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PHRM 100 – PDD > PDD 09: Solid Oral Dosage Forms – Powder Processing > Flashcards

PDD 09: Solid Oral Dosage Forms – Powder Processing Flashcards

1
Q

What does tablet production require?

A

several steps to transform a mixture of powders into an intact tablet that will perform as required

  • each step is called a unit operation
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2
Q

What components must be combined to produce a tablet?

A

active pharmaceutical ingredient(s) + excipients

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3
Q

What are the optimal properties that must be obtained to turn powders into tablets?

A
  • flow characteristics
  • compactability
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4
Q

What are the 4 unit operations?

A
  • mixing
  • milling
  • granulation
  • tabletting
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5
Q

What are unit operations?

A

steps to transform a mixture of powders into an intact tablet

  • generally the smallest possible number of unit operations is preferable
  • order and number of unit operations can vary between different formulations
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6
Q

What is powder mixing?

A

unit operation that aims to treat two or more components so that each unit of each component lies as closely as possible in contact with units of other components

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7
Q

What is random mixing?

A

statistical process in which a bed of particles is repeatedly split and recombined until there is an equal chance of any individual particle being at any given point in the mix at any one time

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8
Q

What is the purpose of mixing?

A

to ensure that each dosage unit (tablet) contains the correct amount/concentration of active ingredients and excipients

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9
Q

What type of mixtures are powders?

A

neutral mixtures

  • no spontaneous mixing or separation occurs
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10
Q

What are the mechanisms of mixing? (3)

A
  • convection
  • shearing
  • diffusion
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11
Q

Mixing

What is convection?

A

transfer of large groups of particles

  • rapid macroscopic mixing, but no mixing within group of particles
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12
Q

Mixing

What is shearing?

A

occurs when a layer of material flows over another layer, breaking up lumps of material

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13
Q

Mixing

What is diffusion?

A

moving powder bed dilates, decreasing the density

  • moving particles can move through the void spaces by gravitational forces
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14
Q

What are the 3 types of mixers?

A
  • tumbling mixers
  • agitator mixers
  • high speed mixer-granulator
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15
Q

What determines what type of mixers are used?

A

properties of the powder

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16
Q

What are tumbling mixers?

A
  • great for free flowing powders
  • small shearing forces are not enough to break up aggregates
  • can promote segregation
  • convection is main mechanism of mixing
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17
Q

What are agitator mixers?

A
  • able to quickly mix large quantities of material
  • prone to dead spaces
  • difficult to clean
  • high shearing forces allow mixing of particles that tend to aggregate
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18
Q

What are high speed mixer-granulators?

A
  • two unit operations in one vessel reduce chance of segregation
  • high shear forces not compatible with sensitive compounds
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19
Q

What is segregation?

A

opposite of mixing, resulting in separation of powder components

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20
Q

What factors affect mixing and promote segregation? (4)

A
  • particle size
  • particle shape
  • particle density
  • proportion of API
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21
Q

How does particle size affect mixing and promote segregation?

A
  • particles should be uniform in size to prevent percolation
  • smaller particles tend to aggregate due to Van der Waals forces
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22
Q

How does particle shape affect mixing and promote segregation?

A

spherical particles have optimal flow properties – acicular or flat particles prolong mixing time due to agglomeration

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23
Q

How does particle density affect mixing and promote segregation?

A

particles which differ in density are sensitive to segregation due to vibration

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24
Q

How does proportion of API affect mixing and promote segregation?

A

for very potent APIs (<1% w/w) it may be necessary to sequentially build up the amount of material in the mixer

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25
Q

Particle Size

What can differences in particle size lead to?

A

segregation

26
Q

Particle Size

What are the 3 types of segregation?

A
  • percolation segregation
  • trajectory segregation
  • elutriation segregation
27
Q

What is percolation segregation?

A

small particles fall between the voids of larger particles

28
Q

What is trajectory segregation?

A

during mixing, larger particles have more mass and therefore more momentum allowing them to move greater distances than smaller particles

29
Q

What is elutriation segregation?

A

aka dusting out – when material is discharged from a container, dust flies up and is suspended in air before settling on top of the powder bed

30
Q

What is granular convection?

A

particles of greater density (or smaller particles) have a tendency to move downward – this leads to larger, less dense particles ‘floating’ on top

31
Q

What is center of mass?

A

more dead space around larger particles means center of gravity of whole system will shift under movement to a lower level by moving smaller or denser particles down

32
Q

What are convective forces?

A

vibration induced convective flow moves particles upwards in middle of container and downwards on wall of container

  • convective currents are too narrow for larger particles
33
Q

Describe the direct effect of particle shape on tabletting.

A

spherical particles flow very well but can segregate from non-spherical particles due to lower contact surface area

  • similar particle shapes are preferred
34
Q

Particle Shape

What is monoclinic ibuprofen?

A
  • suboptimal flowability
  • forms brittle tablets
35
Q

Particle Shape

What is orthohombic ibuprofen?

