Tablet 2 Nsu.ppt

(1)

Tablet Dosage

Forms

Dr. Mohammad Shariare

(2)

Tablet production



Powders intended for compression into tablets must

possess two essential properties



Powder fluidity



The material can be transported through the

hopper into the die



To produce tablets of a consistent weight



Powder flow can be improved mechanically by

the use of vibrators, incorporation of glidants.



Powder compressibility



_{The property of forming a stable, intact compact}

(3)

Compressed Tablets



Compressed tablets may be produced by

three basic methods:



Wet granulation

(4)

Steps for Tablet

Production

(5)

Processing Steps for Tablet

Production

(6)

(7)

The importance of mixing



_{There are very few pharmaceutical products that contain only one}

component. In the vast majority of cases several ingredients are

needed so that the required dosage form functions as required.



_{Whenever a product contains more than one component a mixing}

or blending stage will be required in the manufacturing process.

This may be in order to ensure an even distribution of the active

component(s), to ensure an even appearance, or to ensure that

the dosage form releases the drug at the correct site and at the

desired rate.



_{Tablets, capsules, sachets and dry powder inhalers}

-

_{mixtures of solid particles (powder mixing)}

-

_{Emulsions and creams - mixtures of immiscible liquids}

(8)

Definition and objectives of

mixing



Mixing may be defined as a unit operation that aims to

treat two or more components, initially in an unmixed or

partially mixed state, so that each unit (particle,

molecule etc.) of the components lies as nearly as

possible in contact with a unit of each of the other

components.



If this is achieved it produces a theoretical 'ideal‘

(9)

Types of mixtures

1. Positive mixtures



_{Positive mixtures are formed from materials such as gases or}

miscible liquids which mix

spontaneously

and

irreversibly

by

diffusion, and tend to approach a perfect mix.



_{There is no input of energy required with positive mixtures if the}

time available for mixing is unlimited.



_{In general materials that mix by positive mixing present no}

problems during product manufacture.

2. Negative mixtures



_{With negative mixtures the components will tend to separate out.}



_{If this occurs quickly, then energy must be continuously input to}

keep the components adequately dispersed, e.g. with a suspension

formulation,



_{With other negative mixtures the components tend to separate very}

slowly, e.g. emulsions, creams and viscous suspensions.



_{Negative mixtures are generally more difficult to form and maintain}

(10)

Types of mixtures

3. Neutral mixtures



Neutral mixtures are said to be static in

behaviour, i.e. the components have no

tendency to mix spontaneously or

segregate spontaneously once work has

been input to mix them.



Examples of this type of mixture include

(11)

MECHANISMS OF MIXING

AND

DEMIXING

Powders:



In order that powders may be mixed, the

powder particles need to move relative to

each other.



There are three main mechanisms by which

powder mixing occurs, namely

(12)

MECHANISMS OF MIXING

AND

DEMIXING

Liquids:



_{The three main mechanisms by which liquids are}

mixed are

bulk transport, turbulent mixing

and

(13)

Powder segregation

(demixing)



Segregation is the opposite effect to mixing, i.e.

components tend to separate out.



_{This is very important in the preparation of pharmaceutical}

products, because if it occurs, a mix may change from

being random to being non-random, or a random mix may

never be achieved.



_{Care must be taken to avoid segregation during handling}

after powders have been mixed, e.g. during transfer to

filling

machines,

or

in

the

hopper

of

a

tablet/capsule/sachet-filling machine.



Segregation will cause an increase in content variation in

(14)

Powder segregation

(demixing)



If segregation of granules occurs in the hopper of a filling

machine an unacceptable variation in weight may result.



_{Segregation is more likely to occur, or may occur to a}

greater extent, if the powder bed is subjected to

vibration and when the particles have greater flowability.



_{The three main mechanisms by which segregation occur}

are:

percolation, trajectory

and

elutriation

segregation.



Approaches to minimize segregation

.

(15)

Powder mixing

equipments

(16)

Powder mixing

equipments

Fluidized bed mixer

(17)

Mixing of other Dosage

Forms

MIXING OF MISCIBLE LIQUIDS AND

SUSPENSIONS



Propeller mixers



Turbine mixers



_{Inline mixers}

MIXERS FOR SEMISOLIDS



Planetary mixers

(18)

Granulation



Tablets contain diluents, binders, disintegrants and

lubricants to provide the desired characteristics for

tablet manufacture and efficacious use.



