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Production of tablets

Aulton 28-31

• Write down a standard specification for atablet

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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