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Production of tablets
Aulton 28-31
• Write down a standard specification for atablet
2
Flow chart for production oftablets
Mixing
Tabletting
Packing
Dry or wet granulation
Wet granulation
Drying
Milling and sieving
Compression
Sieving
Milling
Mixing
• Standard equipment High share mixers Tumbling mixers
• Y-cone• Rotating cube• Double cone
Fluidized bed Agitator mixers
• Things to consider Homogeneity Risk for overmixing
• Can lead to demixing• Influence by properties of the
particles High share rates
• Effects the particle size in weekpowders
Scaling up• Not always linear
3
Homogeneity
• Type of mixtures Positive mixtures -
spontaneously homogenously:solutions
Negative mixtures-spontaneously separate:emulsions
Neutral mixtures neutral:powders
• Neutral mixtures Homogeneity depends on the
handling and processingconditions
• Testing homogeneity• Test composition of samples• Problems
Size of the sample How to obtain the sample
(Sample thief)• Promote homogeneity
Particles of the same size Equal density of particles Irregular particles
Requirements on the powder
• It has to have goodflowability
• Easily mixed with otherparticles
• Good compatibility andcompression properties
• Homogenous colouring etc• Friction and adhesion
properties
• Granulation or directcompressible excipients
• Other reasons forgranulation To obtain homogenous
distribution of activesubstance for low doseformulations
Decrease the amount ofdust
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Granulation• Granulation is the process in
which primary powder particlesare made to adhere to formgranules
• Wet granulation obtained viasolvent addition and mechanicalwork that densify the wet mass
Granulation mechanisms• Nucleation
Particle particle interactions• Growth
Independent particles adhere tothe nucleolus
Coalescence of the nucleus.• Re shaping
Granules break and arereshaped during the granulationprocess
• Snowballing Formation of large spherical
aggregates (often too large)
Growth mechanisms
Coalescence
Breakage
Transfer
Layering
5
Granulation equipment Planetarymixers
• Equipment Hobart, Collet
• Process Granulation solution is slowly
added to the powder in the mixer• Advantage
Not particular sensitive forvariations
• Disadvantages Slow which requires several other
production steps (sieving drying) Large material losses
Intensive mixer• Equipment
Diosna, Fielder• Process
A three blade router that is locatedhorizontal and gives a fast mix and ablade that divide the granulate
• Advantage A rapid process without the need for
sieving• Disadvantages
Requires high degree of control to obtainthe right particle size
Can require some type of IPC to determinewhen granulation is completed
6
Fluid bed granulator• Equipment
Aeromatic, Gatt• Process
The solution is spread over afluidized powder bed and thegranulate is simultaneous dried
• Advantage Combined drying and granulation Fast Easy to automate
• Disadvantage Expensive Considerable process development is
needed
Spray dryer• Process
A particles dispersion is spraydried to produce larger particles.The particle size is dependent onconcentration of solid anddroplet size of the spray
• Advantages Can be used when granulation
does not work Rapid process and short drying
times• Disadvantages
Expensive
7
Extruders, Pelletisation• Process
Used to produce compactpellets
Process steps• Dry mixing• Wet granulation (require
more water than normalgranulation does)
• Extruding• Spheronization• Drying• Sieving
DryingThings to consider
What temperature to use. What doyou think governs this?
Explosive safe equipment may beneeded
Environmental problems How much rest solvent will the
product contain How does the drying process affect
the granulate
Most products bind some solvent Bound water
• Difficult to remove by drying• Not available for chemical reactions• Does not freeze• The first layer of water molecules
around a particle• Crystal water
Free water• Capillary water (still difficult to dry
away)• Other water trapped in the structure
but having normal vapour pressure
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Definitions
• Rh relative humidity
• Equilibrium moisture content(EMC) The equilibrium content of
moisture at a given Rh%€
Rh% =PH2O in the air
PH2O in saturated air
Water content
Rh%
EMC
Loss of water from a drying solid
Tray drier
Principle The granulate is spread onto bricks
that are put in a heating cabinetwith circulating air
Rate of drying
•Used for Weak granulates
• Disadvantages Slow, up to 24h Risk for migration of the substance
• Advantage Good for weak granulates Not particularly sensitive
to changes∂H∂t
= hcAΔT
Time
moisture contentDrying at the surface
Transport of vapour from inside the bed
CMC
9
Fluidized bed
Principle Air is blown through the bed
at a speed such that theparticles in the bed arefluidized and move freelyfrom each other.