One important requirement is that the drug mixture

flow freely from the hopper of the tablet press into

the dies to enable high speed compression of the

powder mix into tablets.



Granulations also increase material density thus

(19)

(20)

Six Reasons to Granulate

􀂄 There are six key reasons to granulate!

􀂄 All six are based on the need to tablet or encapsulate a product.

􀂄 These six “reasons” are the key to improving and optimization of an

existing blend or of individual ingredients.

1.To Improve Flow

􀂄 Powder flow is important throughout the entire tablet making process.

􀂄 Weighing/Batching - accuracy

􀂄 Milling- consistency

􀂄 Blending- content uniformity

􀂄 Granulating - repeatability

􀂄 Tablet Compression – to meet the objectives

(21)

Flow Properties



Flow properties of a material result from

many forces.



The different types of forces that can act

between solid particles are:



Frictional forces



Surface tension forces



Mechanical forces caused by interlocking of

particles of irregular shape



Electrostatic forces

(22)

2. Compressibility

􀂄 Tablet Press speeds vary from 48 tablets per minute to over 15,000 tablets

per minute.

􀂄 The average press runs at 3000 tpm or 50 tablets per second.

􀂄 The ability for a powder to compress quickly is imperative.

3. Fines & Control Dust

􀂄 Fine particles & dust are often the main cause of poor flow, poor compression,

cross contamination, and poor content uniformity.

􀂄 Tablet compression and capsule filling machines perform best with a particle

size distribution within a range of 40-200 mesh

Large Particles

<20 Mesh

850 μm/10-20%

Fines

>200 Mesh

75 μm/10-20%

Intermediates

40-120 Mesh

(23)

4. Control Segregation

􀂄 Segregation means that powders are not staying mixed and are

separating. This leads to content uniformity issues and table weight &

hardness control.

5. Density Control

􀂄 Density variation within a single ingredient equates to major problems

with tablet & capsule manufacturing across the board.

􀂄 Bulk density variation of ingredients within the blend is a recipe for

trouble

6. Capture & fuse “Active”

􀂄 There are 2 things “Actives and Excipients” within a formulation.

􀂄 Sometimes we granulate the entire blend and other times we granulate

individual ingredients.

(24)

Mechanisms of Granulation

There are Five Particle Bonding Mechanisms,



_{Adhesion and cohesion forces in the immobile liquid films}



_{Interfacial forces in mobile liquid films within the granules}



_{Formation of solid bridges after solvent evaporation}



_{Attractive forces between solid particles}

(25)



Adhesion and cohesion forces in immobile liquid

films

between individual primary powder particles.



_{Interfacial forces in mobile liquid films}



_{Solid bridges}

Partial mellting, Binder hardening, crystalization of dissolved sub.



Attractive forces

between

solid particles



Mechanism

of

granule formation

Mechanisms of Granulation

(26)

Wet Granulation



The wet granulation technique involves the wet

massing of the powders, wet sizing or milling and

drying after the preparatory steps (weighing and

mixing).



The technique employs a solution, suspension or

slurry containing a binder which is usually added to

the powder mixture.



However the binder may be incorporated dry into the

powder mix and the liquid may be added by itself.



Once the granulating liquid has been added, mixing

(27)

27

(28)

Wet Granulation

Weighing and Blending

:



Active ingredient, diluent and

disintegrating agents are weighed and

mixed by mechanical powder blender until

uniform



Examples:



Diluent: lactose, microcrystalline cellulose,

powdered sucrose and calcium phosphate.



disintegrating agents: croscarmellose, corn, PVP,

(29)

Wet Granulation

Preparing the Damp Mass:



A liquid binder is added to the powder mixture to

facilitate adhesion of the powder particles.



A damp mass is formed and is used to prepare the

granulation.



A good binder results in appropriate tablet hardness

and does not hinder the release of drug from the tablet.



Overwetting can cause the tablets to become too hard

and underwetting can result in tablets that are too soft

and tend to crumble.



Examples: povidone, glucose solution (25-50%),

(30)

Wet Granulation

Screening the damp mass into pellets or

granules:



_{The wet mass is pressed through a screen to}

prepare the granules.



