spaces or holes through which liquid or air may pass.
Greater porosity leads to greater fine generation because the granules are very loose which makes it easy to break off into fine particles.

Question 15

What is the process of tableting with wet granulation?

Answer 15

raw materials –> mix & blend –> wet granulation to make wet granules –> dry the granules –> mixing to make final blend –> compaction into tablet

Question 16

What are the pros and cons of wet granulation?

Answer 16

Pros:
1. The ingredients don’t get segregated when they are made into granules so there is a uniform mixture
2. Granules flow better because they are bigger
Cons:
1. Lower tablet strength because idk
2. Not good for APIs suceptible to hydrolysis or degradation due to heat
3. Over granulation: granules formed become too large, cohesive, or dense due to excessive binding liquid or prolonged granulation time.

Question 17

What is the process of wet granulation?

Answer 17

1. Particles are sprayed with water/binder
2. The particles agglomerate –> this creates the granules

Question 18

What is the machine parts used in high shear wet granulation?

Answer 18

1. Impeller that rotates at the base of the mixture
2. High speed chopper that continually breaks up the wet mass

Question 19

What are the different bonds formed in high shear wet granulation?

Answer 19

1. Adhesion & cohesion forces
2. Interfacial forces in mobile liquid films within the granules
3. Formation of solid bridges after solvent evaporation

Question 20

Once you spray binding agent onto the particles, they start to stick together in various stages. What are these stages?
Which of these stages are suitable to be dried?

Answer 20

1. Pendular stage
2. Funicular stage
3. Capillary stage
4. Droplet

Funicular and capillary stages are suitable to be dried.

Question 21

In HSWG, what are different ways solid bridges can be formed between granules during the drying stage?

Answer 21

1. The binders holding the granule togther harden/crystallize to form the solid bridge
2. The granules dissolve in some of the solvent, and when the ingredient is crystallise, the dissolved part acts as the solid bridge.

Question 22

What is the process by which granules are formed in high shear wet granulation?

Answer 22

1. Nucleation: the droplet comes into contact with the particles and nucleates
2. The nuclei bind to each other to form granules

Question 23

What are the kinds of nuclei that can be formed during high shear wet granulation? How are they formed?

Answer 23

1. Nuclei with air trapped inside: same size solid + binder form this nuclei by the coalescnece mechanism
2. Nuclei with a liquid core: larger binder droplet + smaller solid form this nuclei by the immersion mechanism

Question 24

What happens during nucleation when the liquid flux is too high?

Answer 24

Caking –> too much liquid inside the particles

Question 25

What happens during nucleation when the liquid penetration is too low?

Answer 25

Pooling –> too much liquid outside the particles

Question 26

What are the ideal flux and liquid penetration conditions for drop controlled nuclei (which is the most desireable)?

Answer 26

The flux of the drop should be low because a slower speed allows you to control the system
The liquid should absorb almost immediately

Question 27

How does spreading coefficient affect a granules mechanical properties?

Answer 27

1. Good spreading coefficient: liquid spreads well over the surface –> better wetting –> good formation of interparticle liquid bridges –> solid bridge formation upon
   drying –> denser and stronger granules.
2. Bad spreading coefficient: liquid doesnt spread well –> poor penetration –> drug particles loosely attached –> more open structure formed after drying –> lower density –> more friable (tend to break apart easily)

Question 28

During granule consolidation in high shear wet granulation, what are the 2 different kinds of growth that can occur?

Answer 28

1. Steady growth
2. Induction growth

Question 29

What happens during steady growth in HSWG?

Answer 29

1. Granule size increases continuously with increasing granulation time and amt of binder solution
2. Granule size enlargement commences immediately after the addition of binder liquid.

Question 30

What happens during induction growth in HSWG?

Answer 30

There is a delay in granule size growth after adding the binder, then aft that the granule size increases with increasing granulation time

Question 31

Why do mechanically deformable materials undergo steady growth and not induction growth?

Answer 31

Mechanically deformable materials are able to squeeze out binder liquid effectively when they collide, allowing it to grow, unlike non deformable materials.