A

better flowability and compressibility

36
Q

What are the methods to prevent segregation? (6)

A
  • sieving
  • milling
  • crystal engineering
  • careful handling
  • granulation
  • ordered mixing
37
Q

Preventing Segregation

What is sieving?

A

selection of particle size fractions so that components (drug(s) + excipients) are of a similar particle size range

38
Q

Preventing Segregation

What is milling?

A

reducing particle size, creating similar size distribution

  • can be performed at any stage of powder processing, usually after granulation
39
Q

Preventing Segregation – Milling

What are the 4 types of mills?

A
  • cutter mills
  • hammer mills
  • ball mills
  • fluidized energy mills

choice of mill depends on powder characteristics and desired product – generally particles should only be as small as needed

40
Q

Preventing Segregation – Milling

What is cutter milling?

A
  • size reduction down to 100 μm possible
  • stationary knives are positioned on the walls, second set of knifes is attached to rotor
  • size depends on: rotor size, gap between knives
41
Q

Preventing Segregation – Milling

What is hammer milling?

A
  • size reduction down to 10 μm possible
  • hammers are connected to high speed rotors which grind materials against walls
  • particles of desired size selected through a screen
  • large capacity but not suitable for hard particles due to excessive wear
42
Q

Preventing Segregation – Milling

What is ball milling?

A
  • allows production of very fine particles < 10 µm
  • size reduction by impact and attrition
  • completely enclosed system, ideal for toxic materials
  • difficult to clean
43
Q

Preventing Segregation – Milling

What is fluidized energy milling?

A
  • size reduction down to 1 μm possible
  • size reduction by impaction in a high turbulence area
  • no moving parts reduces wear and makes cleaning easy
  • high energy impact not suitable for some materials
44
Q

Preventing Segregation

What is crystal engineering?

A

controlled crystallization to produce crystals with optimal size and shape

45
Q

Preventing Segregation

What is careful handling?

A

reduce powder movement after mixing

  • can be accomplished by using equipment that performs multiple unit operations at once rather than using multiple pieces of equipment
46
Q

Preventing Segregation

What is granulation?

A

to achieve controlled powder agglomeration

47
Q

Preventing Segregation

What is ordered mixing?

A

adsorption of micronized particles onto larger carrier particles

48
Q

What is granulation?

A

powder particles agglomerate into larger granules (0.2-0.5 mm)

49
Q

What are the 3 types of granulation?

A
  • wet granulation
  • dry granulation
  • extrusion/spheronization
50
Q

What are the purposes of granulation? (6)

A
  • increases the bulk density of the powder blend (fluffy to dense, reduces dusting out)
  • improves flowability
  • reduces segregation
  • improves compactability
  • promotes uniformity of product
  • improves dissolution of particles by addition of hydrophilic binders
51
Q

What is wet granulation?

A

granules are formed by addition of a small amount of liquid (water, ethanol, isopropanol) to the powder blend

  • the combination is then mixed using a high shear or fluidized bed granulator
  • after granulation the granules are dried – this can be followed by milling if necessary
  • a binder such as povidone can be included in the granulating liquid to bind particles together
52
Q

What is dry granulation?

A

granules are formed by compressing powder into a large tablet (slug) or into ribbons or
pellets

  • after compaction, slugs or ribbons are milled into granules of appropriate size
  • rather than using liquids, this process depends on high pressure
  • dry granulation is appropriate for moisture sensitive and heat labile drugs (no high temperature drying step in dry granulation)
53
Q

What is extrusion/spheronization?

A

multistep process to make uniform spherical particles – allows formation of large, dense pellets with high proportion of API

  • mixing of dry ingredients
  • wet massing – addition of fluid and mixing
  • extrusion
  • spheronization
  • drying
54
Q

What are the goals to aim during tablet manufacturing? (5)

A
  • strong and hard enough
  • uniform content
  • chemical and physical stability
  • free from defects
  • elegant finish
55
Q

What are the 2 types of tablet manufacturing techniques?

A
  • direct compression
  • granulation then compression
56
Q

Tablet Manufacturing

What is direct compression?

A

most efficient method of tablet manufacturing

  • mainly used for rapidly dissolving APIs or formulations of potent APIs in which the excipients control the flowability and compactability
  • blended tablet components are fed into a tablet press for compression and tablet formation
  • no other steps are required
  • only possible if powder blend compresses into a tablet without further processing
57
Q

Tablet Manufacturing

Direct Compression

A
  1. mixing – API, diluents, dry binders
  2. milling
  3. mixing – glidants, lubricants, disintegrants, binders
  4. compression
58
Q

When compressibility is an issue, what method is the method of choice before tabletting?

A

granulation

59
Q

Tablet Manufacturing

Dry Granulation

A
  1. mixing – API, diluents, dry binders
  2. dry granulation
  3. milling
  4. mixing – glidants, lubricants, disintegrants, binders
  5. compression
60
Q

Tablet Manufacturing

Wet Granulation

A
  1. mixing – API, diluents, dry binders
  2. wet granulation – wet binders
  3. drying
  4. milling
  5. mixing – glidants, lubricants, disintegrants, binders
  6. compression

PHRM 100 – PDD (14 decks)

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