This may be done by hand or with special

equipment that prepares the granules by

extrusion through perforations in the apparatus.



The resultant granules are spread evenly on

(31)

Wet Granulation

Drying the granulation:



Granules may be dried in thermostatically controlled ovens

that constantly record time, temperature and humidity.

Sizing the granulation by screening:



_{After drying, the granules are passed through a screen of a}

smaller mesh. The degree of reduction of granule size

depends on the size of the punches to be used.



_{In general, the smaller the tablet to be produced, the}

smaller the granules.



_{Sizing of granules is necessary so that die cavities for}

(32)

Wet Granulation

Adding lubrication and blending

:



After dry screening, a dry lubricant is

dusted over the spread-out granulation

through a fine mesh screen.



Lubricants improve flow of granulation from

hopper to die cavity.



They prevent adhesion of the tablet and

the die wall during ejection of tablet from

the machine.



_{E.g. magnesium stearate, calcium stearate,}

stearic acid etc.

(33)

Wet Granulation

(34)

Wet Granulation



Wet Granulation Machines:

(35)

All in one Granulation

methods

for Wet Granulation



Technological advances allow the entire

process of granulation to be completed in a

single machine called the fluid bed granulator

where the granulation is completed in a

continuous fluid bed process.



Another method called microwave vacuum

(36)

Fluid Bed Granulator



The fluid bed granulator performs the

following steps:

Preblending the formulation powder (API,

diluent, disintegrant) in bed with fluidized air

Granulating the mixer by spraying onto the fluidized powder bed, a suitable

liquid binder (aq. Soln of acacia, hydroxypropyl cellulose, povidone)

(37)

Fluid Bed Granulator

(38)

Fluid Bed Granulator

(39)

Fluid Bed Granulator

Advantages:



_{One unit so saving labor cost, transfer loses and time}



_{2-6 time greater heat transfer than tray dryer}



_{Uniform drying….prevent mottling.}



_{Process can be automated once parameters}

optimized

Disadvantages:



_Expensive



_{Multiple process variable}



_{Filter clocking, demixing, electrostatic charge, solvent}

(40)

Microwave Vacuum

Processing



_{All the steps are completed in a single piece of}

equipment



The use of microwave reduces drying time

considerably.



_Method:

Mixed

Wetted

Agglomerated

_dried

Added lubracants

screened

(41)

Dry Granulation



In this method, the powder mixture is

compacted in large pieces and subsequently

broken down or sized into granules.



For this method, either the active ingredient

or the diluent must have cohesive properties.



Dry granulation is especially applicable to

(42)

Dry Granulation



There are two methods by which dry granulation can be

performed:

1) Slugging: After weighing and mixing, the powder is

slugged or compressed into large flat tablets. The slugs are

then broken by hand or a mill and passed through a screen

of desired mesh for sizing.

Then lubricant is added and tablets are prepared by

compression.

When a single slugging process is insufficient to produce

the desired granular properties, the slugs are sometimes

screened, slugged once again and screened once more.

(43)

Dry Granulation

2) Roller Compaction: powder compactors may also

be used to increase the density of a powder by

pressing it between rollers at 1 ton to 6 tons of

pressure. The compacted material is broken up, sized

and lubricated and tablets are prepared by

compression.

The roller compaction method is often preferred to

slugging.

Common binding agents: methyl cellulose (MC) or

hydroxymethyl cellulose (HMC)

(44)

Dry Granulator – Roller

Compactor

(45)

Dry Granulation

(46)

Direct compression



There are very few substances that may be

compressed directly. E.g. sodium chloride,

potassium chloride sodium bromide etc.



Direct compression materials should have the

following properties: 1) good flow and

compressibility 2) inert

(47)

Direct compression



Tablets are compressed directly from powder

_{Tablets are compressed directly from powder}

blends of the active ingredient and suitable

excipients



No pretreatment of the powder blends by wet

_{No pretreatment of the powder blends by wet}

or dry granulation procedures is necessary

(48)

Advantages of Direct

Compression



Advantages:



_Economy



Machine: fewer manufacturing steps and pieces of

equipment



_{Labor: reduce labor costs}



_{Less process validation}



Lower consumption of power



_{Elimination of granulation process}

_:



_{Heat (wet granulation)}



_{Moisture (wet granulation)}



High pressure (dry granulation)



_Note

_:



_{Processing without the need for moisture and heat which is}

inherent in most wet granulation procedures.