• Important processparameters Air speed Temperature
• Used for Is a good choice for most
granulates
•Advantage High level of heat transfer Fast High degree of process control Most of the drying occurs at the
surface of the particle Less risk for migration
•Disadvantages A more complex process than tray
drying Greater loss of material than in tray
drying Risk for breaking of the granulate Risk of static electricity
Migration of dissolvedsubstances during drying
Since drying often involves thetransport of solution within the particleor the particle bed, dissolvedsubstances are transported togetherwith the solution, which can lead to non-homogeneous distribution of thesesubstances.This will lead to
• Loss of active substance (fluidbed) or dose variation (traydrying)
• Discoloration - Spots”• Transport of binders which
changes the strength of thegranulate
How can migration be minimise? Use as small amount of the
granulation solution as possible.Ensure that the granulate is wettedevenly.
If possible avoid tray drying When using tray drying, mix the
powder after drying. Use vacuum drying or microwave
drying if transport within the particleis seen as important.
Use non-soluble excipient orexcipients that adsorb migratingsubstances.
Use a viscous solution.
10
Control of drying process
Control of the powder moisture content of the
powder• Amount of dry
substance• Equilibrium content
Distribution of moisture inthe powder bed
Particle size of the granulate Migration of substance in
the powder or the powderbed
Control of the process Moisture content of the air Temperature
• Outlet air• Difference between the outlet
and the inlet air• In the drying chamber
During validation• Temperature in different part of
the equipment• Drying profile of the powder
Dry granulation• Equipment
tablet machines Roller compactors Rotary press (slugger)
• Process The powder is pressed together
• Advantage Less risk for effects on the active
substance by heat and moisture• Disadvantage
Difficult to obtain homogenousmaterial for low dose products
11
Tabletting
Compression:• Compression of the powder• Deformation of the particles
and deformation anddensification of granules• Particle fragmentation• Physical interaction of
particlesBridging between solid materialBridging mediated by solutionBridging due to binderIntermolecular attraction(adsorption bridging)Mechanical interlocking
Tabletting• Important process parameters
Weight Hardness Friability
• Problems during tabletting Segregation of the powder Low flowability Capping and lamination Adhesion or sticking of the powder to
punches High friction during tablet ejection Variation in important process parameters Low strength
12
Punches
• Determine the design ofthe tablet
• Why is the look of tablesimportant?
Compression
• A powder compressibilitydetermines to what degree itsvolume will changes underpressure
• Compression involves severalsteps Reorganisation of the powder
leading smaller powder volume Breakage of brittle powder Deformation of particles Closer particle contact leading
to bridging and particle particleadhesion
Compression
Release ofcompression force
Elastic deformation
Plasticdeformation
13
Evaluation of compression• Characterizing the finished
tablets Use of an electron microscope
to study the tablet• Change in particle size• Plastic deformation
Studying the particles that areformed upon disintegration
Measure hardness of tablets Measure pore structure
• BET isotherm• Volume to density
measurements
• Characterisation of compressionand decompressions processes Force on the upper and lower
punches over time Relationship between force
from the upper and lowerpunches
Force from the punchesversus the tablet volumeporosity
Force from the upper andlower punches in relation tothe hardness
Pressure-hardness and quality
• A good powder shouldbe able to withstandhigh pressures withoutcapping or lamination
• A good powder has alarge region in which thehardness is linear inrelation to the punchpressure
Pressure
Hardness
14
Compression properties of powders.elasticity and brittleness
• Important for tablet production• Measured by blending the material with
1% magnesium stearat according thefollowing scheme
• Store for 24 h and measure the crushingstrength of the tablets
• Elastic material will show andifference in crushing strengthas B>A>C
• Fragmenting (brittle material)will not show any differenceaccording to method used
• Elastic material A will cap B will be weak C will cap or laminate
2 s30 s2 sCompress at75 mPa for
30 min5 min5 minBlend for
CBA
Heckel equation• The compression can be described as an
reaction that eliminates pores
• A reflects particle rearrangement• K reflects particle deformation• Procedure dependent parameters• Not easy to interpreter for granules and
pours powder particles€
ln 1E
= KP + A
E = porosity,P = pressure
• Typical Heckel plot
• Phase I: reflects particle fractionand reposition
• Phase II: linear region that obeythe expression
• Phase III: decompression phase
ln(1
/E)
Phase IIPhase I
Phase III
pressure
15
Changes in tablets aftercompression
• Decrease in hardness Decrease in particle
adhesion due to entrapmentof water in the capillaries
Changes in particlecomposition due tosolubilisation of thecompounds by adsorbedwater
Amorphous materials aresofter due to wateradsorption
Slow elastic reformation ofthe deformed material
• Increase in hardness Increase in binding strength
due to there-crystallisation ofamorphous material ordissolved material
Changes in the microstructuredue to viscous deformation orchanges in amorphous,semicrystalline orpolymorphous material
Terms to know from today's lecture
• Demixing when prolonged mixing times lead to thesegregation of a powder
• Snowballing: formation of large aggregates duringgranulation
• CMC: the critical moisture concentration the waterequilibrium water content at given relative humidity
• Compressibility: to what extent the volume changesunder pressure