PDD 09: Solid Oral Dosage Forms – Powder Processing Flashcards
What does tablet production require?
several steps to transform a mixture of powders into an intact tablet that will perform as required
- each step is called a unit operation
What components must be combined to produce a tablet?
active pharmaceutical ingredient(s) + excipients
What are the optimal properties that must be obtained to turn powders into tablets?
- flow characteristics
- compactability
What are the 4 unit operations?
- mixing
- milling
- granulation
- tabletting
What are unit operations?
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
What is powder mixing?
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
What is random mixing?
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
What is the purpose of mixing?
to ensure that each dosage unit (tablet) contains the correct amount/concentration of active ingredients and excipients
What type of mixtures are powders?
neutral mixtures
- no spontaneous mixing or separation occurs
What are the mechanisms of mixing? (3)
- convection
- shearing
- diffusion
Mixing
What is convection?
transfer of large groups of particles
- rapid macroscopic mixing, but no mixing within group of particles
Mixing
What is shearing?
occurs when a layer of material flows over another layer, breaking up lumps of material
Mixing
What is diffusion?
moving powder bed dilates, decreasing the density
- moving particles can move through the void spaces by gravitational forces
What are the 3 types of mixers?
- tumbling mixers
- agitator mixers
- high speed mixer-granulator
What determines what type of mixers are used?
properties of the powder
What are tumbling mixers?
- great for free flowing powders
- small shearing forces are not enough to break up aggregates
- can promote segregation
- convection is main mechanism of mixing
What are agitator mixers?
- 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
What are high speed mixer-granulators?
- two unit operations in one vessel reduce chance of segregation
- high shear forces not compatible with sensitive compounds
What is segregation?
opposite of mixing, resulting in separation of powder components
What factors affect mixing and promote segregation? (4)
- particle size
- particle shape
- particle density
- proportion of API
How does particle size affect mixing and promote segregation?
- particles should be uniform in size to prevent percolation
- smaller particles tend to aggregate due to Van der Waals forces
How does particle shape affect mixing and promote segregation?
spherical particles have optimal flow properties – acicular or flat particles prolong mixing time due to agglomeration
How does particle density affect mixing and promote segregation?
particles which differ in density are sensitive to segregation due to vibration
How does proportion of API affect mixing and promote segregation?
for very potent APIs (<1% w/w) it may be necessary to sequentially build up the amount of material in the mixer
Particle Size
What can differences in particle size lead to?
segregation
Particle Size
What are the 3 types of segregation?
- percolation segregation
- trajectory segregation
- elutriation segregation
What is percolation segregation?
small particles fall between the voids of larger particles
What is trajectory segregation?
during mixing, larger particles have more mass and therefore more momentum allowing them to move greater distances than smaller particles
What is elutriation segregation?
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
What is granular convection?
particles of greater density (or smaller particles) have a tendency to move downward – this leads to larger, less dense particles ‘floating’ on top
What is center of mass?
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
What are convective forces?
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
Describe the direct effect of particle shape on tabletting.
spherical particles flow very well but can segregate from non-spherical particles due to lower contact surface area
- similar particle shapes are preferred
Particle Shape
What is monoclinic ibuprofen?
- suboptimal flowability
- forms brittle tablets
Particle Shape
What is orthohombic ibuprofen?
better flowability and compressibility
What are the methods to prevent segregation? (6)
- sieving
- milling
- crystal engineering
- careful handling
- granulation
- ordered mixing
Preventing Segregation
What is sieving?
selection of particle size fractions so that components (drug(s) + excipients) are of a similar particle size range
Preventing Segregation
What is milling?
reducing particle size, creating similar size distribution
- can be performed at any stage of powder processing, usually after granulation
Preventing Segregation – Milling
What are the 4 types of mills?
- 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
Preventing Segregation – Milling
What is cutter milling?
- 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
Preventing Segregation – Milling
What is hammer milling?
- 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
Preventing Segregation – Milling
What is ball milling?
- allows production of very fine particles < 10 µm
- size reduction by impact and attrition
- completely enclosed system, ideal for toxic materials
- difficult to clean
Preventing Segregation – Milling
What is fluidized energy milling?
- 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
Preventing Segregation
What is crystal engineering?
controlled crystallization to produce crystals with optimal size and shape
Preventing Segregation
What is careful handling?
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
Preventing Segregation
What is granulation?
to achieve controlled powder agglomeration
Preventing Segregation
What is ordered mixing?
adsorption of micronized particles onto larger carrier particles
What is granulation?
powder particles agglomerate into larger granules (0.2-0.5 mm)
What are the 3 types of granulation?
- wet granulation
- dry granulation
- extrusion/spheronization
What are the purposes of granulation? (6)
- 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
What is wet granulation?
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
What is dry granulation?
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)
What is extrusion/spheronization?
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
What are the goals to aim during tablet manufacturing? (5)
- strong and hard enough
- uniform content
- chemical and physical stability
- free from defects
- elegant finish
What are the 2 types of tablet manufacturing techniques?
- direct compression
- granulation then compression
Tablet Manufacturing
What is direct compression?
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
Tablet Manufacturing
Direct Compression
- mixing – API, diluents, dry binders
- milling
- mixing – glidants, lubricants, disintegrants, binders
- compression
When compressibility is an issue, what method is the method of choice before tabletting?
granulation
Tablet Manufacturing
Dry Granulation
- mixing – API, diluents, dry binders
- dry granulation
- milling
- mixing – glidants, lubricants, disintegrants, binders
- compression
Tablet Manufacturing
Wet Granulation
- mixing – API, diluents, dry binders
- wet granulation – wet binders
- drying
- milling
- mixing – glidants, lubricants, disintegrants, binders
- compression