(49)

Disadvantages of Direct

Compression



_{Differences in particle size and bulk density between drug}

and diluents may lead to segregation within the

granulation. It causes a problem in content uniformity.



_{A large dose drug may present problems with direct}

compression if it is not easily compressible by itself.



_{The direct compression diluents may interact with the drug.}



_{Static charge may build up on the drug because of the dry}

(50)

Tablet Production



There are different types of tableting machines.



The machines vary in their productivity but their

basic function and operation are similar.



The machines consist of steel die cavity by the

pressure exerted by the movement of two steel

punches, a lower punch and an upper punch.



Two major types of tableting machines are: (1)

(51)

Tablet Compression

Machines



Hopper

for holding and feeding

granulation to be compressed



Dies

that define the size and shape of the

tablet



Punches

for compressing the granulation

within the dies



Cam tracks

for guiding the movement of

the punches



Feeding mechanisms

for moving

(52)

Single Punch Tablet Press



This method describes the basic mechanical process of

tablet compression. The process is as follows:



_The

_{lower punch}

_drops



The

feed shoe

filled with granulation from the

hopper

is positioned over and fills the

die cavity



_The

_{upper punch}

_{lowers and compresses the fill,}

forming the tablet.



_The

_{upper punch}

_{retracts as the}

_{lower punch}

_rises

with the formed tablet to the precise level of the stage



_The

_{feed shoe}

_{moves over the}

_{die cavity}

_{, shoves the}

tablet aside and once again fills the

cavity

with

granulation to repeat he process.

(53)

Single Punch Tablet Press

(54)

Single Punch Tablet Press

(55)

Upper and

Lower Collar

Collar locker

(56)

Rotary Tablet Machines



These are equipped with multiple punches and

dies which operate in a continuous rotating

movement of the punches.



A single rotary press can produce 1150 tablets

per minute.



Double rotary presses with 27, 33, 37, 41 or 49

sets of dies and punches and dies are available.



Some can produce 10,000 tablets per minute.



Multiple layered tablets are produced by

(57)

Multi-station rotary presses



The head of the tablet machine that holds the upper

punches, dies and lower punches in place rotates.



As the head rotates, the punches are guided up and down

by fixed cam tracks, which control the sequence of filling,

compression and ejection.



The portions of the head that hold the upper and lower

punches are called the upper an lower turrets



The portion holding the dies is called the die table.



The pull down cam (C) guides the lower punches to the

(58)

Multi-station rotary presses



The punches then pass over a weight-control cam (E),

which reduces the fill in the dies to the desired

amount.



A swipe off blade (D) at the end of the feed frame

removes the excess granulation and directs it around

the turret and back into the front of the feed frame.



The lower punches travel over the lower compression

(59)

Multi-station rotary presses



After the moment of compression, the upper punches

are withdrawn as they follow the upper punch raising

cam (H)



The lower punches ride up the cam (I) which brings

the tablets flush with or slightly above the surface of

the dies.



The tablets strike a sweep off blade affixed to the

front of the feed frame (A) and slide down a chute

into a receptacle.



_{At the same time, the lower punches re-enter the pull}

(60)

Multi-station rotary presses

(61)

Multi-station rotary presses

(62)

Multi-station rotary presses

(63)

Tablet Dedusting



To remove traces of loose powder adhering

(64)

Tablet Processing

Problems

Manufacturing Defects:

During the routing production of tablets so many defects arise with the finished tablets may be due to either some faults in tablet formulation or in the tabletting equipment and sometimes due to both reasons.

The defects are as follows: ---•Capping and Lamination. •Picking and Sticking. •Mottling.

•Binding in the Die. •Weight variation. •Hardness Variation •Double impression.

Capping and Lamination:

(65)

Reason

Due to the entrapment of air among the particles or granules during the compression and does not escape until the compression pressure is removed.

•Too much pressure on compression.

•Presence of either excess of fine powders of granules or less amount of fines in granules. •A granulation that is too dry tends to cap or laminate for lack of cohesion.

•Often deep concave punches produce tablets that cap.

•The wear and tear of punches and dies is also responsible for capping. •The wrong setting of dies or punches also causes capping and lamination. •Due to moist and soft granulation.

Recover

•Slowing tableting rate.

•By granulating the material.

•By reducing the pressure adjustments. •By reducing the speed of the machine.

•By addition of hygroscopic substance. E.g. sorbitol to maintain a proper moisture level. •By replacing the worn out dies and punches.

•By correcting the level of the top of the lower punch so as to coincide with the level of the upper surface of the die.

•By changing the wear and tear of the punches and dies.

•By using proper granules and required amount of fine powders.

Capping and Lamination

(66)

In picking a small surface of the tablet material is removed by the punches and adheres to the surface of punches therefore the resulting tablets show a pitted surface instead of smooth surface. In sticking the tablet material i.e. the granules adhere to the die wall and thereby the lower punch cannot move freely.

Reason:

•For the presence of scratches or engraving or embossing on the punches. •For using wet granulation during compression.

•Sticking may be happened due to the use of damp granules or, due to worn out dies and punches. •Excessive moisture may be responsible.

•Low melting point substances, either active ingredient or additives may soften from heat compression and thus can cause sticking and picking.

Recover:

•Lettering should be designed as large as possible.

•By using chromium plated punches for producing a smooth non-adherent face. •By using dry granules and by adding a lubricant to the granules.

•By replacing the worn out dies and punches.

•In some cases colloidal silica added to formula acts a polishing agent and makes the punch faces smooth sometimes additional binder or a change in binder may make the granules more cohesive and therefore less adherent.

•By using higher melting point materials as diluent.

•In case of excessive moisture further drying of the granules.

Picking and Sticking

(67)

This defect occurs in the colored tablets. Mottling is an unequal distribution of

color on a tablet, with light or dark areas standing out in an otherwise uniform

surface.

Causes:

•Due to the difference of colors in the drugs and the added excipients.

•Due to the colored degraded products of the drug.

•Due to the migration of dyes during drying of granules, and

•Due to the use of colorants in direct compression formulation.

Prevention:

•By using a dye which can mask the color of tablet ingredients.

•By changing the solvent system of the granulation.

•By drying the granules at a low temperature.

•By changing the binder system.

•By grinding to a smaller particle size.

Mottling

(68)

During binding in the die the ejection of the tablet is difficult and is often

accompanied by a characteristic noise. The edges of the tablets become rough.

Causes:

•Due to poor lubrication of granules.

•Due to dried granules.

•Due to dirty or worn out dies.

•Due to seep downward of the fine powder from granules thus forms a thick

layer on the die which hinders the free movement of the punches.

Recover:

•Lubricating the granules properly

•Using granules of having proper cohesive properly

•Replacing the worn out dies

•Cleaning the dirty dies.

(69)

Weight varies beyond the specifications.

Causes:

This problem due to the following reasons:

-•Poor flow of granules to the die

•Size separation of granules i.e. small and large size granules.

•Presence of too fines in the granules.

•Separation of the mixed ingredients of granules

•Less quantity of poor mixing of lubricants.

•Due to automatic change in the adjustment of punches.

•In rotary tablet making machines this defect is due to unequal length of lower

punches.

Overcome:

•Making granules of good flow properly.

•Proper granulation

•Removing the too fines from the granulation etc. according to the causative factors.

(70)

The tablet varies greatly in hardness.

Reasons:

The reasons for this variation are the same as discussed under weight

variation. Apart from these reasons other factors include

•Weight of material.

•Space between the upper and lower punches at the time of compression.

•Inappropriate pressure applied on the upper punches

•Excessive proportions of fatty lubricant such as magnesium stearate.

•Some times on normal storage of tablets.

Problem:

It is important to note that the tablets should not be harder than

required. The hard tablets may not disintegrate in the required period of time and

to soft tablets may not withstand the hazards of during handling, transporting and

dispensing.

Overcome:

•This defect should be made up by solving the causative factors.

(71)

This defect occurs in those tablets on which letters are printed. This involves only

lower punch which has a monogram to produce a impression on the tablet during

compression. On some machines the punch moves downwards and then travels

uncontrolled upward to a short distance to push the tablet out of the die. During its

free travel it rotates and makes second impression on the tablet. This impression is

generally lighter than the original impression. The new tablet making machines are

fitted with devices which prevent the rotation of the lower punch.